Manifestation of renin angiotensin system modulation in traumatic brain injury

Abstract

Traumatic brain injury (TBI) alters brain function and is a crucial public health concern worldwide. TBI triggers the release of inflammatory mediators (cytokines) that aggravate cerebral damage, thereby affecting clinical prognosis. The renin angiotensin system (RAS) plays a critical role in TBI pathophysiology. RAS is widely expressed in many organs including the brain. Modulation of the RAS in the brain via angiotensin type 1 (AT₁) and type 2 (AT₂) receptor signaling affects many pathophysiological processes, including TBI. AT₁R is highly expressed in neurons and astrocytes. The upregulation of AT₁R mediates the effects of angiotensin II (ANG II) including release of proinflammatory cytokines, cell death, oxidative stress, and vasoconstriction. The AT₂R, mainly expressed in the fetal brain during development, is also related to cognitive function. Activation of this receptor pathway decreases neuroinflammation and oxidative stress and improves overall cell survival. Numerous studies have illustrated the therapeutic potential of inhibiting AT₁R and activating AT₂R for treatment of TBI with variable outcomes. In this review, we summarize studies that describe the role of brain RAS signaling, through AT1R and AT2R in TBI, and its modulation with pharmacological approaches.

1. Introduction

Traumatic brain injury (TBI) is a serious cause of injury-related death and disability in the United States, with approximately 2.8 million cases reported each year (Nelson et al. 2019; Taylor et al. 2017). TBI increases the long-term risk of developing neurodegenerative disorders such as Alzheimer's Disease (AD), Parkinson's disease (PD), chronic traumatic encephalopathy (CTE), and epilepsy (Acosta et al. 2015; Annegers and Coan 2000; Mayeux et al. 1995). Although technological and therapeutic advancements in preceding decades have improved, the quality and length of life for those suffering from TBIs, there are no existing FDA-approved pharmacological therapies to improve functional outcomes. TBI is associated with posttraumatic and progressive neuroinflammation, characterized by a complex cascade of inflammatory responses (Finnie 2013). TBI can range from mild to severe and can be classified into two stages, primary and secondary (Chiu et al. 2016; Nguyen et al. 2016). Primary damage is a direct result of the initial injury or insult (Prasetyo 2020). This disrupts cerebral blood flow (CBF) and metabolism, resulting in a shift to anaerobic glycolysis, lactic acid accumulation and increased blood brain barrier (BBB) permeability, and subsequently brain edema. Eventually, inefficient anaerobic metabolism leads to a failure of energy-dependent membrane ion pumps and reduction of ATP stores (Werner and Engelhard 2007). Secondary damage occurs after the primary insult. The release of cellular inflammatory mediators and pro-inflammatory factors, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin1 ß (IL-1ß), leads to neuroinflammation, followed by cell death, and ischemia (Prasetyo 2020; Werhane et al. 2017). This phase includes depolarization of neuronal membranes, resulting in an increased release of stimulatory neurotransmitters and an influx of sodium and calcium ions. Accumulation of calcium ions activates proteases and lipid peroxidase enzymes, which increase the intracellular concentrations of amino acids, fatty acids and free radicals. Finally, upregulation of caspases, Interleukin 1ß converting enzyme (ICE-like proteins), translocases, and endonucleases leads to alteration of biological membranes and inhibition of deoxyribonucleic acid (DNA) repair (Werner and Engelhard 2007). The renin angiotensin system (RAS) plays a fundamental role in controlling blood pressure, electrolyte balance, and metabolic hemostasis (Sigmund and Grobe 2020). Existence of RAS in the brain indicates that several brain functions are regulated through RAS receptors (Sigmund and Grobe 2020). The aim of this review is to describe the role of RAS alterations in TBI.

2. The Renin angiotensin system (RAS) in the brain

The brain RAS is involved in the regulation of a vast majority of cardiovascular functions, including blood pressure, cardiac output, vascular tone and peripheral circulation (Volpe et al. 2002). However, the presence of an autonomous RAS in the adult brain serves to underline its unique role in the central nervous system (Ganten et al. 1971; Jackson et al. 2018). Modulation of the brain RAS has been implicated in the pathogenesis of several brain disorders including TBI, multiple sclerosis (MS), Alzheimer’s disease (AD) and other dementias, Parkinson’s disease (PD) and stroke (Abiodun and Ola 2020). There are two main pathways for RAS signaling in the brain: the peripheral or forebrain pathway, that incorporates the circumventricular organs (CVOs), and the central pathway for local production of angiotensin, that links the medulla oblongata and the hypothalamus (Jackson et al. 2018). Brain RAS dysregulation was shown to be associated with neurodegeneration, neuroinflammation, and oxidative stress (Abiodun and Ola 2020).

