Table III-.

Animal studies documenting the effects of ARBs/AT2R agonists on cognition

1.Inhibition of cognitive decline in mice fed a high-salt and cholesterol diet by the angiotensin receptor blocker, olmesartan [120].
Animals	8 wk old male C57BL6 fed a high-salt, high cholesterol diet (HSCD) vs normal diet (ND)
Model	Diet induced cognitive impairment
Treatment/Intervention	PO olmesartan (3 mg/kg/d) or vehicle administered from age 8 wks – age 12 wks
Results/Conclusion	HSCD in mice was associated with significant learning impairment and cognitive decline. Olmesartan inhibited HSCD induced cognitive decline and significantly improved cognitive function to a level similar to that of ND mice. It also reduced BP and superoxide anion production as well as improved serum cholesterol and glucose concentrations.

2.Amelioration of cognitive impairment in the type-2 diabetic mouse by the angiotensin II type-1 receptor blocker candesartan [95].
Animals	8 and 15 wk old male diabetic (KK-Ay) and WT (C57BL6) mice
Model	Diabetes induced cognitive impairment
Treatment/Intervention	Candesartan at 2 different “nonhypotensive” doses (0.001% or 0.005%) given in chow at libitum Short-term treatment Initiated at age 15 wks (continued for 5 wks) Long-term treatment Initiated at age 8 wks (continued for 7 wks)
Results/Conclusion	Long-term Candesartan treatment markedly improved cognitive function to a level similar to that of age-matched controls. The lower dose of Candesartan (0.001%) starting from 8 wks of age also significantly restored cognitive function at 7 wks post treatment. Short-term administration of Candesartan (0.005%) starting from 15 wks of age inhibited the inevitable cognitive decline seen in untreated KK-Ay mice, with no apparent change in BP

3.Valsartan lowers brain β-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease [111].
Animals	6 mo old WT and AD (Tg2576) mice
Model	Transgenic AD model of cognitive impairment
Treatment/Intervention	PO valsartan (10 mg/kg/d or 40 mg/kg/d), delivered in the drinking water for 5 mos
Results/Conclusion	Valsartan significantly promoted learning, acquisition and retention. It also significantly improved spatial, reference memory function during the probe test and resulted in a 2–3 fold reduction in soluble Aβ oligomers in the cerebral cortex, a reduction that coincided with their cognitive functional improvements. These beneficial effects were seen at doses ≤ those recommended for humans.

4.Telmisartan prevented cognitive decline partly due to PPAR- γ activation [124].
Animals	8 wk old adult male ddY mice given ICV Aβ 1–40
Model	Amyloid induced cognitive impairment
Treatment/Intervention	PO telmisartan or losartan (100 mg/kg/d) in drinking water (treatment duration 28d)
Results/Conclusion	Both telmisartan and losartan prevented Aβ 1–40 induced cognitive impairment. However the effect of losartan, which has a lower PPAR-ᵞ agonistic effect, was less than that of telmisartan. This may be partly due to PPAR-ᵞ activation (since co-treatment with to PPAR-ᵞ antagonist GW9662 partially inhibited this beneficial effect). Telmisartan also significantly reduced Aβ deposition, whereas losartan did not.

