Small molecules targeting cyclooxygenase/prostanoid cascade in experimental brain ischemia: Do they translate?

Jianxiong Jiang; Ying Yu

doi:10.1002/med.21744

. Author manuscript; available in PMC: 2022 Mar 1.

Published in final edited form as: Med Res Rev. 2020 Oct 22;41(2):828–857. doi: 10.1002/med.21744

Small molecules targeting cyclooxygenase/prostanoid cascade in experimental brain ischemia: Do they translate?

Jianxiong Jiang ¹, Ying Yu ¹

PMCID: PMC7906918 NIHMSID: NIHMS1638738 PMID: 33094540

Abstract

Acute brain ischemia accounts for most of stroke cases and constitutes a leading cause of deaths among adults and permanent disabilities in survivors. Currently, the intravenous thrombolysis is the only available medication for ischemic stroke; mechanical thrombectomy is an emerging alternative treatment for occlusion of large arteries and has shown some promise in selected subsets of patients. However, the overall narrow treatment window and potential risks largely limit the patient eligibility. New druggable targets are needed to innovate the treatment of brain ischemia. As the rate-limiting enzyme in the biosyntheses of prostanoids, cyclooxygenase (COX), particularly the inducible isoform COX-2, has long been implicated in mechanisms of acute stroke-induced brain injury and inflammation. However, the notion of therapeutically targeting COX has been diminished over the past two decades due to significant complications of the cardiovascular and cerebrovascular systems caused by long-term use of COX-2 inhibitor drugs. New treatment strategies targeting the downstream prostanoid signaling receptors regulating the deleterious effects of COX cascade have been proposed. As such, a large number of selective small molecules that negatively or positively modulate these important inflammatory regulators have been evaluated for neuroprotection and other beneficial effects in various animal models of brain ischemia. These timely preclinical studies, though not yet led to clinical innovation, provided new insights into the regulation of inflammatory reactions in the ischemic brain and could guide drug discovery efforts aiming for novel adjunctive strategies, along with current reperfusion therapy, to treat acute brain ischemia with higher specificity and longer therapeutic window.

Keywords: agonist, antagonist, excitotoxicity, infarction, inhibitor, neuroinflammation, neuroprotection

1. Brain ischemia

Stroke is a group of medical conditions in which the blood supply to some part of the brain is reduced or interrupted, thereby preventing the involved brain regions from receiving oxygen, glucose, and other nutrients, and eventually leading to brain cell death. Despite the continual marked advances in stroke unit care, acute stroke remains in leading causes of deaths in adults and neurological disabilities among survivors, as its prevalence continues to rise, particularly in the developing world ^1,2. There are two main types of stroke: ischemic stroke associated with the insufficient blood flow and hemorrhagic stroke mainly caused by intracerebral or subarachnoid bleeding. Of all stroke cases, approximately 87% are caused by brain ischemia, 10% are intracerebral hemorrhage stroke, and only 3% are subarachnoid hemorrhage stroke ^3,4. The conventional thrombolytic treatment approved by the U.S. Food and Drug Administration (FDA) for ischemic stroke utilizes the tissue plasminogen activator (tPA) to convert plasminogen into active plasmin, which then can breakdown blood clots (thrombi) formed in the ischemic brain tissues. However, tPA is only recommended for administration in 4.5 hours after the onset of a stroke ^5,6, or else its benefits are likely outweighed by the potential risks in excitotoxic injury, peripheral bleeding, and even hemorrhagic transformation ^7,8. For patients who are over 80 or had a previous stroke, the treatment window is only about 3 hours. For these reasons, up to 65% of ischemic stroke patients are not eligible for tPA-mediated thrombolytic therapy.

As an emerging option for patients with acute brain ischemia, the endovascular therapy by intra-arterial mechanical thrombectomy provides an interventional procedure of removing blood clots from brain blood vessels with a slightly longer therapeutic time window, i.e., 6 hours after the symptom onset ⁹. Though it can further improve functional outcomes in patients who also receive tPA treatment ¹⁰, thrombectomy is currently restricted to occlusions in large arteries and postsurgical complications, such as intracranial bleeding and damage to the blood vessels at the operative sites, raise serious concerns ^11,12. Therefore, there remains an unmet high demand for new therapies with longer therapeutic window, higher efficacy, and lower risk in severe side effects for patients who suffer from the long-lasting devastating consequences of acute brain ischemia. Disappointingly, multiple once-promising drug candidates focusing on the early pathogenic targets failed to provide sufficient benefits in recent clinical studies for acute brain ischemia ^13,14. An important conclusion one can draw from these monumental efforts is that the early pathogenic targets might be transitory after the stroke onset; thus, for new strategies seeking longer therapeutic windows, one must look into the secondary signaling events that are triggered by the initial excitotoxic cascade and, in turn, aggravate the progression of neuronal injury following the acute brain ischemia ¹⁵. A such prominent delayed pathophysiological process that emerged during the past decades is brain inflammation or neuroinflammation ¹⁶.

2. Postischemic neuroinflammation

The conventional concept that stroke is simply a disorder of blood vessels has profoundly been expanded during the past two decades largely owing to the recognition of inflammation in the brain. Acute brain ischemia initially triggers neuronal excitotoxicity due to the lack of energy source and oxygen, and later is characterized by a cascade of inflammatory reactions that involve the injured brain tissues and progress for several days following the onset of ischemic symptoms. The inflammatory processes after ischemic stroke are initially highlighted by the induced expression of many inflammatory mediators, such as adhesion molecules, inflammatory cytokines, mitochondria-derived reactive nitrogen species (RNS) and reactive oxygen species (ROS), followed by the breakdown of blood-brain barrier ^17–20. The blood-brain barrier disruption can further intensify neuroinflammation by enabling infiltration of the peripheral inflammatory and immune cells into the ischemic brain regions. For instance, the infiltrated neutrophils are a main source of matrix metalloproteinases (MMPs), resulting in further damage to the endothelial tight junction proteins and extracellular matrix of the neurovascular units. Consequently, the activation of microglia and astrocytes along with peripheral myeloid cell influx into the ischemic sites characterize the extended phase, triggering brain edema and potential hemorrhagic transformation. The affected brain areas are therefore subject to the secondary insults, provoking another wave of inflammatory reactions, oxidative stress, neuronal death, and so forth ^16,21–25.

Given that inflammatory processes very likely contribute to the delayed ischemic injury and lead to the aggravation of neurological outcomes, harnessing certain key inflammatory pathways may prevent the secondary neuronal injury. As such, interventions aiming to control these inflammatory reactions in the ischemic brain might provide attractive therapeutic strategies with potentially extended treatment window and afford beneficial effects that could complement the thrombolytic therapy in ameliorating postischemic brain damage ^15,26. The anti-inflammatory strategies for neuroprotection after acute brain ischemia have been focused on intervening with the innate immune system by decreasing microglial activation ^27,28, blocking neutrophil adhesion and infiltration ^29,30, diminishing the ROS and RNS levels ^31,32, and inhibiting interleukin-1 (IL-1) signaling ³³. However, given the uncertainty of translational validity of therapeutically targeting these signaling pathways, additional knowledge of the postischemic neuroinflammation is necessary to the identification of druggable anti-inflammatory targets for delayed interventions of brain ischemia.

3. COX-1/2 as conventional targets

Cyclooxygenase (COX) is a key rate-limiting enzyme in the biosyntheses of prostanoids, which mediate another large complex inflammatory cascade that has been widely studied in acute brain ischemia and many other inflammation-associated neurological conditions. Up to date, two COX isozymes have been discovered: COX-1 and COX-2. The COX-1 is constitutively expressed across the mammalian body to maintain homeostatic prostanoids, which are essential for numerous physiological functions under normal conditions. COX-2, on the other hand, is generally undetectable in most normal tissues and cells but with some exception in vascular endothelial cells of normal hamsters, where a significant amount of COX-2 is found ³⁴. However, COX-2 is induced by fever, infection, inflammation, hypertension ³⁵, and other stimuli from growth factors and excessive neuronal activities ³⁶, and is widely considered as a chief pro-inflammatory mediator (Figure 1). COX-2 is quickly and strongly induced in the brain by acute neurological insults including strokes and seizures ^37–41. In the rat model of transient middle cerebral artery occlusion (MCAO), the COX-2 mRNA expression is considerably upregulated in the ischemic but not the contralateral hemisphere as early as 6 hours following ischemia and maximizes with a five-fold induction at 12 hours after MCAO ³⁸. In rats with 20-minute global ischemia, the COX-2 protein level in the hippocampus begins to increase 4 hours after onset of ischemia and can reach a maximum at 24 hours after ischemia ³⁹. The rapid upregulation of COX-2 is also found in infiltrating neutrophils, vascular endothelial cells, and neurons in infarcts of human ischemic brains, raising the possibility that the enzymatic products of COX-2 may contribute to the mechanisms of ischemic injury in the humans ⁴².

The increase in COX-2 expression leads to the biosyntheses of five types of prostanoids (Figure 1): prostaglandin D2 (PGD₂), prostaglandin E2 (PGE₂), prostaglandin (PGF_2α), prostacyclin or prostaglandin I2 (PGI₂), and thromboxane A2 (TXA₂). These COX products are rapidly (within seconds) and vigorously (~30 fold) increased upon decapitation-induced brain global ischemia ^43–45, suggesting an immediate and dramatic increase in COX enzyme activity itself before the long-lasting elevation in COX expression and a key role for prostanoid cascade in response to stroke onset. Though short-lived, these small bioactive lipids in turn dynamically bind and act on a suite of G protein-coupled receptors (GPCRs): two receptors (DP1 and DP2) activated by PGD₂; four (EP1, EP2, EP3, and EP4) activated by PGE₂; each of the other three prostanoids acts on a single receptor (FP, IP, and TP) (Figure 1). Because prostanoids play essential roles in both initiating and sustaining the inflammatory reactions, the inhibition of COX-2 by a variety of selective and nonselective inhibitors is considered as a general strategy to treat inflammation-associated disease conditions including acute brain ischemia.

