Sigma-1 receptor signaling: A potential therapeutic approach for ischemic stroke

Abstract

Strokes constitute over 50% of all neurological diseases, standing as the foremost cause of physical and mental disability. Currently, there are no widely accepted gold standard treatments for ischemic strokes beyond intravenous thrombolysis and mechanical thrombectomy applied during the acute therapeutic window. Therefore, the need for novel treatments targeting crucial signaling mediators involved in ischemic stroke is of utmost importance. The sigma-1 receptor (S1R), a molecular chaperone located at mitochondria-associated endoplasmic reticulum membranes (MAM), has exhibited neuroprotective effects when modulated by synthetic and endogenous agents across various cerebrovascular diseases. In this review, we describe the emerging therapeutic role of S1R agonists and antagonists in regulating blood-brain barrier (BBB) dysfunction, neuroinflammation, and neurocognitive impairment following ischemic stroke.

Introduction

Ischemic stroke, characterized by the sudden loss of blood circulation to an area of the brain, leads to a cascade of neurological deficits and remains a leading cause of death and disability worldwide. ¹ The significance of stroke as a global health challenge cannot be overstated. It not only affects millions of individuals annually but also imposes substantial burdens on caregivers and healthcare systems, thus underscoring the paramount importance of enhancing ischemic stroke outcomes through the development of novel therapeutic approaches.^2,3 Ischemic stroke disrupts the blood-brain barrier (BBB), leading to compromised cerebral blood flow (CBF) regulation, oxidative stress, inflammation, and loss of neural connections.^{4 –8} This multifaceted assault underscores the complex cascade of events triggered by ischemic stroke, adding to the comprehensive challenges faced in its aftermath. Despite advancements in acute management and prevention strategies such as mechanical thrombectomy or intravenous recombinant tissue plasminogen activator, effective treatment options are limited, emphasizing the need to explore new therapeutic targets.^9,10

One promising target in this realm is the sigma-1 receptor (S1R), a chaperone protein that resides mainly at the mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) and is abundantly expressed in the neurons and glial cells of the central nervous system (CNS).^11,12 Notably, alterations in S1R expression have been associated with diverse neurological diseases such as Alzheimer’s disease, traumatic brain injury, cancer, and substance use disorders.^{13 –15} Studies have indicated that the modulation of S1R signaling through various ligands or microRNAs (miRNAs) may play a role in conferring cardioprotection in rodent models of myocardial infarction, heart failure, and cardiac hypertrophy.^{16 –18} Recent research also suggests S1R involvement in modulating neuroinflammation and associated processes following ischemic stroke. However, the current evidence on the therapeutic potential of S1R in neuroprotection and its involvement in crucial cellular mechanisms for ischemic stroke recovery is fragmented. Therefore, in this review, we aim to bridge this gap by discussing recent advancements in targeting S1R in ischemic stroke, with a specific focus on molecular mechanisms influenced by both agonists and antagonists of this receptor.

The structure and functions of the sigma-1 receptor

The human S1R is encoded by the SIGMAR1 gene located on chromosome 9p13, comprising four exons and three introns. ¹⁹ Previous research revealed that the S1R consists of 223 amino acids with a single transmembrane domain revealed by crystallographic studies, ²⁰ although the two-pass transmembrane model was widely accepted for a long time.^{12,21 –24} The first crystal structure of the full-length human S1R in conjunction with two chemically diverse ligands, PD144418 and 4-IBP, unveiled a trimeric configuration with a single transmembrane domain in each protomer. ²⁰ In this model, the N-terminus is oriented towards the ER lumen and the C-terminal domain of the protein, which features a cupin-like β-barrel containing the ligand-binding site at its center, faces the cytosolic side. In contrast to this model, recent findings from another study using an ascorbate peroxidase (APEX2)-based proximity-tagging propose that the orientation of the S1R places the majority of its structure within the ER lumen, leaving only a short N-terminus facing the cytosol.^20,25 Studies indicate that ligands mediate alterations in S1R oligomerization, with agonists and antagonists affecting oligomer dissociation and stabilization, respectively.^{26 –28} Currently S1R lacks a confirmed endogenous ligand; however, several potential candidates have been identified including N,N-dimethyltryptamine (DMT), neuro-active steroids such as progesterone (P4), and endogenous sphingolipids.^{29 –31}