5.Angiotensin Receptor Blocker Prevented β-Amyloid–Induced Cognitive Impairment Associated With Recovery of Neurovascular Coupling [105].
Animals	8 wk old male WT, AD (APP23) and ICV Aβ injected mice
Model	Transgenic AD model and Amyloid induced cognitive impairment
Treatment/Intervention	Treatment started at age 8 wks and continued until age 13 wks. Experiment 1 APP23 and WT mice were treated with PO olmesartan (1 mg/kg/d) or vehicle. Experiment 2 Aβ ICV injected mice were treated with PO olmesartan (0.5 mg/kg/d, 1 mg/kg/d) or vehicle Experiments 3 and 4 Aβ ICV injected mice were treated with PO olmesartan (1 mg/kg/ d), hydralazine (30 mg/kg/d), nifedipine (10 mg/kg/d) or vehicle
Results/Conclusion	Olmesartan (0.5 and 1.0 mg/kg/d) significantly attenuated ICV Aβ induced cognitive dysfunction, independent of its Aβ or BP lowering effect. Hydralazine and nifedipine reduced BP like olmesartan but did not improve cognitive performance. In fact, they showed impairments comparable with that of vehicletreated animals. Olmesartan also significantly improved learning and memory in APP23 mice compared with vehicle treatment. It also significantly improved CBF, cerebrovascular reactivity and autoregulation and reduced ROS production to levels comparable with those of WT.

6.Candesartan improves memory decline in mice : Involvement of AT1 receptors in memory deficit induced by intracerebral streptozotocin [94].
Animals	8 wk old Swiss albino mice- ICV STZ (0.5 mg/kg/d) administered twice 48 h apart (days 1 and 3)
Model	STZ/Diabetes induced cognitive impairment
Treatment/Intervention	Early IP Candesartan sub-hypotensive doses (0.05 and 0.1 mg/kg/d) or vehicle days 1–14 Delayed IP Candesartan (0.1 mg/kg/d) started days 20–27
Results/Conclusion	Chronic candesartan treatment prevented STZ induced impairments in learning and memory. It significantly improved acquisition, retention and spatial memory. Such improvements were long lived when treatment began early but when treatment was delayed until substantial memory deficit was apparent, candesartan mediated improvement did not last. Candesartan also considerably reduced oxidative stress and free radical formation.

7.Telmisartan, a partial agonist of peroxisome proliferator-activated receptor γ , improves impairment of spatial memory and hippocampal apoptosis in rats treated with repeated cerebral ischemia [102].
Animals	250–300 g Male Wistar rats Day 1: vertebral arteries were electro-coagulated Day 2: Temporary BCCAO, using clips to interrupt CBF for 10 min followed reperfusion and repeated again 1 h later
Model	CCH induced cognitive impairment/VCI
Treatment/Intervention	PO telmisartan (0.3, 1, and 3mg/kg/d) was given for 7 d. On the 8th d, administration was performed either 1 h before (pre) occlusion and continued for another 6 d or administered 1 h (post) occlusion and continued for another 6 d (14 d treatment total)
Results/Conclusion	Chronic treatment with Telmisartan (pre- and post-ischemic) for 14 d significantly improved spatial memory and attenuated ischemia induced cognitive impairment in a dose-dependent manner. It also suppressed neuronal cell death (TUNELpositive cells) in the hippocampus after cerebral ischemia.

8.Nonhypotensive Dose of Telmisartan Attenuates Cognitive Impairment Partially Due to Peroxisome Proliferator-Activated Receptor- gamma Activation in Mice With Chronic Cerebral Hypoperfusion[99].
Animals	9 wk old male C57BL/6 mice- BCAS induced CCH
Model	CCH induced cognitive impairment/VCI
Treatment/Intervention	Low (non-hypotensive) dose: PO telmisartan (1 mg/kg/d) ± PO GW9662 (1 mg/kg/d) High (hypotensive) dose: PO telmisartan (10 mg/kg/d) ± PO GW9662 (1 mg/kg/d) or vehicle Treatment was initiated 7 days before BCAS surgery and continued until 30 days after BCAS
Results/Conclusion	Only the non-hypotensive dose of telmisartan ameliorated cognitive decline and improved spatial working memory in BCAS/CCH mice. It also significantly alleviated CCH induced microglial/astroglial activation, reduced cerebral mRNA expression of inflammatory cytokines (MCP-1 and TNF-α), reduced endothelial oxidative stress, oligodendrocyte loss and demyelinating changes in white matter. The protective effects against white matter lesions were, at least partially, mediated by PPAR-ɣ activation as they were partially offset by GW9662 cotreatment.