3.1. Selective COX-2 inhibitors

The COX-2 enzyme was first identified and sequenced in 1988 and confirmed in 1991 ⁴⁶, leading to the rise for development of selective inhibitors for COX-2. In less than eight years, the first COX-2 inhibitors (COXIBs) were developed and commercialized, with Celebrex (celecoxib) and Vioxx (rofecoxib) launched in 1999 (Figure 2). The COX-2 selective inhibitors are effective for relief from pain and inflammation without causing significant gastrointestinal complications, common side effects of the traditional nonsteroidal anti-inflammatory drug (NSAIDs), which are nonselective COX inhibitors ^47,48. The early success in the development of selective COX-2 inhibitor drugs led to the broad interests of targeting COX-2 for inflammation-associated conditions including ischemic stroke (Table 1). The first COX-2 selective inhibitor that was investigated for therapeutic benefits in experimental brain ischemia was NS398 (Figure 2), which is about 42-fold selective on COX-2 over COX-1. Treatment with COX-2 selective inhibitor NS398 twice daily for 3 consecutive days was able to decrease the ischemia-induced PGE₂ and reduce the infarct volume without affecting arterial pressure, blood glucose, or body temperature in a rat model of transient MCAO ³⁸. Likewise, treatment with another COX-2 selective inhibitor SC58125 (Figure 2) for 3 days decreased the ischemia-induced hippocampal PGE₂ and CA1 neuronal death after global ischemia in rats ³⁹. Furthermore, systemic treatment with NS398 reduced the neurological deficit and infarction in mice following permanent MCAO ⁴⁹. In line, COX-2-deficient mice showed lower vulnerability to ischemic brain injury and N-methyl-D-aspartate (NMDA)-mediated neurotoxicity when compared to their wild-type cohorts ⁵⁰. In contrast, the overexpression of COX-2 in postnatal neurons led to a nearly 10-fold increase in PGE₂ level in the brain and enlarged the infarct volume in mice after transient MCAO ⁵¹, In the same study, pretreatment with selective COX-2 inhibitor SC58236 (Figure 2) shrank the infarct volume in wild-type mice but not in COX-2 transgenic mice, indicating a dose effect of the COX-2 expression on ischemic injury. These early preclinical findings utilizing genetic ablation and pharmacological inhibition reveal that COX-2 induced by ischemic insults contributes to neuronal injury in the ischemic brain, suggesting that pharmacological inhibition of COX-2 might represent a promising anti-inflammatory strategy to treat ischemic stroke.

Figure 2. — Nonselective and selective COX-1/2 inhibitors tested in experimental brain ischemia. The IC₅₀ values on COX-1 and COX-2 of each compound are indicated.

Table 1.

COX inhibition in recent preclinical studies on brain ischemia.

Animal models	Major therapeutic outcomes	References
Transient MCAO (2 hr) induced in adult Sprague-Dawley rats	Treatment with COX-2 selective inhibitor NS398 (20 mg/kg, i.p., twice per day) beginning 6 hr after ischemia onset decreased the ischemia-induced PGE₂ in the injured brain 24 hr after MCAO and reduced the infarct volume 3 days after MCAO without affecting mean arterial pressure, blood glucose, or rectal temperature.	Nogawa et al., 1997
Global ischemia (20 min) induced in adult male Sprague-Dawley rats	Treatment with COX-2 selective inhibitor SC58125 (30 mg/kg, p.o., once per day) or nonselective inhibitor piroxicam (30 mg/kg) decreased the ischemia-induced PGE₂ in the hippocampus 24 hr after global ischemia and reduced CA1 neuronal death 3 days after global ischemia.	Nakayama et al., 1998
MCAO induced in adult C57BL/6 mice	Genetic ablation of COX-2 decreased the infarct volume 4 days after focal ischemia without affecting the cerebral blood flow.	Iadecola et al., 2001
Transient MCAO (1 hr) induced in adult male C57BL/6 mice	COX-2 overexpression in postnatal neurons increased the PGE₂ level in the brain and enlarged the infarct volume 4 days after ischemia; pretreatment with COX-2 inhibitor SC58236 (30 mg/kg, p.o., once at 4 hr before MCAO) reduced the infarct volume in wild-type mice but not in COX-2 transgenic mice 4 days after MCAO.	Dore et al., 2003
Permanent MCAO induced in adult male C57BL/6 mice	Treatment with COX-2 selective inhibitor NS398 (10 mg/kg, i.p., twice per day for 3 days) reduced the neurological deficit and the infarct volume 4 days after MCAO; NS398 (10 mg/kg, i.p.), when administered 1 hr before and after MCAO and again 6 hr after MCAO, reduced the infarct volume 24 hr after MCAO.	Sugimoto and Iadecola, 2003
Transient MCAO (2 hr) induced in adult male Sprague-Dawley rats	Oral treatment with COX nonselective inhibitor indomethacin (2.5 mg/kg per day) beginning 3 days before MCAO enhanced the neurogenesis for up to 28 days after ischemia without changing the infarct volume.	Hoehn et al., 2005
Transient forebrain ischemia (10 min) induced in adult male Wistar rats	Treatment with ibuprofen with high dose (100 mg/kg immediately after reperfusion, and 50 mg/kg daily for the next 6 days) led to a long-lasting protection of CA1 hippocampal neurons 4 weeks after ischemia.	Park et al., 2005
Permanent cerebral hypoperfusion induced in adult male Wistar rats	Treatment with the nonselective COX inhibitor indomethacin (3 mg/kg, i.p., for 3 days) did not improve the survival rate or learning disability but aggravated the neuronal injury in the CA1 and CA3 regions; treatment with selective COX-2 inhibitor NS398 (15 mg/kg, i.p., for 3 days) improved the survival rate and abolished the learning disability but exacerbated the neuronal injury and did not prevent the glial activation.	Institoris et al., 2007
Motor cortex stroke ischemia induced in adult male Long-Evans rats	Long-term oral treatment with NS398 (2 mg/kg) only provided limited functional improvement but caused an increase in lesion size.	Silasi and Kolb, 2007

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3.2. Nonselective COX inhibitors

As selective COX-2 inhibitors capture most attention owing to their promising neuroprotection against ischemic injury, several nonselective COX inhibitors were also tested in animal models of cerebral ischemia and showed some therapeutic potential (Table 1). Oral administration of piroxicam (Figure 2), an NSAID that nonselectively inhibit both COX-1 and COX-2, decreased the ischemic injury-induced PGE₂ in the hippocampus and reduced CA1 neuronal death after global ischemia in rats ³⁹. Ibuprofen (Figure 2), another traditional NSAID, when administered with high doses (50-100 mg/kg), caused a long-lasting protection of hippocampal CA1 neurons in a rat model of transient forebrain ischemia presumably via elevating the interleukin-1 receptor antagonist ⁵². However, it should be noted that the COX inhibition did not always lead to beneficial effects following brain ischemia. Systemic treatment with nonselective COX inhibitor indomethacin (Figure 2) did not decrease the infarct volume in a rat model of transient MCAO, although the NSAID was able to reduce microglial activation and enhance the neurogenesis following brain ischemia ⁵³. Moreover, administration of indomethacin in a rat model of permanent cerebral hypoperfusion did not improve either the animal survival rate or learning disability as anticipated. On the contrary, COX inhibition by indomethacin exacerbated the hypoperfusion-induced neuronal injury in the hippocampal CA1 and CA3 regions ⁵⁴. In the same study, NS398 increased the proportion of rats displaying neuronal damage and did not prevent the glial activation, although it improved the survival rate and reduced the learning impairment ⁵⁴. Similarly, long-term treatment with NS398 caused an increase in lesion size in rats with motor cortex stroke, though a limited functional improvement was observed ⁵⁵.

The contradiction in outcomes of these pharmacological studies is not uncommon, as similar conflicting results were also observed in a large number of animal studies on seizure models ^56–58. The differences of ischemic models used in these preclinical studies (Table 1), such as methods for the ischemic induction (focal vs. global), duration of ischemia (transient vs. permanent), animal species (mouse vs. rat), sex (male vs. female), and age (young vs. old), might potentially be contributary factors. In addition, the dose, dosing frequency, dosing duration, as well as the pharmacodynamic and pharmacokinetic properties of these COX inhibitors (Figure 2), including selectivity, off-target activities, in vivo half-lives, and brain penetration, could also affect the therapeutic outcomes. It is worth noting that the selective COX-2 inhibitors overall showed more consistent and profound neuroprotection following brain ischemia than the nonselective COX inhibitors (Table 1), suggestive of a dominant role of the induced COX-2 in ischemic stroke-related neuronal damage. The COX-2 induction leads to the syntheses of five different prostanoids that act on a total of nine GPCRs, which mediate a myriad of detrimental and beneficial effects (Figure 1) ^57,59. The past two decades also witnessed an increasing recognition of the notorious adverse effects of COX-2 selective inhibitor drugs that are associated with serious complications such as heart attack and stroke, suggesting that some COX downstream prostanoid signaling pathway might be protective in the microvascular systems ⁶⁰. The Hyde and Jekyll nature of COX signaling cascade inspired us with a notion that targeting certain downstream prostanoid receptor might represent an alternative anti-inflammatory and neuroprotective strategy for the delayed treatment of brain ischemia with more specificity than the general blockade of the entire COX cascade (Figure 1).