The subcellular localization of S1R, as revealed by extensive electron-microscopic data, is highly dependent on the specific cell and organ types. Primarily located in the MAM, the S1R is also discernible in other cellular compartments, such as the plasma membrane, nuclear membrane, mitochondrial membrane, and nucleoplasmic reticulum. ³² Under physiological conditions, S1R associates with the chaperone-binding immunoglobulin protein (BiP) to form a complex at the MAM; however, upon the ligand stimulation or exposure to stress, the S1R dissociates from BiP and translocates from the MAM to other cellular compartments or interacts with type 3 inositol 1,4,5-trisphosphate receptor (IP3R3), thus ensuring proper Ca²⁺ influx into the mitochondria from the ER. ³³ To date, S1R involvement has been reported in multiple cellular processes, including protein folding, Ca²⁺ homeostasis, inflammatory response, autophagy, neurotransmission, mitochondrial dysfunction, ER stress, and reactive oxygen species (ROS) scavenging (Figure 1). Moreover, S1Rs are one of several putative molecular targets of methamphetamine and cocaine. ³⁴

Figure 1.

Roles of Sigma-1 receptor in regulating cellular functions. The Sigma-1 Receptor is implicated in multiple signaling pathways, including those related to autophagy, protein folding, oxidative stress, inflammation, neurotransmission, and apoptosis. Its precise role in these processes is still an active area of research. Figure created with BioRender.com.

The role of sigma-1 receptor activation in BBB protection after ischemic stroke

The disruption of the BBB impacts the onset of neurological impairment in ischemic stroke. Intact tight junctions (TJs) between brain endothelial cells protect the brain parenchyma from blood-borne agents and provide a significant obstacle to the entry of immune cells and exogenous compounds into the CNS.^35,36 Following an ischemic stroke, there is a reduction in BBB integrity, leading to heightened paracellular permeability, vasogenic edema, hemorrhagic transformation, and aggravated neuroinflammation.^37,38 Autophagy, a complex process crucial for removing misfolded or aggregated proteins and clearing damaged organelles, plays a significant role in ischemia-induced BBB breakdown, including the degradation of occludin. ³⁹ Recent studies have indicated that S1R activation provides beneficial effects by modulating autophagic flux in neurons and astrocytes in the context of Alzheimer’s disease, amyotrophic lateral sclerosis, and other neurological conditions.^{40 –42} Although autophagy has been observed in various neurovascular unit cell types (astrocytes, pericytes, microglia, neurons, and brain vascular endothelial cells) following ischemic stroke, the underlying mechanisms involving S1R, particularly in BBB protection, are not fully elucidated.^43,44 A recent study using a photothrombotic middle cerebral artery occlusion (MCAO) model of ischemic stroke demonstrated that the novel S1R agonist YZ001 enhances pericyte survival by inhibiting autophagy, thereby alleviating BBB damage and reducing infarct volume. ⁴⁵

Several studies indicated that activation of S1R can modulate cognitive functions and maintain BBB integrity post-stroke via a variety of mechanisms. For example, treatment with a highly selective S1R agonist PRE-084 has been shown to ameliorate BBB impairment after brain ischemia reperfusion in mice via restoring the expression of the BBB TJ proteins occludin, claudin-5, ZO-1, and VE-cadherin at 7 days after bilateral common carotid artery occlusion (BCCAO). ⁴⁶ Administration of PRE-084 also increased the expression of S1R in brain microvascular endothelial cells, ameliorated neuronal injury, and improved neurobehavioral performance in this study. It was also demonstrated that S1R activation in BBB-associated astrocytes induced by PRE-084 treatment increased glia-derived neurotrophic factor (GDNF) secretion in BCCAO model, resulting in attenuation of ischemic stroke-induced BBB disruption. ⁴⁶ This work suggested that GDNF derived from astrocytes binds to the GFRα1-RET complex on the plasma membrane of endothelial cells, facilitating the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. The activation of this pathway has been previously shown to play an essential role in ameliorating BBB damage through the regulation of TJ protein expression.^47,48 Finally, dexmedetomidine, an α2-receptor agonist pain medication, was shown to significantly upregulate S1R in mice after MCAO, ameliorating BBB hyperpermeability and impaired brain function. ⁴⁹ These neuroprotective effects were diminished when S1R was blocked, indicating that dexmedetomidine exerts its protective role through S1R-mediated signaling pathways. Mechanistically, dexmedetomidine alleviated endothelial monolayer hyperpermeability, dysregulated expression of occludin, and the release of inflammatory factors TNF-α, IL-6, and CCL2 in human brain microvascular endothelial cells, confirmed with in vitro assays using oxygen-glucose deprivation/reoxygenation (OGD/R) model. ⁴⁹ In summary, elucidating pivotal mediators and molecular pathways associated with both S1R inhibition and activation holds the potential for novel treatments aimed at protecting the BBB following ischemic stroke (Figure 2).