9.Blockade of AT1 Receptors Protects the Blood–Brain Barrier and Improves Cognition in Dahl SaltSensitive Hypertensive Rats [104].
Animals	5 wk old, male DSS/H rats (≈190 g)
Model	CCH induced cognitive impairment/VCI (hypertensive rats)
Treatment/Intervention	PO olmesartan at a nonhypotensive dose (1 mg/kg/d) for 4 weeks
Results/Conclusion	Olmesartan significantly ameliorated the cognitive deficits and markedly restored BBB function and expression of genes encoding occludin, claudin-5, collagen-IV, and MMP-9 without affecting BP in DSS/H rats.

10.Telmisartan protects against cognitive decline via up-regulation of brain-derived neurotrophic factor / tropomyosin-related kinase B in hippocampus of hypertensive rats [101].
Animals	12–14 wk old, SHRSPs
Model	CCH induced cognitive impairment/VCI (hypertensive rats)
Treatment/Intervention	Treated for 28 days with either: PO telmisartan (1 mg/kg/d) PO GW9662 (1 mg/kg/d)- PPAR-ɣ inhibitor PO telmisartan + PO GW9662 (1 mg/kg/d) PO telmisartan + TrkB antagonist ANA-12 (0.5 mg/kg/day) or PO vehicle
Results/Conclusion	Telmisartan treated SHRSPs showed significantly better spatial learning and reference memory than all other groups. Telmisartan protected against cognitive decline via up-regulation of BDNF/TrkB and partial activation of PPAR-ɣ in the hippocampus of SHRSPs, independent of BP-lowering.

11.Peroxisome Proliferator-Activated Receptor-gama Activation With Angiotensin II Type 1 Receptor Blockade Is Pivotal for the Prevention of Blood-Brain Barrier Impairment and Cognitive Decline in Type 2 Diabetic Mice [119].
Animals	15 wk old male KKAy (T2DM) and C57BL/6J mice
Model	Diabetes induced cognitive impairment
Treatment/Intervention	PO Telmisartan (1 mg/kg/d) or vehicle &/or PPARγ antagonist GW9662 (0.35 mg/kg/d) in drinking water for 7 wks
Results/Conclusion	KKAy mice treated with telmisartan had markedly improved cognitive function and preserved BBB integrity. Telmisartan also reduced swelling and MMP activity by its antioxidative and anti-inflammatory properties. This improvement was reduced with GW9662 Co-treatment.

12.Role of central angiotensin receptors in scopolamine-induced impairment in memory, cerebral blood flow, and cholinergic function [97].
Animals	12–15 wk old Swiss albino mice
Model	Anticholinergic (Scopolamine) induced cognitive impairment
Treatment/Intervention	PO Candesartan (0.05 and 0.1 mg/kg) was administered daily for 7 days and on the 7th day IP Scopolamine (3 mg/kg) was given
Results/Conclusion	Candesartan prevented scopolamine induced amnesia, restored CBF and ACh level, and decreased AChE activity and MDA level. However, the effect of the ARB candesartan on memory, CBF, ACh level, and oxidative stress was blunted by concomitant blockade of AT2R.The authors concluded that activation of AT1R appears to be involved in the scopolamine-induced amnesia and that AT2R contribute to the beneficial effects of candesartan.

13.Angiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders [93].
Animals	9 wk old male C57BL/6 mice
Model	CCI (TBI) induced injury
Treatment/Intervention	SQ Candesartan (1 mg/kg/d)
Results/Conclusion	Candesartan treatment significantly improved spatial learning and memory, 4 wks after CCI injury. It was associated with a significant reduction in lesion volume, neuronal cell death and activated microglial cells. PPARɣ inhibition reduced, but didn’t eliminate the beneficial effect of candesartan.