2.1. Angiotensinogen and Renin

Angiotensinogen (AGT) is made in the liver and secreted into the circulatory system, is the precursor of other bioactive angiotensin peptides. This precursor protein is converted to angiotensin I (ANG I) by the renal enzyme renin, a rate limiting RAS enzyme synthesized in the kidneys and secreted into the blood (Fountain and Lappin 2020). Renin catalyzes the cleavage of AGT into ANG I, which is rapidly converted to ANG II by angiotensin converting enzyme (ACE) (Paz Ocaranza et al. 2020). In the brain, renin and AGT are synthesized in astrocytes (Intebi et al. 1990; Jackson et al. 2018; McKinley et al. 2003). Renin is secreted as the inactive molecule prorenin, which can be activated by proteolysis or non-catalytically by binding to a prorenin receptor (PRR). Hyperactivation of renin/prorenin signaling impairs cognitive function due to activation of the Ang II/AT₁R axis (Jackson et al. 2018).

2.2. Angiotensin-converting enzymes (ACE, ACE2)

In the canonical RAS pathway, ACE converts ANG I into ANG II, while in the non-canonical or counter-regulatory RAS axis, ACE2 cleaves ANG I and ANG II to yield the peptides ANG-(1–9) and ANG-(1–7) respectively (Paz Ocaranza et al. 2020). ACE is expressed in the central nervous system (CNS) and can be found at high concentrations in the subfornical organ, organum vasculosum laminae terminalis (OVLT), area postrema, and median eminence (McKinley et al. 2003). Upregulation of ACE leads to aggravated inflammation, cell death and impairs cognitive function by increased activation of AT₁R signaling (Jackson et al. 2018).

2.3. Angiotensin (Ang) II

Ang II is a vasoactive peptide and stimulates production of reactive oxygen species (ROS), neuroinflammation, neurodegeneration, and neurotoxicity via AT1R signaling. It has been implicated in several diseases including coronary artery disease (CAD), stroke, and hypertension (Forrester et al. 2018; Hirooka et al. 2006; Ito et al. 2001; Landmesser et al. 2002; Rueckschloss et al. 2002). In the brain, Ang II regulates cerebral blood flow (CBF), hormone release and neuroinflammation. It is also highly involved in processes relating to complex cognitive functions (Benicky et al. 2011; Jackson et al. 2018; Saavedra et al. 2011; Villapol et al. 2012).

2.4. Angiotensin II receptor type 1(AT₁R)

The angiotensin II receptor type 1 (AT₁R) is a G-protein coupled receptor (GPCR) that is localized to astrocytes, neurons, vascular endothelial cells, and oligodendrocytes (Jackson et al. 2018; Saavedra 2005). Although brain activation of the AT₁R is critical for various cerebrovascular functions, its hyperactivation results in endothelial dysfunction and excessive inflammation, with progression to disorders like hypertension, brain ischemia and cognitive impairment (Phillips and De Oliveira 2008; Saavedra 1992; Saavedra 2012; Saavedra et al. 2011). From a mechanistic standpoint, ANG II binding and activation of AT₁R signaling mediates endothelial dysfunction oxidative stress and inflammation by increasing transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The activation of NF-κB regulates production of pro-inflammatory cytokines, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Rodriguez-Perez et al. 2015; Villapol et al. 2015). A class of medications known as AT₁ receptor blockers (ARBs), approved for management of various cardiovascular conditions, were also shown to have positive effects in brain pathologies. These agents counteract many of the detrimental effects brought about by excessive AT1R stimulation and have shown potential benefits in conditions like stroke, vascular cognitive impairment and Alzheimer’s disease (Torika et al. 2018; Ozacmak et al. 2007; Villapol et al. 2012).