Figure 2.

Impact of Sigma-1 receptor modulation on ischemic stroke recovery. Schematic representation illustrating the effects of sigma-1 receptor antagonists (left) and agonist (right) on blood-brain barrier integrity, tissue damage, and functional recovery following ischemic stroke. Arrows indicate the direction of influence. Figure created with BioRender.com.

The role of sigma-1 receptor activation in ameliorating stroke-induced neuronal damage and functional recovery

Emerging findings suggest that S1R holds promise as a potential target for neuroprotection after ischemia; however, the underlying mechanisms remain poorly understood. An essential contributor to neuronal death following ischemic injury is the disturbance of intracellular Ca²⁺ homeostasis, a process that may be regulated through the activation of S1R. Indeed, treatment of cultured cortical neurons with non-selective sigma receptor agonists 1,3-di-o-tolyl-guanidine (DTG) and carbetapentane as well as the selective S1R agonists (+)-pentazocine and PRE-084 was shown to depress ischemia-evoked intracellular Ca²⁺ elevation in these cells. ⁵⁰ This effect was S1R-dependent and not attributable to non-specific targets like the N-methyl-D-aspartate (NMDA) receptors. Another study found that the DTG derivative, p-BrDPhG, showed significant efficacy in reducing Ca²⁺ overload via S1R when administered post-stroke. ⁵¹ Some in vitro and in vivo studies have collectively highlighted the neuroprotective potential of DMT, an endogenous compound known to activate the S1R. Specifically, the interaction of N,N-dimethyltryptamine (DMT) with S1R was found to enhance the survival of human cortical neurons derived from induced pluripotent stem cells, monocyte-derived macrophages, and dendritic cells under hypoxic conditions. ⁵² This effect, linked to the modulation of hypoxia-inducible factor 1 (HIF-1) activity, suggests a HIF-1-independent mechanism by which DMT promotes cell survival. Further supporting these findings, a study utilizing a rat model of global forebrain ischemia demonstrated that DMT, along with the selective S1R agonist PRE-084, effectively mitigated spreading depolarizations (SDs). ⁵³ These SDs denote waves of cortical depolarization associated with the disruption of ion homeostasis, brain silencing, and are indicative of a poorer functional outcome in ischemic stroke. Additionally, DMT administration was observed to reduce apoptotic and ferroptotic cell death and support astrocyte survival. A recent work showed that a novel S1R agonist, an aniline derivative compound (Comp-AD), can modulate ER stress responses following ischemic stroke, leading to improved functional recovery and reduced infarct volume in a mouse model of transient MCAO. ⁵⁴ Notably, this neuroprotection was associated with an upregulation of S1R and a reduction in ER stress-related proteins, such as p-PERK and p-IRE1α, in the peri-ischemic region.^55,56 Furthermore, the antitussive oxeladin, a selective S1R agonist, was shown to stimulate brain-derived neurotrophic factor (BDNF) secretion by neurons and improve stroke outcomes. ⁵⁷ When administered orally to rats post-stroke, oxeladin significantly improved neurological function and reduced infarct expansion in the subacute phase, without affecting astrogliosis or microgliosis. These studies collectively underscore the crucial role of S1R activation in regulating neuronal Ca²⁺ levels and mediating cellular stress response during ischemic events, highlighting the therapeutic potential of S1R agonists in neuroprotection against stroke-induced cellular damage.