4. G_s-coupled prostanoid receptors

In rodent brains, acute ischemic insult is often followed by rapid and marked increases in prostaglandin products – PGD₂, PGE₂, and PGF_2α, which can be blocked by COX inhibitors, such as indomethacin and ibuprofen ^61,62. The elevated prostaglandins by ischemic stroke are also found in the cerebrospinal fluid of human patients and experimental animals ^63,64. Likewise, the levels of prostacyclin PGI₂ and thromboxane TXA₂ also increase along with COX-2 induction in the ischemic brain ^65,66. Among the nine GPCRs activated by these five bioactive lipids (Figure 1), DP1, EP2, EP4, and IP receptors are coupled to Gα_s that activates adenylyl cyclase to generate cAMP, relax smooth muscles, and thus are also called “relaxant” receptors. As a conventional intracellular second messenger, cAMP binds and activates protein kinase A (PKA) to regulate pleiotropic effects. As such, the cAMP-activated PKA subsequently translocates to the cell nucleus, where it acts on transcription factors including the cAMP-responsive element-binding protein (CREB) ⁶⁷. The activated CREB in turn binds to CRE sites to regulate the expression of genes that are involved in the neuronal plasticity and regeneration ⁶⁸. On the other hand, cAMP can enhance the cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs), also called the exchange factors directly activated by cAMP (EPACs) (Figure 1). The activated EPAC then can stimulate the downstream effectors Rap GTP-binding proteins 1/2 (RAP1/2) to regulate a variety of pathogenic events such as neurotoxicity and neuroinflammation ^69–71. However, whether EPAC is directly involved in ischemic injury remains to be determined.

4.1. DP1 receptor

Following a 20-minute episode of global cerebral ischemia in rats, the PGD₂ level in the hippocampus can be quickly induced by up to 80-fold ⁷². Similarly, in neonatal mouse brain after hypoxic ischemia, the PGD₂ level rises by 90-fold, but only 6-fold and 45-fold for PGE₂ and PGF_2α, respectively ⁷³, indicative of PGD₂ as the most ample lipid metabolite that is derived from the cell membrane-released arachidonic acid in the ischemic brain. PGD₂ is synthesized directly from intermediate PGH₂ by PGD₂ synthase (PGDS), which has two isozymes: lipocalin PGDS (L-PGDS, or β-trace protein) and hematopoietic PGDS (H-PGDS) ^74–76. PGD₂ binds to two GPCRs: Gα_s-coupled DP1 and Gα_i-coupled DP2, which, upon activation by PGD₂, respectively upregulates or downregulates the adenylate cyclase that synthesizes cAMP (Figure 1). The PGD₂ signaling-induced cAMP in turn activates PKA or other downstream effectors to regulate multiple physiological and pathological functions, such as inhibition of platelet aggregation, relaxation and contraction of smooth muscles, vasodilation, and vasoconstriction ^77,78. In the human body (https://www.ncbi.nlm.nih.gov/gene/5729), the DP1 receptor is mainly distributed in colon, endometrium, heart, lung, immune system, etc., whereas its expression in the brain is relatively low under normal conditions. However, both DP1 and H-PGDS in the mouse brain can be induced by hypoxic ischemia ⁷³, presumably contributing to the elevated PGD₂ signaling in the ischemic brain (Figure 1).

Interestingly, PGD₂ or DP1 selective agonist BW245C (Figure 3) can prevent neuronal death induced by the glutamate toxicity in cultured rat hippocampal organotypic slices and neurons presumably through acting on DP1 receptor in a cAMP/PKA-dependent manner, whereas DP2 activation by DK-PGD₂ promoted neuronal loss ⁷⁹. The neuroprotection of DP1 receptor and detrimental effect of DP2 were also recently confirmed in rat hippocampal cultures that were treated by aluminum for neuronal injury ⁸⁰. Genetic ablation of the DP1 receptor aggravated ischemic brain injury and enhanced neurological dysfunction following transient ischemia in mice without affecting physiological parameters, such as arterial blood pressure, core body temperature, or cerebral blood flow. In addition, DP1 receptor activation by BW245C showed neuroprotection against glutamate-induced neuronal excitotoxicity in a concentration-dependent manner ⁸¹. These findings were confirmed by Taniguchi et al., who also demonstrated that the ischemic lesion in neonatal mouse brain after hypoxic ischemia was increased in H-PGDS/L-PGDS double knock-out mice, but not in L-PGDS or DP2 knock-out mice (Table 2). It was also found that the endothelial cells were severely damaged in H-PGDS/L-PGDS and DP1 knock-out mice; therefore, it is possible that PGD₂ signaling via DP1 in the neonatal brain exerts neuroprotective effects via preventing endothelial cell degeneration ⁷³. Interetestingly, the infarct size was in inverse relation to the amount of PGD₂ production in L-PGDS, H-PGDS, and H-PGDS/L-PGDS knock-out mice, as the PGD₂ levels in L-PGDS, H-PGDS, and H-PGDS/L-PGDS knock-out mice were 46%, 7%, and 1%, respectively, of that in the wild-type cohorts ⁷³. These two preclincal studies provide evidence that the DP1 receptor activaiton might represent a therapeutic strategy for ischemic stroke. However, future study is needed to examine the therapeutic effects of selective DP1 agonists in animal models of transient or permanent MCAO in order to validate the receptor as a potential phamracological target for ischemic injury.

Table 2.

Targeting G_s-coupled prostanoid receptors for experimental brain ischemia.

Receptor	Animal model	Major therapeutic outcomes	Reference
DP1	Transient MCAO (90 min) induced in adult male C57BL/6 mice	Genetic ablation of the DP1 receptor enhanced ischemic brain injury and neurological dysfunction after transient ischemia 4 days after MCAO without affecting the mean arterial blood pressure, cerebral blood flow, or core body temperature.	Saleem et al., 2007
DP1	Hypoxic ischemia (30 min) induced in C57BL/6 neonatal mice (P7)	The ischemic lesion was increased in H-PGDS/L-PGDS double knock-out mice or DP1 knock-out mice, but not in L-PGDS knock-out mice 24 hr and 7 days after hypoxic ischemia; the infarct size was in inverse relation to the amount of PGD₂ production in L-PGDS, H-PGDS, and H-PGDS/L-PGDS knock-out mice.	Taniguchi et al., 2007
EP2	Transient MCAO (90 min) induced in adult male C57BL/6 mice	Global deletion of the EP2 receptor exacerbated the infarct volume and neurological deficit 24 hr after MCAO without affecting the cerebral arterial vasculature or cerebral blood flow.	McCullough et al., 2004
	Permanent MCAO induced in adult male C57BL/6 mice	Global EP2 deficiency increased the infarct volume 24 hr after MCAO without altering the cerebral blood flow.	Liu et al., 2005
	Transient MCAO (90 min) induced in adult male C57BL/6 mice	Global ablation of the EP2 receptor or pre-treatment with agonist ONO-AE1-259-01 (1 or 2 nmol, i.c.v.) 45-50 min before MCAO exacerbated the infarct volume and neurological deficit 4 days after MCAO without affecting the gross vascular anatomy of the brain, cerebral blood flow, body temperature, or mean arterial blood pressure.	Ahmad et al., 2010
	Permanent MCAO induced in adult male C57BL/6 mice	Global EP2 deficiency increased the infarct volume and neurological deficit 7 days after MCAO.	Ahmad et al., 2010
	Transient MCAO (45 min) induced in adult male C57BL/6 mice	Tamoxifen-induced postnatal deletion of the EP2 receptor reduced the infarct volume, neurological deficit, and neuroinflammation 2 days after MCAO without altering the peripheral immune mobilization in the spleen; treatment with EP2 antagonist benzoxazepine 52 (10 mg/kg, p.o., 2 dose at 4.5 and 24 hr after MCAO onset) reduced the infarct volume, neurological deficit, and post-stroke weight loss 3 days after MCAO.	Liu et al., 2019
	Transient MCAO (45 min) induced in adult male and female C57BL/6 mice	EP2 deletion in neurons but not in myeloid or endothelial cells reduced the infarct volume in male and female mice in a gene dose dependent manner 2 days after MCAO.	Liu et al., 2019
	Transient MCAO (45 min) induced in adult male C57BL/6 mice	Treatment with EP2 antagonist TG6-10-1 (5 or 10 mg/kg, p.o., 3 doses at 4.5, 12 and 24 hr after MCAO onset) reduced the infarct volume, neurological deficit, and cytokine induction 3 days after MCAO.	Li et al., 2020
EP4	Transient MCAO (60 min) induced in adult male C57BL/6 mice	Treatment with EP4 selective agonist ONO-AE1-329 (0.03 or 0.3 mg/kg, s.c., once at 3 hr after MCAO) reduced the infarct volume in a dose-dependent manner 24 hr after MCAO; treatment with ONO-AE1-329 (0.3 mg/kg, s.c., twice at 2 and 8 hr after MCAO) reduced the infarct volume and neurological deficit 24 hr after MCAO.	Liang et al., 2011
	Transient MCAO (60 min) induced in adult male F1 hybrid B6D2F1/J mice	Treatment with ONO-AE1-329 (0.03 mg/kg, s.c., once at 3 hr after MCAO) improved the rotarod performance at both 2 day and 7 days after MCAO.	Liang et al., 2011
	Transient MCAO (45 or 60 min) induced in adult male and female C57BL/6 mice	Neuronal EP4 ablation increased the infarct volume 24 hr after MCAO, which was reversed by treatment with ONO-AE1-329 (0.3 mg/kg, s.c., once at 3 hr after MCAO).	Liang et al., 2011
	Transient MCAO (30, 45, or 60 min) induced in adult male C57BL/6 mice	Tamoxifen-induced EP4 deletion in endothelial cells increased the infarct volume 24 hr after MCAO, which was reversed by treatment with ONO-AE1-329 (0.3 mg/kg, s.c., once at 3 hr after MCAO); endothelial EP4 deletion did not affect the cerebral blood flow or mean arterial pressure.	Liang et al., 2011
	Transient MCAO (60 min) induced in adult male and female C57BL/6 mice	Treatment with EP4 selective agonist L-902688 (0.75 μg/kg, i.p., 2 doses at 1 and 24 hr after MCAO) decreased the infarct volume and neurological deficit 2 days after MCAO without affecting the post-stroke weight loss, survival, or the cerebral blood flow	Akram et al., 2013
	Transient MCAO (90 min) induced in adult male Sprague-Dawley rats	Treatment with L-902688 (0.3 or 1.0 mg/kg, i.v., once at 1.5 hr after MCAO) reduced the infarct volume, blood-brain barrier breakdown, the induction of IL-1β, IL-6, MMP-3/9, and preserved the tight junction proteins 24 hr after MCAO; treatment with L-902688 (1.0 mg/kg, i.v., once at 1.5 hr after MCAO) reduced the long-term neurological deficit for up to 3 weeks after MCAO.	DeMars et al., 2018
IP	Transient MCAO (60 min) induced in adult male Long-Evans rats	Overexpression of PGIS by adenovirus-mediated gene delivery into the lateral ventricle 3 days before but not after ischemia reduced infarct volume 24 hr after MCAO.	Fang et al., 2006
	Transient MCAO (90 min) and permanent MCAO induced in adult male C57BL/6 mice	Genetic deletion of IP receptor exacerbated the infarct volume and neurological deficit 4 days after transient MCAO and 7 days after permanent MCAO without altering cerebral blood flow, body temperature, or arterial blood pressure; pre- or post-treatment with IP selective agonist beraprost (50 or 100 μg/ml, p.o.) decreased infarct volume and neurological deficit in wild-type mice but not in IP knock-out mice 4 days after transient ischemia; treatment with beraprost (100 μg/ml, p.o.) 4.5 hr after MCAO onset decreased the neurological deficit and infarct volume in wild-type mice 7 days after permanent MCAO began.	Saleem et al., 2010
	Transient global brain ischemia (12 min) induced in adult young and old male C57BL/6 mice	Genetic ablation of IP receptor increased the cognitive deficit, hippocampal CA1 pyramidal neuronal death, microglial activation, and myeloperoxidase activity, and decreased the phosphorylation of CREB in both young and old adult mice.	Shakil and Saleem, 2013
	Transient global brain ischemia (12 min) induced in adult young and old male C57BL/6 mice	Post-treatment with IP agonist beraprost (25, 50, or 100 μg/ml, p.o.) attenuated neuronal death, astrogliosis, microbial invasion, and myeloperoxidase activity, and increased the phosphorylation of CREB in both young and old adult mice in a dose-dependent manner.	Shakil and Saleem, 2014