14.Candesartan prevents impairment of recall caused by repeated stress in rats [90].
Animals	2 mo old Male Wistar rats (weight 140–160 g)
Model	Chronic stress induced cognitive impairment
Treatment/Intervention	PO Candesartan cilexetil (0.1 mg/kg/d) or vehicle for 21d
Results/Conclusion	Candesartan pretreatment effectively prevented chronic stress induced cognitive impairment, it significantly improved recognition memory as well as retrieval and active recall in chronically stressed animals

15.Effect of angiotensin II on spatial memory, cerebral blood flow , cholinergic neurotransmission , and brain derived neurotrophic factor in rats [89].
Animals	8–9 wk old male SD rats given ICV AngII (0.25 and 0.5 μg/side)
Model	AngII induced cognitive impairment
Treatment/Intervention	ICV Candesartan (0.5 and 1.0 μg/side) 5 min before ICV Ang II injection. Donepezil (5 mg/kg, PO) 1 h before ICV Ang II
Results/Conclusion	Ang II caused spatial memory impairment (affected acquisition, consolidation, and recall) with a significant reduction in CBF and ACh. Candesartan and donepezil both prevented Ang II-induced memory impairment, restored CBF and ACh levels.

16.Telmisartan attenuates cognitive impairment caused by chronic stress in rats [118].
Animals	Male Wistar rats, ≈150 g
Model	Chronic stress induced cognitive impairment
Treatment/Intervention	PO Telmisartan (1 mg/kg/d) or vehicle for 21d
Results/Conclusion	Telmisartan effectively restored cognitive function and significantly abolished the deleterious effects of chronic stress on recognition and long-term memory.

17.Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer’s disease model [121].
Animals	~15 mo WT and AD (APP transgenic) mice
Model	Transgenic AD model of cognitive impairment
Treatment/Intervention	Prophylaxis - PO losartan (1 mg/kg/d) started at age ~2 month until age 8 months then increased to 10 mg/kg/d until 12mo (endpoint) Treatment - PO losartan (10 mg/kg/d) given for 3 mos, from age ~15mo until 18 mo (endpoint)
Results/Conclusion	Prophylaxis - Losartan completely prevented the onset of cognitive dysfunction, learning and memory deficits, in adult APP mice, despite unrelenting high levels of soluble Aβ species and Aβ plaque load Treatment - Losartan significantly improved memory acquisition, consolidation and recall performance, in aged APP mice without affecting Aβ accumulation/pathology.

18.The effects of valsartan on cognitive deficits induced by aluminum trichloride and D -galactose in mice [115].
Animals	2 mo old Swiss Albino Mice (25–30 g) given IP AlCl3 (10 mg/kg/day) and D-gal (150 mg/kg/day) for 90 days
Model	Experimentally induced sporadic dementia
Treatment/Intervention	IG Valsartan (20 mg/kg/day) for 60 days
Results/Conclusion	Valsartan prevented cognitive decline and improved learning and memory, restored cholinergic function and attenuated oxidative damage in AlCl3- and D-gal-treated mice.

19.Prophylactic angiotensin type 1 receptor antagonism confers neuroprotection in an aged rat model of postoperative cognitive dysfunction [96].
Animals	20 mo old male Sprague-Dawley rats
Model	Laporascopic surgery-induced cognitive decline in aged rats
Treatment/Intervention	IP candesartan (0.1 mg kg/d) for 14 days pre-treatment
Results/Conclusion	Chronic pre-surgical administration of low dose candesartan effectively prevented surgery-induced spatial learning and memory deficits. It also restored BBB function and reduced glial reactivity, NF-kB and neuroinflammation (IL-1β, TNF-α, and COX-2)

20.Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory [94]
Animals	Young (8–10 wk) and aged (35–38 wk) wistar rats given IP Scopolamine (1 mg/kg)
Model	Age and Anticholinergic (Scopolamine) induced cognitive impairment
Treatment/Intervention	PO ramipril (10 mg/kg/d 8d), IP perindopril (10 mg/kg/d 8d) IP losartan (20 mg/kg/d 8d), PO valsartan (20 mg/kg/d 8d), IP Piracetam (200 mg/kg/d 8d)
Results/Conclusion	Pretreatment with ACEIs and ARBs significantly improved the memory of aged rats and reversed scopolamine induced amnesia in both young and aged animals. ACEIs and ARBs were also superior to Piracetam (positive control) in improving cognition/memory.