2.5. Angiotensin II receptor type 2 (AT2R)

The angiotensin II receptor type 2, AT₂R, is a GPCR found in neurons, astrocytes, oligodendrocytes and microglia (Dupont and Légat 2020; Jackson et al. 2018). It is expressed in parts of the brain related to cognition and behavior, including the cerebral cortex, basal ganglia, and the hippocampus, (Jackson et al. 2018; Umschweif et al. 2014a). In fetal brains, it is involved in neuronal differentiation and synaptogenesis (Timaru-Kast et al. 2012). AT₂R stimulation improves cognitive function and cell survival.It reduces oxidative stress and inflammation by multiple pathways including release of nitric oxide (NO) and bradykinin as well as activation of peroxisome proliferator-activated receptorγ (PPARγ), and the serine-threonine phosphatase PP2A (Jackson et al. 2018; Mogi and Horiuchi 2013; Umschweif et al. 2014a). AT₂R activation also improves neuronal regeneration and reduces vascular damage (Pelisch et al. 2010).

2.6. Angiotensin II receptor type 4 (AT₄R)

Although little information exists regarding the angiotensin II receptor type 4 (AT₄R), it is localized to astrocytes (Holownia and Braszko 2007; Jackson et al. 2018). AT₄R upregulation contributes to cognitive improvement, cell signal transmission, and anti-inflammation (Jackson et al. 2018; Wright and Harding 2004). Dysregulation of AT₄R signaling impairs cognitive function through synaptic dysfunction and neurotransmitter release (Jackson et al. 2018).

2.7. Non-canonical or counter-regulatory RAS axis: ACE-2 / Angiotensin (1–7) / Mas receptor

The non-canonical axis of brain RAS is composed of ACE-2 / Angiotensin (1–7) / Mas receptor, together with angiotensins (1–5), (1–12), (2–8; also known as ANG III), and (3–8; also known as ANG IV) and almandine shares all but its N-terminal amino acid with angiotensin (1,7) (Lu et al. 2013; Paz Ocaranza et al. 2020). ACE-2 cleaves Ang II to yield the angiotensin-related peptide Ang (1–7) which decreases inflammation and oxidative stress and enhances vasodilation (Jiang et al. 2012; Zhang et al. 2008; Zheng et al. 2014). Angiotensin (1–7) is present in many parts of the brain, including the hypothalamus, amygdala, and medulla oblongata (Chappell et al. 1989). Ang (1–7) binds to the Mas receptor (MasR), which initiates a novel signaling cascade resulting in reduced inflammation (Janatpour et al. 2019; Liu et al. 2016). The non-canonical RAS axis ACE-2/Angiotensin (1–7) / MasR is counter regulatory to the canonical Ang II/AT₁R axis. This axis therefore contributes to neuroprotection (Feng et al. 2010; Jiang et al. 2013; Mecca et al. 2011).