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4.2. EP2 receptor

PGE₂, another major prostaglandin product of COX within the brain, is directly synthesized from COX-derived intermediate PGH₂ by the microsomal prostaglandin E synthase-1 (mPGES-1), mPGES-2, or cytosolic PGES (cPGES). Among these three PGES isozymes, mPGES-1 is highly inducible, membrane-bound, and functionally linked to COX-2 in preference to COX-1 for PGE₂ synthesis under pathological conditions (Figure 1) ⁸². PGE₂ is an essential executor of the detrimental effects mediated by induced COX-2 and mPGES-1 in various neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and epilepsy ^57,59,83. The detrimental roles of elevated COX-2 in ischemic stroke is also thought to be largely attributed to the PGE₂ signaling. The levels of PGE₂ are commonly elevated in ischemic brains of human patients as well as experimental animals ^63,64,84,85, with a positive correlation between PGE₂ levels and the severity in clinical outcome of the stroke ⁶³. PGE₂ exerts a wide variety of physiological and pathological functions via acting on a group of GPCRs, namely, EP1, EP2, EP3, and EP4 ⁷¹. These membrane-bound receptors are differentially expressed in neurons, endothelial cells, microglia, and astrocytes throughout the brain and engage with divergent second messenger molecules (Figure 1) ⁷¹.

Given that targeting some PGE₂ downstream signaling pathway might provide more therapeutic specificity than blocking the entire COX cascade by COX inhibitors, these four GPCRs have been investigated as potential therapeutic targets for brain ischemia in preclinical models, with the EP2 receptor as the one studied first and the most by far (Table 2). The EP2 receptor is widely expressed in the human body (https://www.ncbi.nlm.nih.gov/gene/5732), but is mainly found in bone marrow, immune system, reproductive system, and gastrointestinal tract ^78,86, where its activation by homeostatic PGE₂ leads to multiple important physiological functions, particularly in the immunoregulation ⁵⁹. Expression of the EP2 receptor in the CNS areas, such as cerebral cortex and hippocampus, is relatively low under normal conditions, but can be quickly induced in response to stimuli from brain ischemia and epileptic seizures ^19,87, suggestive of its potential involvement in the mediation of pathophysiology of these acute excitotoxic conditions. Interestingly, activation of the EP2 receptor by excessive PGE₂ can strongly promote the brain microglia to generate cytokines and later may contribute to microglial death for the resolution of neuroinflammation ^69,88.

The activation of EP2 receptor by its natural ligand PGE₂ or selective agonist butaprost (Figure 3) was neuroprotective against glutamate receptor activation-mediated excitotoxicity in neuron-enriched cortical and hippocampal cultures, likely via activating the cAMP-PKA pathway ⁸⁹. The neuroprotection from EP2 receptor activation has also been demonstrated by us using several positive allosteric modulators of the receptor in primary cultured neurons that were stimulated with NMDA and glycine for excitotoxic induction ^90,91. Global congenital deletion of the EP2 receptor in mice led to considerable increases in the cerebral cortical infarction and neurological dysfunction 24 hours after a 90-minute episode of MCAO without affecting the overall brain vasculature or cerebral blood flow ⁸⁹. Likewise, the genetic ablation of EP2 receptor also enlarged the infarct volume 24 hours after permanent MCAO in mice ⁹². These short-term exacerbating effects from the EP2 deletion can be extended to 4 days after transient MCAO and 7 days after permanent MCAO in mice ⁹³, accentuating the long-lasting detrimental effects of the EP2 receptor ablation following brain ischemia. In line, intracerebroventricular administration of EP2 selective agonist ONO-AE1-259-01 (Figure 3) before the MCAO onset decreased the infarct volume and relieved the neurological deficit in mice in a dose-dependent manner ⁹³. These earlier studies using genetic global deletion and pharmacological inhibition suggest that the EP2 receptor activation by PGE₂ might play some neuroprotective role after brain ischemia (Table 2).

However, the activation of EP2 receptor did not always result in beneficial effects following excitotoxic injury. Treatment with PGE₂ or butaprost aggravated the NMDA-induced neuronal excitotoxicity in glia-containing cortical cultures through a cAMP- but not PKA-dependent manner ⁹⁴. In a recent animal study (Table 2), the tamoxifen-induced deletion of EP2 or the conditional ablation of the neuronal form of the receptor – but not the endothelial or myeloid form – decreased the cortical infarction and neurological deficit after a 45-minute episode of MCAO in mice ¹⁹. Markedly, these beneficial effects from postnatal or neuron-specific ablation of the EP2 receptor were able to be recapitulated in wild-type mice that were treated by an EP2-selective antagonist benzoxazepine 52 (Figure 3) in the same animal model of transient focal ischemia ¹⁹. We have recently developed selective EP2 antagonists that are highly potent and have adequate pharmacodynamic and pharmacokinetic profiles, and several of these novel compounds showed remarkable neuroprotective and anti-inflammatory effects after prolonged seizures and other acute neurological insults ^95–100. Interestingly, post-stroke EP2 inhibition by a bioavailable and highly brain-permeable antagonist TG6-10-1 (Figure 3) was found to decrease the neurological deficit, infarct volume, and expression of three prototypic inflammatory cytokines, i.e., IL-1β, IL-6, and tumor necrosis factor α (TNF-α), in the brain after a 45-minute episode of transient ischemia in mice ¹⁰¹.