S1R plays a crucial role in activating defense mechanisms against oxidative stress in various neurological disorders by modulating nuclear factor erythroid 2-related factor 2 (NRF2), a key transcription factor that regulates the expression of antioxidant response element-dependent genes. For example, S1R activation by PRE-084 was found to improve locomotor defects in a zebrafish model of amyotrophic lateral sclerosis by enhancing antioxidant protection through NRF2 signaling and boosting maximal mitochondrial capacity. ⁵⁸ Another study demonstrated that upregulation of S1R ameliorated sepsis-induced myocardial injury by promoting the nuclear translocation of NRF2, which activated the antioxidant enzyme HO1, thereby alleviating oxidative stress. ⁵⁹ Furthermore, several reports have suggested that S1R-mediated neuroprotection in retinal neurodegenerative diseases is directly linked to NRF2 signaling in supportive Muller glial cells, with evidence of co-localization of S1R-NRF2 in retinal photoreceptor cells.^{60 –63} Additionally, the enhanced NRF2 signaling observed in primary neuronal-glial cultures from S1R knockout mice may suggest that NRF2 upregulation in both neurons and astrocytes is essential for promoting cell survival and mitigating oxidative stress damage. ⁶⁴ S1R has been shown to be upregulated in penumbral neurons during the acute ischemic stage, potentially providing protection following ischemic brain injury. ⁶⁵ Recently, it has been proposed that the upregulated S1R levels observed in penumbral neurons during the acute phase of ischemic stroke under oxidative stress conditions may play a significant role in enhancing the nuclear production of antioxidant proteins through NRF2 signaling. ⁶⁶ While it has been established that NRF2 activation reduces BBB disruption and oxidative injury caused by cerebral ischemia/reperfusion,^67,68 further analyses are needed to determine whether this effect is mediated by S1R.

A recent study explored the impact of fluvoxamine, a selective serotonin reuptake inhibitor and S1R agonist, on a rat model of focal cerebral ischemia. ⁶⁹ Fluvoxamine significantly reduced infarct volume and ameliorated sensorimotor dysfunction, as indicated by the scores of forelimb and hindlimb placing tests. Importantly, these protective effects were blocked by the S1R antagonist NE-100. Dimemorfan, an antitussive and S1R agonist, has also demonstrated significant neuroprotective effects in a rat model of ischemic stroke. ⁷⁰ Administered either before ischemia or at the time of reperfusion, dimemorfan substantially reduced the size of the infarct zone. This reduction was associated with decreased expression of inflammatory markers and a reduction in oxidative/nitrosative stress, and apoptosis in the affected cortical areas. The treatment notably suppressed glutamate accumulation and its downstream pathological events. These investigations suggest that S1R activation may play major roles in cortical infarct volume reduction and mitigate neuroinflammatory responses in the aftermath of an ischemic stroke.

The S1R agonists TS-157 and SA4503 have shown promise in stroke recovery, particularly through mechanisms that promote neurite outgrowth and functional recovery. TS-157, an alkoxyisoxazole-based S1R agonist, initially demonstrated its safety and brain permeability. ⁷¹ In vitro, TS-157 has been shown to induce neurite outgrowth via S1R activation and ERK phosphorylation (pERK), highlighting its role in neuronal development. ⁷¹ Complementing these findings, SA4503, another S1R agonist, exhibited increased S1R expression in peri-infarct areas in rats and improved sensorimotor functions. ⁷² This was linked to elevated levels of synaptic proteins, neurabin and neurexin, crucial for neurite outgrowth and brain repair.^73,74 Additionally, a separate study on SA4503 demonstrated its direct effect on axonal growth in cultured naive hippocampal neurons, showing enhanced axonal length independent of glial cells and associated with the inhibition of voltage gated Ca²⁺ influx. ⁷⁵ In vivo studies revealed that both TS-157 and SA4503 significantly accelerated motor function recovery in rat models with transient MCAO.^71,72 These studies collectively affirm the significant role of S1R agonists like TS-157 and SA4503 in advancing stroke recovery, with their ability to not only foster neurite outgrowth and enhance synaptic protein levels, but also directly influence neuronal regeneration.