3. The brain RAS and TBI

Modulation of the RAS is associated with neuroprotection following TBI (Fouda et al. 2016), as shown schematically in Figure 1. The pathophysiology of TBI can be overcome by blocking of AT₁R, which serves to prevent vasoconstriction, apoptosis, and neuroinflammation, and activation of AT₂R signaling, which leads to vasodilatation, anti-inflammation, and neuro-regeneration (Li et al. 2005; Timaru-Kast et al. 2012; Vadhan and Speth 2020). Together, these reduce secondary ischemia, one of the detrimental post-TBI outcomes (Leker and Shohami 2002). AT₁R signaling has implications in neuroinflammation and microglial activation via several different pathways, including the extracellular signal-regulated kinase (ERK1/2) and mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) pathways (Timaru-Kast et al. 2019). Upregulation of AT₂R expression improves microcirculation, cognitive performance, motor function, and neuroprotection following TBI (Kiprianova et al. 1999; Umschweif et al. 2014a; Yaka et al. 2007). Inhibition of AT₁R using a low dose (0.1 mg/kg) of the ARB candesartan after insult in the controlled cortical impact (CCI) mouse model improved neurological function and decreased neutrophil granulocyte infiltration and microglial activation without affecting blood pressure (Timaru-Kast et al. 2019). Although blocking AT₁R using candesartan increased polarization of the anti-inflammatory neuroregenerative M₂a microglial phenotype, it did not affect the expression levels of the inducible (iNOS) and endothelial (eNOS) nitric oxide synthases following TBI (Timaru-Kast et al. 2019). M2 microglial expression of regenerative markers, chitinase-3-like protein 3 (Ym1) and arginase 1 (Arg1),were shown to vary with age (Timaru-Kast et al. 2019). Young mice release these markers sooner than aged mice after injury, and correlates with the delayed response of aged to injury (Timaru-Kast et al. 2019). A similar age-related difference in expression levels is observed for the mRNAs encoding AT₁R and AT₂R. Due to a gene duplication, mice express two subtypes of the AT₁R (AT₁a and AT₁b) that share 95% similarity at the amino acid level, while only a single gene exists in humans (Dasgupta and Zhang 2011; Timaru-Kast et al. 2019). When the expression of mRNAs encoding AT₁a, AT₁b, and AT₂R was examined in young (2 months old) and aged (21 months old) mice before TBI, no age-related changes in AT₁a mRNA levels were observed but AT₁b and AT₂R mRNA levels were higher in the naïve aged mice. One to three days after TBI, expression of AT₁a mRNA was unchanged in young mice, but decreased to nearly half level in injured aged mice. Young mice also exhibited an increase in AT₁b, and AT₂R mRNA levels at 24 h and returned to the naïve level by 72 h after TBI. In elderly mice, the levels of AT₁b, and AT₂R mRNAs did not change within 72 h of TBI. Moreover, candesartan did not significantly reduce the expression of proinflammatory cytokines such as IL-6, IL-1β, and TNF-α after injury in either age group. In aged and young mice mRNA expression of AT₁a was not affected 5 days after injury, although brain damage was reduced. Furthermore, candesartan reduced posttraumatic mortality in aged mice (Timaru-Kast et al. 2019). Candesartan treatment decreased intracranial pressure (ICP) and improved BBB permeability in male Wistar rats without impacting brain water content (Khaksari et al. 2018). Another study showed that while CCI resulted in microgliosis, neuronal and capillary loss in young mice, administration of the ANG I derivative peptide Ang (1–7) after TBI contributed to physiological and functional recovery by reducing activation of microglia and astrocytes, decreasing lesion volume, and increasing microvascular density (Janatpour et al. 2019). Although blood pressure was not monitored and only young mice were used, it is unlikely that Ang (1–7) would not have impacted blood pressure in normotensive animals, particularly in light of the observation that Ang (1–7) decreases the microglial inflammatory response (Janatpour et al. 2019). The limitation of this study was that they did not use aged mice, however, others have found that Ang (1–7) reduced microglial inflammatory response in senescence-accelerated mouse-prone 8 (SAMP8) 8-month-old mice, suggesting that some responses to Ang (1–7) treatment might be similar in young and aged mice (Jiang et al. 2018). Further research, in mice of different age groups, is needed to detail the effect of Ang (1–7) in TBI. With stretch injury, ANG II activates proinflammatory cytokines IL-1β, TNF-α, and caspase-3, resulting in BBB impairment and increased brain damage and initiates neuroinflammation and cell death by stimulating transforming growth factor beta 1 (TGF-β1), matrix metalloproteinases (MMPs), and oxidative stress (Abdul-Muneer et al. 2018). These were reversed by the AT₁R antagonist losartan. Administration of losartan (100 μg/mL) to cultured rat cortical neurons prior to stretch injury decreased the expression of oxidative and nitric oxide-mediated stress markers such as 4-hydroxynonenal (4HNE) and 3-nitrotyrosine (3NT) (Abdul-Muneer et al. 2018). Treatment of wild type (WT) and AT₁R knock out (KO) mice with the AT₁R blockers candesartan and telmisartan improved cognitive and motor function (Villapol et al. 2015). AT₁R KO mice are less prone to CCI injury than WT, suggesting that AT₁R activation has a deleterious effect post-TBI (Villapol et al. 2015). Both sartans reduced lesion volume and improved both short-term and long-term cognitive performance, but candesartan showed more promise with long-term treatment (Villapol et al. 2015). Although a low-dose of candesartan reduced brain injury, medium and high doses (0.5 –1 mg/kg) caused impairments in cerebral perfusion due to reductions in systolic blood pressure (Timaru-Kast et al. 2012 ).Candesartan treatment administered post- injury in mice reduced the expression of nitric oxide (NO) as well as inflammatory cytokines IL-1β, IL-6, and TNF-α (Timaru-Kast et al. 2012). Administration of candesartan post injury also reduced lesion volume and activated PPARγ, thereby reducing neuronal cell death and microglial activation, while the PPARγ antagonist T0070907 reduced this effect. Candesartan decreased expression of TGFβ1 and increased TGFβ3 in cortical and hippocampal astrocytes by unknown mechanisms, leading to reduced neuroinflammation (Villapol et al. 2012). PPARγ activation contributed to the neuroprotective effects of telmisartan and candesartan (Villapol et al. 2015). In a heat-acclimated (HA) mouse model of TBI, HA increased the expression of AT₂R, resulting in neuroprotection and neurogenesis (Umschweif et al. 2014a; Umschweif et al. 2014b). This was associated with increased levels of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase A (TrkA), tropomyosin receptor kinase B (TrkB), hypoxia-inducible factor 1a (HIF-1a), and nerve growth factor (NGF). Post-injury treatment with the AT₂R antagonist PD123319 inhibited these beneficial AT2R mediated pathways and offset neuroprotection. In another study, the AT₂R agonist CGP42112A improved cognitive function after injury and increased expression of BDNF, NGF, extracellular-regulated kinase 1/2 (ERK1/2), and protein kinase B (AKT), whereas PD123319 decreased expression of these neurotrophins (Umschweif et al. 2014a). CGP42112A also improved the migration pathway of neuronal progenitor cells (NPCs) in the subventricular zone (SVZ) after TBI (Umschweif et al. 2014a). Although effective in the pre-clinical setting, CGP42112A has several limitations that may preclude its use in the clinic. As a peptide that is rapidly degraded in vivo, it must be administered by continuous intracerebroventricular infusion (Umschweif et al. 2014a). Moreover, its high binding affinity but low potency makes it difficult to work with, as much higher doses are needed for receptor stimulation than for receptor occupancy. Such high doses can result in loss of AT₂R selectivity and can counteract its efficacy and result in adverse effects (Iwanami et al. 2015; Unger and Dahlöf 2010).