These apparently contradicting outcomes from the early and recent studies might result from the perplexing complications caused by the congenital global ablation of the receptor (Table 2). Widely expressed in the periphery and the brain, the G_s-coupled EP2 exerts many fundamental functions in normal physiological conditions. The global EP2 knock-out mice are widely known for developmental and other homeostatic adjustments that lead to complications including impaired fertility and hypertension ^102–104. Mouse transcript database reveals that the EP2 expression in the brain is dynamically regulated (https://www.ncbi.nlm.nih.gov/gene/19217). During the early stages of development, the EP2 mRNA level in the CNS continuously rises from E11.5 to E18 by nearly eight-fold. However, its mRNA expression in adult cortex dramatically decreases to only about 25% of that at E18, indicating that the EP2 expression is high in the developing brain but remains very low in the adult brain. As such, the EP2 receptor might play some essential but unidentified roles during the early brain development when its expression is high. Indeed, the global congenital ablation of EP2 impairs some fundamental neural functions, such as sensorimotor gating, synaptic plasticity, and hippocampal long-term depression (LTD) and long-term potentiation (LTP), leading to considerable neurological dysfunctions ^105,106. On the contrary, postnatally induced deletion or conditional ablation of EP2 preserves the normal functions of the receptor during early development of the brain, and thus do not phenocopy the behavioral and cognitive impairments found in the global EP2 knock-out mice ¹⁹. Nonetheless, the overall neuroprotective and anti-inflammatory effects from two well-characterized small-molecule EP2-selective antagonists – benzoxazepine 52 and TG6-10-1 – in mouse MCAO models provide promising evidence that pharmacological inhibition of the EP2 receptor by small-molecule compounds is a feasible strategy to mitigate the neuronal inflammation and damage after acute brain ischemia (Table 2).

4.3. EP4 receptor

As the other currently known G_s-coupled receptor of PGE₂, the EP4 subtype resembles the EP2 subtype in both expression and signaling transduction (Figure 1). However, the functional coupling to cAMP appears less efficient for the EP4 than that for EP2, and the EP4 receptor also mediates several other pathways, such as extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB or Akt)/mammalian target of rapamycin (mTOR), and p38 mitogen-activated protein kinase (MAPK) pathways ^78,107. Similar to EP2, the EP4 receptor is widely distributed in the human body, especially in the CNS, dorsal root ganglion, bone marrow, thyroid, heart, kidney, lung, pancreas, spleen, intestine, colon, uterus, and urinary bladder (https://www.ncbi.nlm.nih.gov/gene/5734), and has been implicated in both physiological and pathological conditions. In the CNS, the EP4 receptor is constitutively expressed in neurons of hippocampus, cortex, and striatum, whereas its expression in endothelial cells is elevated during the early reperfusion after brain ischemia ¹⁰⁸.

The differential expression of the EP4 receptor in various types of brain cells inspired investigation to reveal the cell type-specific functions of the receptor in ischemic injury (Table 2). Conditional EP4 ablation in neurons aggravated the injurious outcomes of transient MCAO in mice, and similar results were demonstrated in mice with postnatal ablation of the receptor in endothelial cells¹⁰⁹, suggesting that the EP4 receptor activation in these two cell types aggravates the ischemic injury. Subcutaneous administration of an EP4-selective agonist, ONO-AE1-329 (Figure 3), following brain ischemia lessened the infarction and neurological deficit, causing a long-term substantial improvement in rotarod performance of the animals ¹⁰⁹. Similarly, L-902688 (Figure 3), another potent EP4-selective agonist, when interperitoneally administered immediately after transient brain ischemia, reduced the infarct volume and improved neurological functions but did not reverse the weight loss or improve the survival after a one-hour MCAO in mice. Further, the post-stroke EP4 receptor activation by L-902688 recapitulated the benefits of COX-2 selective inhibitor NS-398 in the same study ¹¹⁰. Similarly in rats, the post-stroke treatment with L-902688 dose-dependently decreased the cerebral infarction, disruption of the blood-brain barrier, and induction of MMPs and cytokines after transient MCAO, causing a chronic reduction in neurological dysfunction for up to 3 weeks after ischemia ¹¹¹. Taken together, these interesting findings suggest that the EP4 receptor activation by selective small-molecule agonists is neuroprotective following acute ischemic insults presumably via lessening the neuroinflammatory reactions and blood-brain barrier damage.

4.4. IP receptor

Prostacyclin PGI₂ is synthesized from PGH₂ by tissue-specific prostaglandin I synthase (PGIS) (Figure 1). PGI₂ – via G_s-coupled IP receptor – mainly inhibits platelet activation to prevent formation of the platelet plug that is involved in primary hemostasis. Additionally, the endothelial IP receptor activation leads to smooth muscle relaxation and vasodilation ¹¹². Given that PGI₂ counteracts the thromboxane TXA₂’s effects of vasoconstriction and platelet aggregation, the balance between TXA₂ and PGI₂ has long been known essential to the homeostasis of cerebral blood flow ¹¹³. Following a transient global cerebral ischemia, the level of PGI₂ in the rat hippocampus began to increase along with the COX-2 expression as early as 30 min after the onset of brain ischemia ⁶⁶. The hippocampal PGI₂ level then maximized at two days after the ischemia and remained well above that of the sham conditions for more than 2 weeks, indicating its quick induction and long-lasting effect in the ischemic brain following acute brain ischemia.

As the direct enzyme for PGI₂ biosynthesis, PGIS showed a delayed increase in both mRNA and protein expression levels in the ischemic cortex at 2-3 days after transient ischemia in rats. PGIS protein is mainly found in endothelial cells with slightly less expression in neurons, microglia, and astrocytes ⁶⁵. Interestingly, the overexpression of PGIS through adenovirus-mediated gene delivery into the rat lateral ventricle 3 days before the introduction of focal cerebral ischemia-reperfusion reduced infarct volume (Table 2), indicating a neuroprotective role of PGIS via enhancing PGI₂ synthesis that leads to a favorable PGI₂/TXA₂ ratio. These results together with early findings that some PGI₂ analogs showed considerable protective effects against ischemic damages suggest that the PGI₂ signaling via its IP receptor may represent a physiological mechanism of self-redemption of the brain against acute ischemic injury ^114,115.

The IP receptor is overall highly expressed in human brain and is also readily detected in most other organs, such as heart, lymph node, endometrium, placenta, prostate, intestine, thyroid, and urinary bladder (https://www.ncbi.nlm.nih.gov/gene/5739). Genetic deletion of the PGI₂ receptor IP exacerbated the infarct volume and neurological deficit after both permanent and transient ischemia but did not change the cerebral blood flow, body core temperature, or arterial blood pressure during the reperfusion ¹¹⁶. In contrast, treatment with IP selective agonist beraprost (Figure 3) decreased the infarct volume and neurological deficit in wild-type mice but not in IP knock-out mice after transient or permanent ischemia ¹¹⁶, validating the IP as the therapeutic target of beraprost. The genetic deficiency of IP receptor also led to cognitive deficit, hippocampal CA1 pyramidal neuronal death, microglial activation, and myeloperoxidase activity, and a decrease in the phosphorylation of CREB in both young and old mice after transient global brain ischemia ¹¹⁷. However, treatment with beraprost attenuated the ischemia-associated neuronal death, astrogliosis, microbial invasion, and myeloperoxidase activity, and increased the phosphorylated CREB in the same mouse model of global ischemia ¹¹⁸. These findings using combined genetic and pharmacological strategies together reveal a neuroprotective role for the PGIS-PGI₂-IP signaling axis in the ischemic brain.

5. G_q-coupled prostanoid receptors

The EP1, FP, and TP receptors are coupled to G_q and their activation by their corresponding cognate prostanoids stimulates phospholipase C (PLC) that hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) (Figure 1). IP3 then promotes the release of Ca²⁺ from the endoplasmic reticulum into cytoplasm via acting on specific IP3 receptors on the endoplasmic reticulum membrane that function as Ca²⁺ channels. On the other hand, DAG directly activates certain Ca²⁺-dependent isoforms of protein kinase C (PKC) that lead to the Ca²⁺ influx current via the voltage dependent Ca²⁺ channels ¹¹⁹. The EP1, FP, and TP receptors are also classified as “contractile” type of prostanoid receptors in that the increase in cytosolic Ca²⁺ often leads to the contraction of smooth muscle cells.

5.1. EP1 receptor

The human EP1 receptor is highly expressed in colon, kidney, lung, spleen, and stomach (https://www.ncbi.nlm.nih.gov/gene/5731). In the brain, EP1 receptor is primarily found in neurons and endothelial cells, and its expression is dynamically regulated by ischemic injury in a time-dependent manner. The mRNA level of EP1 receptor is upregulated by nearly 50% in ischemic brain tissues at 4 hours after the occlusion begins, and then resides to basal levels 10-20 hr later. Intriguingly, by 48 hr after the ischemia onset, EP1 mRNA in the affected brain areas increases again by more than 50% above the basal levels ^85,120. Though EP1 is also expressed in microglia of the brain, the microglial form of EP1 is much less abundant than its neuronal and endothelial counterparts and may not necessarily be relevant to the post-stroke inflammation-associated brain injury ^121,122. Therefore, it is unlikely that the well-established detrimental role of the EP1 receptor is directly mediated by neuroinflammatory mechanisms after ischemic stroke. Instead, the EP1 receptor mediates neurotoxicity after brain ischemia via dysregulating the intracellular Ca²⁺ homeostasis, as the Ca²⁺ influx into neurons via the L-type calcium channels is a common molecular mechanism underlying excitotoxic injury, and modulating these calcium channels can lead to neuroprotection ^123,124. As such, EP1 receptor activation likely impairs the Na⁺-Ca²⁺ exchanger that constitutes an essential self-redemption mechanism by which neurons dispose of the excessive cytosol Ca²⁺ during excitotoxic insults ¹²².