Recent studies have converged on the pivotal role of S1R in modulating ASIC1a channels, key players in mediating Ca²⁺ influx.^76,77 These investigations revealed that stimulation of S1R leads to a suppression of ASIC1a channel activity in cortical neurons, a finding that could have significant therapeutic implications. Activation of ASIC1a was shown to stimulate downstream Ca²⁺ influx pathways including NMDA and (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptors and voltage-gated Ca²⁺ channels which were then inhibited upon S1R activation. ⁷⁸ Immunohistochemical analyses demonstrated the colocalization of S1R, ASIC1a, and A-kinase anchoring peptide 150 (AKAP150) within cortical neurons, indicating a complex interplay at the cellular level. ⁷⁹ Further experiments underscored that the influence of S1R activation on ASIC1a is contingent on the activation of a PTX-sensitive G-protein and stimulation of AKAP150 bound calcineurin. This intricate signaling cascade mediated by S1R not only influences ASIC1a channel activity but also suggests a broader impact on neuronal function and pathology. These findings highlight the potential of targeting the S1R-ASIC1a axis as a novel neuroprotective strategy in ischemic stroke.

The neuroprotective properties of dextromethorphan (DM), a widely used antitussive, have gained significant attention in various CNS injury models, including ischemic stroke. ⁸⁰ DM’s effectiveness extends to addressing ischemic depolarizing events, such as periinfarct SDs, which exacerbate infarct size by increasing metabolic demand and causing mismatches in CBF and metabolism. ⁸¹ These protective actions are crucial in mitigating glutamate-induced neurotoxicity, a common pathological feature in focal and global ischemia, seizures, and traumatic brain injury.^{82 –84} A study utilizing distal MCAO in mice showed that the S1R agonists, DM and carbapentane, reduced the severity of hypoperfusions associated with SDs and anoxic depolarization, thus mitigating the expansion of severely hypoperfused cortex areas and improving overall CBF during acute focal ischemia. ⁸⁵ Despite its promising preclinical efficacy, clinical applications of DM are challenged by its rapid metabolism to dextrorphan, limiting its central bioavailability. ⁸⁶ However, this limitation can be addressed through co-administration with low-dose quinidine, which inhibits the first-pass elimination of DM, enhancing its systemic concentrations. ⁸⁰

The therapeutic agent ulinastatin (UTI) has been found to upregulate S1R and BiP in a study utilizing the MCAO model in rats, improving neurological function and grip strength. ⁸⁷ This suggests a neuroprotective effect of UTI via the modulation of S1R and BiP during ischemia/reperfusion injury. Another S1R agonist, cutamesine, was evaluated for safety and efficacy in ischemic stroke recovery in a phase 2 clinical trial. ⁸⁸ Administered to patients within 48 to 72 hours after stroke onset, the trial found cutamesine safe and well-tolerated. Although primary efficacy measures showed no significant improvement overall, a post hoc analysis revealed that patients with moderate-to-severe strokes improved more notably on higher doses as defined by the National Institutes of Health Stroke Scale. ⁸⁸

The S1R agonist PRE-084 has demonstrated remarkable neuroprotective and immune-modulatory capabilities in various contexts of stroke and related comorbid conditions. In an embolic stroke model, PRE-084 treatment led to significantly reduced infarct volumes and improved behavioral outcomes. ⁸⁹ This effect was accompanied by modulation of cytokine levels, marked by a reduction in pro-inflammatory cytokines (TNFα, IL-1α, IL-1β and IL-2) and an enhancement in anti-inflammatory cytokines (IL-4, IL-10 and CM-CSF). Furthermore, the role of PRE-084 extended to conditions commonly comorbid with stroke, such as type 2 diabetes mellitus (T2DM), a notable risk factor for stroke. ⁹⁰ A study examining PRE-084 in a T2DM mouse model revealed its potential to ameliorate white-matter damage and cognitive functions after stroke. ⁹¹ Specifically, a long-term (21 days) administration of PRE-084 post-stroke onset improved white-matter injury by increasing axon and myelin density, reducing demyelination, and enhancing expression of myelin-related proteins. These findings suggest that S1R activation could foster oligodendrogenesis and aid in functional recovery of white matter in stroke associated with T2DM.