Figure 1. RAS modulation through AT₁R, AT₂R, and Angiotensin (1–7)/MasR affect the brain after TBI via different pathways.

A, RAS alteration following insult. B and C, AT₂R activation and AT₁R suppression contributes to neuro-regeneration and anti-inflammation by activating various mechanisms. D, Stimulation of Angiotensin (1–7) / MasR reduces microglial activation to an inflammatory phenotype and increases neuroprotection. E, Upregulation of AT₄R improves memory function but has not been implicated in TBI.

4. Conclusions

TBI is a critical public health concern and no effective medications are available. Preclinical studies show that RAS modulationis likely to play a significant role in the treatment of TBI. Local RAS in the brain is mediated by signaling through angiotensin II receptors type 1 and 2 (AT₁R and AT₂Rs). Suppressing AT₁R decreases secondary brain damage and neurological impairment following TBI, due to the reduction in neuroinflammation and microglial activation. AT₂R upregulation contributes to improved cognitive and motor function in rodent models of TBI. In the brain, AT₂R stimulation activates many protective pathways such as BDNF, PPARγ, Akt, and ERK1/2. Inhibition of AT₁R with ARBs such as candesartan and telmisartan is limited by their effects on systolic blood pressure. Low dose candesartan therapy shows promise in rodent models of TBI models. In conclusion, more studies using varying times and dosages will be required to assess the impact of AT₁R and AT₂R signaling in the brains of rodent TBI models.

Table 1.