The genetic deletion of EP1 receptor consistently alleviated various neuronal injuries that are caused by excitotoxicity, oxygen-glucose deprivation, and the transient cerebral ischemia (Table 3) ¹²². The reduction in brain infarction and neurological deficit found in EP1 knock-out mice after ischemic injury has been validated by several research groups using MCAO models that differ in the duration of occlusion (Table 3) ^120,125,126. These studies also suggest that the EP1 deficiency does not noticeably change the cerebral blood flow ^122,127, post-stroke weight loss ¹²⁵, or the brain major vasculature ¹²⁶. Pharmacological inhibition of the EP1 receptor by selective antagonists ONO-8713 or SC51089 (Figure 4) considerably decreased the infarction and neurological dysfunction in rodent models of both permanent MCAO ¹²⁸ and transient MCAO ^{120,122,127,128}. It should be noted that treatment with EP1 antagonist SC51089 seems to have a long therapeutic time window (up to 12 hours after reperfusion begins), and its benefits sustain over time (up to 2 weeks) and do not show any sex difference ¹²⁸. Moreover, the EP1 receptor may also provide a mechanistic link between the neuroinflammatory responses and the MMPs-mediated blood-brain barrier breakdown after brain ischemia ¹²⁰. These important preclinical studies together provide evidence that targeting the EP1 receptor might represent an emerging strategy to relieve the destructive outcomes of acute brain ischemia and the subsequent blood-brain barrier damage (Table 3).

Table 3.

Targeting G_q-coupled prostanoid receptors for experimental brain ischemia.

Receptor	Animal model	Major therapeutic outcomes	Reference
EP1	Transient MCAO (20 min) induced in adult male C57BL/6 mice	Genetic ablation of the EP1 receptor or treatment with EP1 selective antagonist SC51089 (10 μg/kg, i.p., twice per day) beginning at 5 min or 6 hr after ischemia attenuated the infarct volume, neurological deficit, and brain swelling 3 days after MCAO without affecting cerebral blood flow.	Kawano et al., 2006
	Transient MCAO (90 min) induced in adult male C57BL/6 mice	EP1 deficiency reduced infarct volume 4 days after MCAO without affecting the post-stroke weight loss.	Ahmad et al., 2006
	Transient MCAO (90 min) induced in adult male C57BL/6 mice	EP1 deficiency decreased the arterial partial pressure of oxygen level during the ischemic stage and improved the ipsilateral cerebral blood flow during the reperfusion without affecting the brain vasculature network.	Saleem et al., 2007
	Transient MCAO (90 min) induced in adult male C57BL/6 mice	Treatment with EP1 antagonist ONO-8713 (0.1, 1, or 10 nmol, i.c.v.) immediately before MCAO reduced the infarct volume 4 days after ischemia without affecting cerebral blood flow.	Ahmad et al., 2008
	Transient MCAO (25 min) induced in adult male and female C57BL/6 mice	Female mice had smaller infarcts than male mice 3 days after transient ischemia; treatment with EP1 antagonist SC51089 (5, 10, or 20 μg/kg, i.p., twice per day) beginning at 5 min, 6 hr, or 12 hr, but not 24 hr after reperfusion decreased the infarct volume in male mice 3 days after ischemia; treatment with SC51089 (10 μg/kg, i.p., twice per day) beginning at 5 min after reperfusion reduced the infarct volume by 41% in female mice 3 days after ischemia.	Abe et al., 2009
	Permanent MCAO induced in adult male C57BL/6 mice	SC51089 (10 μg/kg, i.p., twice per day) beginning at 6 hr after MCAO onset reduced the infarct volume by 39% 24 hr after ischemia.	Abe et al., 2009
	Transient MCAO (25 min) induced in adult male C57BL/6 mice	Treatment with SC51089 (10 μg/kg, i.p., twice per day for 3 days) beginning at 6 hr after reperfusion led to long-term reduction (2 weeks after ischemia) in the infarct volume, the atrophy of the ipsilateral hemisphere, and functional deficit.	Abe et al., 2009
	Transient MCAO (60 min) induced in adult male C57BL/6 mice	Genetic deletion of EP1 decreased the infarct volume, blood-brain barrier breakdown, MMP-9/-3 activity, and ICAM-1 expression in the cortex 24 hr after ischemia.	Frankowski et al., 2015
	Transient MCAO (90 min) induced in adult male Wistar rats	Treatment with EP1 antagonist SC51089 (3 mg/kg, i.v.) at 3, 18, and 28 hr after reperfusion reduced infarct volume, decreased the blood-brain barrier permeability, preserved the tight-junction proteins, prevented the hemorrhagic transformation, attenuated the MMP-9/-3 activity, and reduced the MPO and ICAM-1 levels in the cortex 48 hr after ischemia.	Frankowski et al., 2015
FP	Transient MCAO (90 min) induced in adult male C57BL/6 mice	Genetic ablation of the FP receptor reduced infarct volume and improved neurological dysfunction 4 days after transient ischemia without affecting cerebral blood flow, body temperature, or arterial blood pressure; treatment with FP selective agonist latanoprost (100 μg/kg, p.o., once) 30 min after reperfusion began aggravated neurological dysfunction and brain infarction in wild-type mice 4 days after MCAO but not in FP knock-out mice.	Saleem et al., 2009
FP	Permanent MCAO induced in adult male C57BL/6 mice	Genetic ablation of the FP receptor or treatment with antagonist AL-8810 (1 or 10 mg/kg, i.v., once) immediately after permanent MCAO began reduced neurological dysfunction and infarct volume in a dose-dependent manner 2 days after MCAO began.	Kim et al., 2012
TP	Spontaneously hypertensive stroke prone rats (SHRSP)	Oral treatment with TP antagonist terutroban (30 mg/kg per day for 6 weeks) improved survival, delayed the appearance of brain damage and proteinuria, and reduced the expression of IL-1β, TGF-β, and MCP-1 without affecting the thromboxane in serum and urine.	Gelosa et al., 2010
TP	Transient MCAO (90 min) induced in adult male ICR mice	The expression of TP receptor was upregulated by ischemia/reperfusion injury for up to 7 days after MCAO; post-treatment with TP selective antagonist SQ29548 (10 μl, 2.6 μmol/ml, i.c.v. twice) immediately after reperfusion and again 24 hr later attenuated the activation of microglia/macrophages, induction of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and iNOS, blood-brain barrier destruction, infarct volume, and neurological deficit 3 days and 7 days after MCAO without affecting the cerebral blood flow.	Yan et al., 2016

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Figure 4. — Compounds modulating G_q-coupled prostanoid receptors. The potency of each compound is indicated by EC₅₀, IC₅₀, or K_i value.

5.2. FP receptor

PGF_2α in the brain also can be vigorously induced by brain ischemia in both human patients and experimental animals. PGF_2α is the most induced and abundant prostaglandin in the cerebrospinal fluid of rabbits with focal ischemia, though PGD₂ is the dominant one under normal condition ⁶⁴. In the cat brain, the resting level of PGF_2α is higher than that of PGE₂; following a 15-minute episode of global ischemia, the brain PGF_2α level remains higher than PGE₂, though its induction fold is only about half of that for PGE₂ ⁸⁴. However, in neonatal mouse brain after hypoxic ischemia, the PGF_2α level in the cerebral cortex can increase up to 45-fold, whereas PGE₂ only rises only about 6-fold ⁷³. PGF_2α is synthesized from intermediate PGH₂ by prostaglandin F synthase (PGFS) ¹²⁹, and activates the sole currently known receptor FP, which is coupled to Gα_q ¹³⁰. FP receptor is widely distributed in the human body (https://www.ncbi.nlm.nih.gov/gene/5737), especially in colon, CNS, endometrium, placenta, cardiovascular system, myometrium, ovarian, etc. ⁷⁸ When bound by PGF_2α or other selective agonists, the FP receptor becomes active, followed by the release of Gα_q from the G protein heterotrimeric complex to activate PLC. The activated PLC then is able to hydrolyze PIP2 to DAG and IP3, which in turn activates certain PKC-dependent pathways and initiates Ca²⁺-sensitive signaling, respectively (Figure 1) ^78,131.

Genetic ablation of the FP receptor in mice was shown to reduce the infarct volume and to improve neurological dysfunction after transient ischemia without affecting cerebral blood flow, core temperature, or arterial blood pressure ¹³². Contrariwise, oral treatment with FP receptor selective agonist latanoprost (Figure 4) after the ischemia-reperfusion exacerbated the neurological dysfunction and brain infarction in wild-type mice while had no effect in FP knock-out mice, indicative of the FP as the target of latanoprost’s therapeutic action. In addition, the FP deficiency partially diminished the NMDA-induced excitotoxic brain damage (Table 3) ¹³². Interestingly, the genetic ablation of the FP receptor in mice also alleviated neurological dysfunction and reduced brain infarction following permanent MCAO, and these benefits in FP knock-out mice were recapitulated in their wild-type peers that were systemically treated by FP selective antagonist AL-8810 (Figure 4) in a dose-dependent manner ¹³³. Furthermore, blockade of the FP receptor led to neuroprotection from glucose-oxygen deprivation-induced cell death and ROS formation in cultured hippocampal slices neurons presumably through downregulating the FP receptor-related Ca²⁺ signaling ¹³³. These preclinical findings suggest that PGF_2α signaling via FP receptor contributes to the brain damage and functional deficit caused by acute ischemic injury (Table 3), thereby providing proof-of-concept evidence to support the FP receptor as a promising molecular target for brain ischemia.