Sigma-1 receptor antagonism: Implications for ischemic stroke pathophysiology and treatment

Intriguingly, the neuroprotective effects of S1R modulation are not limited to receptor activation alone. The use of S1RA (E-52862/MR309), a selective S1R antagonist, has been shown to significantly reduce cerebral infarct size and neurological deficits in mice subjected to permanent MCAO. ⁹² Interestingly, these neuroprotective effects were not observed in mice with a genetic deletion of S1R or those pre-treated with the S1R agonist PRE-084, suggesting a complex interplay between S1R agonism and antagonism in stroke pathology. The findings underscore the potential of S1RA as a therapeutic agent for ischemic stroke, especially given its ability to reduce important mediators of post-stroke injury such as MMP-9 expression and reactive astrogliosis surrounding the infarcted cortex.^{93 –95}

A study utilizing both in vitro experiments and rat models has demonstrated that the S1R antagonist haloperidol may offer neuroprotection from ischemic brain injury. ⁹⁶ Haloperidol was observed to prevent cell death related to oxidative stress at low concentrations in vitro, with its protective potency aligning with its affinity for the cloned S1R. This effect was consistent with outcomes from other butyrophenone derivatives and was replicated by a selective S1R antagonist, but not by an agonistic counterpart. In rat models, administering a modest acute dose of haloperidol led to a 50% reduction in the volume of ischemic lesions caused by transient MCAO, suggesting its potential for cerebral ischemic stroke protection.

On the other hand, clinical studies present a contrasting picture regarding the use of haloperidol. Several retrospective cohort studies indicate an increased risk of stroke and mortality in patients treated with haloperidol. A study assessing stroke risk in users of first-generation antipsychotics (FGAs) versus second-generation antipsychotics (SGAs), found significantly higher incident stroke rates in haloperidol users compared to SGA users, with a calibrated hazard ratio of 2.47 (95% CI, 1.14–5.48). ⁹⁷ In contrast, another study assessing stroke risk in non-elderly, non-demented patients using typical versus atypical antipsychotics reported no statistically significant increased risk of haloperidol after matching, with an adjusted hazard ratio of 1.31 (95% CI, 0.54–3.21), despite initial unmatched hazard ratios suggesting an increased risk. ⁹⁸ In elderly patients (aged ≥65 years), higher crude incidence rates for stroke were reported in haloperidol users compared to atypical antipsychotic users, with a calibrated hazard ratio of 1.45 (95% CI, 1.17–1.80). ⁹⁹ Furthermore, a study examining mortality risk in elderly stroke survivors using antipsychotics found that haloperidol users had a higher one-year all-cause mortality risk compared to quetiapine users, with an adjusted hazard ratio of 1.22 (95% CI. 1.18–1.27). ¹⁰⁰ The risk was dose-dependent, with higher doses of haloperidol posing greater risks. ¹⁰⁰ Another study comparing the risk of ischemic stroke between elderly patients taking risperidone and haloperidol, found a higher incidence rate for ischemic stroke in haloperidol users, with an adjusted hazard ratio of 2.02 (95% CI, 1.12–3.62). ¹⁰¹ These findings reveal a significant discrepancy between preclinical and clinical outcomes. While haloperidol demonstrates neuroprotective effects in animal models, its use in humans is linked to an increased risk of stroke and mortality, especially in elderly patients and at higher doses. In non-elderly patients, the evidence is mixed, with some studies indicating an increased risk and others not showing a statistically significant difference.