Summary of experiments on RAS alteration in TBI

Study (Ref.)	Animal Model	Treatment	Dose and Duration	Result
Timaru-Kast, R (Timaru-Kast et al. 2019)	CCI - C57B16N Young, 2 months. Old, 21 months. male mice	Candesartan 10μg/ml	0.1 mg/kg/ SC/ 30 min after injury	Reduction in brain damage and neurological impairment through microglial response reduction and neutrophil granulocyte infiltration.
Janatpour, ZC (Janatpour et al. 2019)	CCI - C57BL/6NCr 8–10-week-old male mice	Ang (1–7) 10.0 mg/mL (micro-osmotic pump); 0.1mg/mL (injections)	1.0 mg/kg/day 2.5 mg/kg/day	Ang-(1–7) improved functional recovery and decreases glial activation.
Khaksari, M (Khaksari et al. 2018)	Wistar Male rats Diffuse TBI induced by Marmarou method	Candesartan	0.3 mg/kg IP, 30 min post-TBI	Reduction in brain edema, BBB disruption, oxidant activity, and ICP level using AT1R inhibition.
Abdul-Muneer, PM (Abdul-Muneer et al. 2018)	E17 Sprague-Dawley rat embryos Stretch injury	Losartan	(100 μg/mL) 30 min prior to the stretch injury	Losartan downregulated oxidative markers, neuroinflammation and neurodegeneration
Villapol, S (Villapol et al. 2015)	CCI - C57BL/6NCr 9-week-old male mice	Candesartan	0.1, 0.5 or 1 mg/kg IP (after injury)	Neuroprotective. Candesartan is better than telmisartan in chronic condition and low dose of candesartan does not affect blood pressure.
	C57BL/6J WT control mice AT1R knockout mice	Telmisartan	1 or 10 mg/kg once per day oral gavage
		PPARγ antagonist (T0070907)	2 mg/kg (after insult)
Umschweif, G (Umschweif et al. 2014b)	CHI - Sabra (Weight Drop Injury) 9–10-week-old male mice	AT2 antagonist PD123319	10 mg/kg/day for 3 days (after injury)	HA stimulated AT2R and increased neuroprotection and neurogenesis. AT2R inhibition reduced these effects.
Timaru-Kast, R (Timaru-Kast et al. 2012)	CCI - C57B16N male mice	Candesartan	low (0.1 mg/kg) med. (0.5 mg/kg) high (1 mg/kg,) SC (30 min after insult)	AT1R repression declined secondary brain damage and inflammation
Umschweif, G (Umschweif et al. 2014a)	CHI - Sabra 9–10-week-old mice	PD 123319	10 mg/kg/day	AT2R activation improved neuroprotection and neurogenesis, through different pathways.
		CGP42112A	0.1, 1.0, or 10.0 ng/kg/min, 3 days post-CHI
Villapol, S (Villapol et al. 2012)	CCI - C57BL/6 9-week-old male mice	Candesartan	1 mg/kg/day	Reduction in neuronal cell death and microglial activation
		PPARγ antagonist T0070907	1.5 mg/kg

Abbreviations

AD

Alzheimer's disease

ACE

Angiotensin converting enzyme

AGT

Angiotensinogen

AKT

Protein kinase B

ANG II

Angiotensin II

ARB

Angiotensin receptor blockers

ARG 1

Arginase 1

BBB

Blood brain barrier

BDNF

Brain-derived neurotrophic factor

CBF

Cerebral blood flow

CCI

Cortical Impact Injury

CAD

Coronary artery disease

CHI

Closed head injury

CNS

Central nervous system

CTE

Chronic traumatic encephalopathy

CVOs

Circumventricular organs

ERK1/2

Extracellular signal-regulated protein kinases 1 and 2

HA

Heat acclimation

HIF-la

Hypoxia-inducible factor - 1 alpha

ICE

Interleukin 1β converting enzyme

ICP

Intracranial pressure

iNOS

inducible nitric oxide synthase

IL-1β

Interleukin 1-β

IL-6

Interleukin-6

IP

Intraperitoneal

JAK/STAT

Janus Kinase and Signal Transducer and Activator of Transcription

JNKs

c-Jun N-terminal kinases

KO

Knock out

MAPK

Mitogen-activated protein kinase

MMP

Matrix Metalloproteinases

mRNA

Messenger ribonucleic acid

MS

Multiple sclerosis

NF-kB

Nuclear factor kappa-light-chain-enhancer of activated B cells

NGF

Nerve growth factor

NADPH

Nicotinamide adenine dinucleotide phosphate

NO

Nitric oxide

eNOS

Endothelial nitric oxide synthase

NPC

neural progenitor cell

OVLT

Organum vasculosum laminae terminalis

PD

Parkinson’s disease

PPARγ

Peroxisome proliferator-activated receptor gamma

PP2A

serine-threonine phosphatase

PRR

Prorenin receptor

RAS

Renin-angiotensin system

ROS

Reactive oxygen species

SAMP8

senescence-accelerated mouse-prone 8

SC

Subcutaneous

SVZ

Subventricular zone

TGFβ1

Transforming growth factor beta 1

TGFβ3

Transforming growth factor beta 3

TNF-α

Tumor necrosis factor alpha

TrkA

Tropomyosin receptor kinase A

TrkB

Tropomyosin receptor kinase B

VCI

Vascular cognitive impairment

WT

Wild type

Yml

Chitinase 3- like 3