5.3. TP receptor

Thromboxane TXA₂ is synthesized from PGH₂ by tissue-specific thromboxane A synthase 1 (TBXAS1), and activates G_q/G_12/13-coupled TP receptor to stimulate new platelets and to increase platelet aggregation (Figure 1) ⁷⁸. TXA₂ is also a well-known vasoconstrictor via regulating Ca²⁺-sensitive signaling pathways in smooth muscle cells ^134,135. Therefore, PGI₂ and TXA₂ in general act as physiological antagonists to each other ⁶⁰. However, there might be some crosstalk between these two main prostanoid signaling pathways, as PGI₂ can activate the TP receptor in blood vessels of hypertensive rats although PGI₂ usually relaxes arteries in normal rodents ¹³⁶. Likewise, PGF_2α also binds to the TP receptor to trigger vascular contraction in healthy rodents ³⁴. In the CNS, the balance between TXA₂ and PGI₂ plays an essential role in the regulation of cerebral blood flow in response to ischemic injury ^113,137. Following a transient global cerebral ischemia, the levels of PGI₂ and TXA₂ in the rat hippocampus increase, and the induction of PGI₂ is faster and higher than that of TXA₂ ⁶⁶, resulting in an long-lasting increase in the PGI₂/TXA₂ ratio and imbalance between these two important blood flow regulators in the ischemic brain. Similarly, following transient focal ischemia, TXA₂ is also elevated in the brain but less than PGI₂ ^65,66, suggesting a pathogenic role of TXA₂ signaling via TP receptor in the ischemic brain. In addition, a genetic associate study identified some specific single nucleotide polymorphisms (SNPs) and haplotypes of human TP gene that are highly correlated to cerebral infarction ¹³⁸, suggesting the TP gene may be associated with the increased susceptibity to ischemic stroke in humans. The TP receptor is widely distributed in the human body (https://www.ncbi.nlm.nih.gov/gene/6915), particularly in colon, endometrium, kidney, spleen, placenta, heart, liver, etc., and its expression in the brain is moderate under normal conditions. Interestingly, the expression of TP receptor has been found to be upregulated for up to 7 days mainly in microglia by ischemia-reperfusion injury in mice ^139,140, suggesting its involvement in postischemic brain inflammation and injury.

TP receptor activation by selective agonist U46619 (Figure 4) increased the expression of several pro-inflammatory molecules, such as IL-1β, IL-6, and the inducible nitric oxide synthase (iNOS), as well as the phosphorylation of ERK, which can be attenuated by TP selective antagonist SQ-29548 (Figure 4) or MEK inhibitor U0126 ¹³⁹. This interesting study revealed a role of TP receptor in microglial activation via the ERK signaling pathway after cerebral ischemia. Intracerebroventricular treatment with SQ-29548 after transient ischemia in mice reduced the infarct volume and neurological deficit without affecting the cerebral blood flow, accompanied by decreases in microglial activation, induction of pro-inflammatory cytokines and iNOS, and blood-brain barrier disruption (Table 3) ¹⁴⁰. Oral treatment with another TP antagonist terutroban (Figure 4) in stroke-prone rats for 6 weeks led to promising benefits including improved survival, delayed appearance of brain damage and proteinuria, and reduced expression of IL-1β, transforming growth factor β (TGF-β), and monocyte chemoattractant protein 1 (MCP1) or chemokine (C-C motif) ligand 2 (CCL2), without affecting the thromboxane levels in serum and urine ¹⁴¹. Future research utilizing TP knock-out mice is required to further validate the role of the TXA₂ signaling via TP receptor in ischemic injury. Nonetheless, these promising findings from pharmacological studies suggest that the TP receptor antagonism could play an important role in the clinical prevention or treatment for cerebral ischemia (Table 3). Indeed, terutroban showed a better antithrombotic activity than that of aspirin and caused a significant reduction in endothelial/platelet activation in patients with previous cerebral ischemia and/or carotid stenosis in a small-scale double-blind, parallel-group study ¹⁴². However, a large-scale randomized, double-blind, parallel-group trial failed to show a superiority of terutroban over aspirin in secondary prevention of cardiovascular and cerebrovascular events among stroke patients with terutroban showing a slight increase in minor bleeding ¹⁴³.

6. G_i-coupled prostanoid receptors

The DP2 and EP3 receptors are currently known prostanoid receptors that are primarily coupled to Gα_i, and their activation leads to downregulation of the cAMP signaling (Figure 1); therefore, they are classified as “inhibitory” type of prostanoid receptors. However, they may also mediate other signaling pathways through the alternative splicing forms or some other unidentified mechanisms.

6.1. DP2 receptor

As the other currently known receptor activate by PGD₂, the DP2 was originally identified as chemoattractant receptor-homologous molecule expressed on the T helper type 2 (Th2) cells (CRTH2) as a biomarker for Th2 cells ¹⁴⁴. In the meantime, this proved to be the same as the orphan G protein-coupled receptor GPR44 expressed in both the CNS and periphery with a high similarity to typical chemoattractant receptors ¹⁴⁵. PGD₂ was subsequently identified as the natural ligand for the GPR44/CRTH2 receptor ¹⁴⁶, and its current official name DP2 was thus introduced. The phylogenetic relationship analysis also suggest that the DP2 receptor belongs to the superfamily of leukocyte chemoattractant receptors and may not evolve from the same phylogenetic tree as other types of prostanoid receptors ¹⁴⁷. The DP2 receptor primarily couples to the G_i in a manner similar to other chemoattractant receptors, as its activation by PGD₂ leads to pertussis toxin-sensitive decreases in cAMP levels and Ca²⁺ mobilization (Figure 1). In addition, the DP2 receptor has been implicated in initiating the PI3K signaling ⁷⁸. In the human body, the DP2 receptor is widely expressed in brain, colon, duodenum, heart, lung, placenta, intestine, stomach, and testis (https://www.ncbi.nlm.nih.gov/gene/11251). There were several studies demonstrating some detrimental and inflammatory effects mediated by PGD₂ in the periphery mainly through the DP2 receptor ^148–150. The selective DP2 agonist 13,14-dihydro-15-keto PGD₂ (DK-PGD₂) (Figure 5) increased, whereas the DP2 antagonist CAY10471 (Figure 5) decreased, the neuronal damage and Ca²⁺ mobilization in cultured rat hippocampal neurons treated with aluminum maltolate ⁸⁰, suggesting a deleterious role of DP2 in neuronal injury. However, the genetic deletion of DP2 in mice has no considerable effect on the infarct volume in either cerebral cortex or basal ganglia after hypoxic ischemia (Table 4) ⁷³. Future studies are needed to expand current limited understanding of the PGD₂/DP2-mediated signaling transduction pathways, particularly in the pathogenesis of ischemic stroke.

Figure 5. — Small molecules targeting G_i-coupled prostanoid receptors. The K_i value of each compound is indicated.

Table 4.

Targeting G_i-coupled prostanoid receptors for experimental brain ischemia.

Receptor	Animal model	Major therapeutic outcomes	Reference
DP2	Hypoxic ischemia (30 min) induced in BALB/cAJcl neonatal mice (P7)	The ischemic lesion in cerebral cortex and basal ganlia was not changed in DP2 knock-out mice 24 hr after hypoxic ischemia.	Taniguchi et al., 2007
EP3	Transient MCAO (90 min) induced in adult male C57BL/6 mice	Treatment with EP3 agonist ONO-AE-248 (0.5, 2.5, and 5.0 nmol, i.c.v.) 50-60 min before MCAO exacerbated the infarct volume in a dose-dependent manner 4 days after MCAO, but did not affect core body temperature, cerebral blood flow, or mean arterial blood pressure.	Ahmad et al., 2007
	Transient MCAO (90 min) induced in adult male C57BL/6 mice	Genetic deletion of the EP3 receptor did not change the infarct volume or cerebral blood flow 24 hr after MCAO.	Li et al., 2008
	Transient MCAO (90 min) induced in adult male C57BL/6 mice	EP3 deficiency decreased the infarct volume and neurological deficit 2 days but not 4 days after MCAO without affecting the mean arterial blood pressure, pH, blood gases (CO₂ and O₂), cerebral blood flow, or body temperature.	Saleem et al., 2009
	Transient MCAO (120 min) induced in adult male and female C57BL/6 mice	Genetic deletion of mPGES-1 diminished the infarct volume, edema, and neurological deficit 24 hr after MCAO; treatment with EP3 selective antagonist ONO-AE3-240 (3 mg/kg, i.p., 3 doses at 2, 8, and 14 hr after MCAO) reduced infarct volume, edema, and neurological deficit 24 hr after MCAO in wild-type but not in mPGES-1 knockout mice.	Ikeda-Matsuo et al., 2010
	Transient MCAO (120 min) induced in adult male and female C57BL/6 mice	EP3 deficiency or treatment with ONO-AE3-240 (1 or 3 mg/kg, i.p., 3 doses at 2, 8, and 14 hr after MCAO) decreased the infarct volume, edema, neurological deficit, neuronal apoptosis, and blood-brain barrier breakdown, preserved the tight junction proteins, and attenuated the microglial activation 24 hr after MCAO without affecting the cerebral blood flow, mean arterial blood pressure, rectal temperature, or brain vasculature.	Ikeda-Matsuo et al., 2011

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6.2. EP3 receptor

The EP3 receptor subtype of PGE₂ mainly couples to G_i for an inhibitory action on the adenylate cyclase, so its activation downregulates the cAMP-mediated signaling (Figure 1). EP3 has several alternative splicing forms that merely differ in their intracellular C-terminus, enabling the receptor to link with other G proteins in addition to G_i. In humans, the EP3-I and EP3-II forms also couple to G_q; the EP3-II and EP3-IV may be associated with G_s ¹⁵¹. Similarly, there are three EP3 variants in mice – α, β, and γ, among which the EP3γ variant appears to also connect with G_s. All α, β, and γ variants can couple to G_12/13 to activate the Rho pathway and Rho-associated protein kinase (ROCK) ¹⁵². As such, the G protein complexes associated with EP3 receptor, in response to PGE₂ binding, dissociate into Gα_i, Gα_12/13, Gα_s, and Gβγ components that are capable of initiating multiple signaling pathways (Figure 1), depending on the cellular and molecular context. Therefore, a differential variant expression pattern of the EP3 is able to provide another level of mediation of the receptor-regulated signaling in different types of cells and tissues. Widely expressed in the human body (https://www.ncbi.nlm.nih.gov/gene/5733), these EP3 variants are particularly abundant in the CNS, cardiovasculature, reproductive system, intestinal epithelium, kidney, and urinary bladder, where they have been implicated in a wide range of physiological and pathological functions ⁷⁸. The expression of EP3 receptor appears to be differentially regulated by excitotoxic insults, as it is upregulated by kainate-induced seizures ¹⁵³, but not by glutamate or ischemic stroke ⁸⁵. However, in the periphery, the EP3 receptor is upregulated together with COX-2 by uterine artery ischemia-reperfusion ¹⁵⁴.