Complementing these findings, another study examined a range of novel antagonists with varying affinities for S1R and D2-like dopamine receptors. ¹⁰² The hippocampal-derived HT-22 cell line was used for an in vitro cytotoxicity assay, where two phenylacetamides, LS-127 and LS-137, were identified as potent neuroprotective agents selective for S1R. Further in vivo testing using a transient MCAO model of stroke in rats demonstrated that both LS-127 and LS-137 significantly attenuated infarct volume by approximately 50%. This study provided additional evidence that S1R selective antagonists can offer neuroprotection in cytotoxic conditions, potentially serving as pharmacotherapeutic agents to minimize neuronal death after ischemic stroke. Moreover, cannabidiol (CBD) has been studied for its effects on S1R antagonism. A study showed that CBD disrupts the regulatory association of S1R with the NR1 subunit of the NMDA receptors, similar to the effects of S1R antagonists. ¹⁰³ This mechanism contributes to the alleviation of NMDA receptor overactivity-related conditions, such as ischemic stroke. ¹⁰⁴ The findings that CBD’s positive effects were absent in S1R knockout mice and reduced by S1R agonists further underscore its antagonist-like activity toward S1R. ¹⁰³ This expands the potential array of molecular targets for CBD in the context of ischemic stroke, in addition to its previously demonstrated antioxidant and anti-inflammatory properties that are beneficial following cerebral ischemia through other molecular pathways. ¹⁰⁵

A study examining P4 demonstrated that its timing of administration is crucial for its neuroprotective effects against ischemia-induced neuronal death and cognitive deficits. ¹⁰⁶ Acute P4 neuroprotection, achieved by administration 1 h before MCAO, appeared to work by antagonizing S1R and thus inhibiting NMDA receptor-induced Ca²⁺ influx. On the other hand, delayed P4 neuroprotection, achieved with administration 48 h before MCAO, was mediated through the P4-receptor (P4R) and Src-ERK1/2 signaling pathway. This dual mechanism of action suggests the potential of P4 to serve as a versatile neuroprotective agent in ischemic stroke, offering both immediate and delayed protective effects. The importance of S1R in post-stroke recovery is further evident in the modulation of phagocytic activity in macrophages and microglia by S1R. It has been reported that depletion of S1R impaired macrophage/microglia efferocytosis, lead to worsened brain damage and neurological deficits in stroke models. ¹⁰⁷ Conversely, the adoptive transfer of intact S1R macrophages to recipient knockout mice facilitated the clearance of dead neurons, reduced infarct area, and improved long-term functional recovery. This novel mechanism of S1R-mediated efferocytosis, dependent on Rac1 activation in macrophages, underscores the pivotal role of the S1R in macrophage/microglia-mediated neuroprotection in ischemic stroke.

Conclusion

The body of research on S1R in ischemic stroke offers a promising avenue for therapeutic interventions. Emerging evidence suggests that both S1R activation and inhibition may play a pivotal role in BBB protection, reducing neuronal damage, and promoting functional recovery after ischemic stroke (Figure 2). Findings from in vitro human cell studies and animal models highlight the potential of S1R agonists (both selective and non-selective) to restore TJ protein expression and dysfunctional cross talk between brain endothelial cells and pericytes or astrocytes induced by ischemia. Results from studies examining S1R activation in the brain by multiple agonists demonstrate the promising therapeutic ability of these compounds to foster neuronal homeostasis in the context of ischemic stroke, reducing stroke volume size and accelerating functional recovery. The underlying mechanisms include a reduction in neuronal ER stress, oxidative stress, inflammation, apoptosis, and influences on synaptic strength and plasticity. The use of antagonists can also provide neuroprotection post-stroke, primarily by regulating microglia/macrophage activation, reactive astrogliosis, NMDA receptor-associated Ca²⁺ influx, and modulating interactions of S1R with multiple signaling molecules.

The studies examined in this review collectively emphasize the multifaceted neuroprotective potential of S1R agonists and antagonists in mitigating damage from ischemic stroke. However, it is important to note that most of the data supporting the potential of S1R as a therapeutic target comes from preclinical studies, with very limited data available from clinical trials in patients. The translation of these findings from animal models to human subjects remains a significant challenge, and more clinical studies are needed to establish the efficacy and safety of S1R-targeted therapies in patients with ischemic stroke. A more in-depth analysis of the complex interplay between S1R agonism and antagonism in stroke pathology needs to be conducted in the future to differentiate the effects and provide a more comprehensive explanation of overlapped effects.

Inclusion and diversity

One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location.

Data availability

All source data supporting the findings of this manuscript are available from the corresponding authors upon request.