Owing to its well-known contribution to the ischemia-reperfusion injuries in peripheral organs, the EP3 receptor was believed to play a similar pathogenic role in the brain ^154,155, inspiring studies on the receptor in experimental brain ischemia (Table 4). ONO-AE-248, an EP3-selective agonist (Figure 5), when administered intracerebroventricularly before a 90-minute ischemia in mice, increased the infarct volume without affecting the animal body temperature, cerebral blood flow, or arterial blood pressure ¹⁵⁵. Interestingly, genetic deletion of the EP3 receptor in mice decreased the infarct volume and neurological dysfunction at 2 days after ischemia-reperfusion ^108,156. In line, intraperitoneal administration of another EP3-selective antagonist ONO-AE3-240 (Figure 5) attenuated the infarct size, brain swelling, and neurological dysfunction following transient MCAO in mice without showing any sexual dimorphism ⁸⁵. Given the less ischemic injury in mPGES-1 knock-out mice compared to the wild-type cohorts and the lack of benefit of ONO-AE3-240 in mPGES-1-deficient mice after transient MCAO, the detrimental effects mediated by mPGES-1 were thought to be at least partially attributed to the PGE₂ signaling via the EP3 receptor. Interestingly, the genetic deficiency in EP3 or post-stroke inhibition of the receptor by ONO-AE3-240 in mice reduced the neuronal apoptosis, blood-brain barrier disruption, and microglial activation, as well as maintained the tight junction proteins in the neurovascular units after transient focal forebrain ischemia ¹⁵⁷. Taken together, these results suggest that the EP3 receptor activation by PGE₂ contributes to ischemia-reperfusion injury via enhancing the apoptotic and inflammatory processes. As such, pharmacological inhibition of the EP3 receptor with small-molecule compounds might provide a promising strategy to relieve brain injury triggered by acute brain ischemia (Table 4).

7. Concluding remarks and perspectives

During the past two decades, mounting concerns over the cardiovascular and cerebrovascular incidents caused by long-term use of COX-2 inhibitor drugs have motivated tremendous efforts for preclinical studies to determine the downstream prostanoid receptors that mediate the deleterious effects of COX-2 in various inflammation-associated conditions. In this regard, the acute brain ischemia is a hot topic for preclinical research owing to enormous impact of the disease and the lack of delayed treatment. Recent marked advances in chemical biology and genetic approaches for gene manipulation provided valuable tools to better understand the physiological and pathological functions of prostanoids and their receptors, which are found far more complex in ischemic injury than we originally believed.

7.1. The devil is in the detail

As the currently known prostanoid receptors that are coupled to Gα_s, the DP1, EP2, EP4, and IP receptors mediate the excitatory signaling pathways via elevating the cytosol cAMP levels (Figure 1). Early studies consistently suggest that global deletion of these receptors exacerbated brain injury in various models of brain ischemia, whereas their activation by their cognate prostanoids or selective small-molecule agonists overall led to neuroprotective and other beneficial effects against ischemic injury (Table 2). However, using genetic strategies with more specificity recently revealed some discrepancy. Conditional deletion of the EP4 receptor in neurons increased the infarct volume 24 hours after MCAO ¹⁰⁹; however, the neuronal EP2 ablation has recently been revealed to reduce the infarct volume 2 days after MCAO ¹⁹, and the results were validated by pharmacological inhibition of the receptor via two independent small-molecule antagonists ^19,101. This incongruity can at least partially be explained by their downstream signaling pathways that might be involved in the regulation of ischemic injury, considering that the activation of Gα_s-coupled receptors can lead to multiple signaling pathways: G protein-dependent PKA and EPAC pathways; G protein-independent β-arrestin signaling (Figure 1) ¹⁴⁷. Intriguingly, systemic treatment with the EP4-selective agonist ONO-AE1-329 reversed the ischemic injury in the neuronal EP4 knockout mice ¹⁰⁹, indicating a yet-to-be-identified molecular mechanism following the EP4 receptor activation. Future studies are required to determine the downstream effectors of G_s-coupled receptors that specifically mediate neuroprotection or deleterious effects following acute brain ischemia (Figure 1). It will also be important to examine the effects of the condition deletion of DP1 and IP receptors in neurons, microglia, and endothelial cells on ischemic injury, and one would not be surprised if the cell-type specific ablations of these two receptors lead to divergent outcomes as they did in the cases of EP2 and EP4.

7.2. Three is better than one

The genetic deletion of the three G_q-coupled prostanoid receptors – EP1, FP, and TP consistently led to decreases in the infarct volume, neurological deficit, and inflammatory damage after various types of ischemic injuries without affecting cerebral blood flow, core body temperature, or arterial blood pressure (Table 3). These broad beneficial effects suggest that inhibition of these “contractile” receptors by small molecules with well-defined pharmacodynamic and pharmacokinetic profiles might represent a promising strategy to treat acute brain ischemia. However, it should also be noted that genetic ablation or pharmacological inhibition of a single of these G_q-coupled receptors cannot fully eliminate the ischemic injury (Table 3), indicating synergistic effects from these prostanoid receptors on postischemic inflammation and damage. Given that their natural ligands PGE₂, PGF_2α, and TXA₂ are all rapidly and robustly induced following acute brain ischemia, combined therapies utilizing small-molecule antagonists that concomitantly target these three receptors should be evaluated in the future for improved outcomes if not a full reverse of the ischemic injury.

7.3. Prostanoid synthases matter

As the inducible form of PGES, mPGES-1 is often co-expressed with COX-2 in neurons, endothelial cells, and microglia, and can be quickly elevated in the cerebral cortex and hippocampus by ischemic injury, contributing to the post-stroke cortical infarction and neurological dysfunction presumably through producing excessive PGE₂ from COX-2-derived PGH₂ (Figure 1) ^82,158. The COX-2 inhibition increases risks in cardiovascular toxicity mainly because it may also lead to nonspecific suppression of the syntheses for other types of prostanoids that might play essential roles in normal physiological conditions, e.g., PGI₂, a well-known important and effective vasodilator ⁶⁰. As such, pharmacological inhibition of mPGES-1 might represent an alternative strategy to treat acute brain ischemia without affecting these beneficial prostanoids ^159,160. The deficiency of the two PGD₂ synthases – H-PGDS and L-PGDS exacerbated the postischemic lesion in both short term and long term after hypoxic ischemia, and the infarct size was in inverse relation to the PGD₂ level in the brain (Table 2). Therefore, selective direct potentiation of H-PGDS and L-PGDS by small-molecule activators might provide a novel strategy to relieve the ischemic injury through elevating the PGD₂ level in the ischemic brain. Because PGD₂ mediates neuroprotection through the DP1 receptor, whereas the DP2 receptor has negligible implication in ischmic injury ⁷³, increasing in PGD₂ level would specifically lead to the DP1-mediate beneficail effects in the ischemic brain. As such, future studies should also be directed to determine the feasiblity targeting prostaglndin synthases, particulary the inducible mPGES-1 and H-PGDS (Figure 1), for new therapis to treat acute brain ischemia.

Acknowledgements

This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) grants R01NS100947 (J.J.) and R21NS109687 (J.J.).

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PERMALINK

Small molecules targeting cyclooxygenase/prostanoid cascade in experimental brain ischemia: Do they translate?

Jianxiong Jiang

Ying Yu

Abstract

1. Brain ischemia

2. Postischemic neuroinflammation

3. COX-1/2 as conventional targets

Figure 1.

3.1. Selective COX-2 inhibitors

Figure 2.

Table 1.

3.2. Nonselective COX inhibitors

4. Gs-coupled prostanoid receptors

4.1. DP1 receptor

Figure 3.

Table 2.

4.2. EP2 receptor

4.3. EP4 receptor

4.4. IP receptor

5. Gq-coupled prostanoid receptors

5.1. EP1 receptor

Table 3.

Figure 4.

5.2. FP receptor

5.3. TP receptor

6. Gi-coupled prostanoid receptors

6.1. DP2 receptor

Figure 5.

Table 4.

6.2. EP3 receptor

7. Concluding remarks and perspectives

7.1. The devil is in the detail

7.2. Three is better than one

7.3. Prostanoid synthases matter

Acknowledgements

REFERENCES

ACTIONS

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Links to NCBI Databases

4. G_s-coupled prostanoid receptors

5. G_q-coupled prostanoid receptors

6. G_i-coupled prostanoid receptors