21.Captopril and Valsartan May Improve Cognitive Function Through Potentiation of the Brain Antioxidant Defense System and Attenuation of Oxidative / Nitrosative Damage in STZ-Induced Dementia in Rat [109].
Animals	220–280g Adult male Wistar rats given ICV STZ (3mg/kg) at days 1&3.
Model	STZ/Diabetes induced cognitive impairment
Treatment/Intervention	PO captopril (50mg/kg/day) and valsartan (30mg/kg/day).
Results/Conclusion	Captopril and valsartan spared memory, reduced cognitive dysfunction and attenuated oxidative stress induced by STZ. These RAS modulators also seemed to potentiate superoxide dismutase (SOD) and catalase (CAT), antioxidant defense systems, in the brains of treated animals.

22.Angiotensin IV Receptors Mediate the Cognitive and Cerebrovascular Benefits of Losartan in a Mouse Model of Alzheimer’s Disease [122].
Animals	3-mo old male APP or WT mice
Model	Transgenic AD model of cognitive impairment
Treatment/Intervention	PO losartan (10 mg/kg/d) or vehicle for 1 mo then losartan animals were separated into: Cohort 1: ICV divalinal (AT4R blocker) or vehicle or in the final month of treatment
Results/Conclusion	Losartan-treated APP mice displayed significantly improved memory retrieval compared with untreated APP mice for all parameters. Losartan had no effect on memory performance in WT mice compared with WT controls. Divalinal countered losartan mediated benefits on spatial learning and memory. Losartan or divalinal administration does not alter Cortical and hippocampal Aβ pathology in App mice.

23.Chronic kidney disease accelerates cognitive impairment in a mouse model of Alzheimer’s disease , through angiotensin II [123].
Animals	9 mo old 5XFAD and wild-type mice fed an adenine-containing diet
Model	Transgenic AD model superimposed with CKD (accelerates cognitive impairment in AD mice)
Treatment/Intervention	PO Olmesartan (1 mg/kg/day) given once daily initiated 2 wks after the start of the adenine diet and continued for the remainder of the 10 wks
Results/Conclusion	Olmesartan significantly reduced the impairments in spatial learning and memory in addition to ameliorating BBB disruption and reducing hippocampal oxidative stress in 5XFAD with CKD.

24.Intranasal telmisartan ameliorates brain pathology in five familial Alzheimer ‘s disease mice [126].
Animals	2 month old 5XFAD mice
Model	Transgenic AD model of cognitive impairment
Treatment/Intervention	IN Telmisartan (1 mg/kg/day as 3 μL drop/nostril) or vehicle started at age 8 wks (continued for 5mos) 3 treatment groups as following: (i) Telmisartan -treated wild-type (WT) as the control group (ii) Telmisartan -treated 5XFAD mice (iii) vehicle-treated 5XFAD mice
Results/Conclusion	Telmisartan treatment improved hippocampus-dependent spatial acquisition and led to “goal-oriented performance” compared to vehicle treated animals. Telmisartan also ameliorated neuronal loss, amyloid burden and gliosis in the brains of 5XFAD mice, and caused a switch of microglia to the neuroprotective phenotype.

25.Candesartan , angiotensin II type 1 receptor blocker is able to relieve age- related cognitive impairment Pharmacological Reports Candesartan , angiotensin II type 1 receptor blocker is able to relieve age-related cognitive impairment [91].
Animals	Male young (2mo old) and Aged (24mo old) wistar rats
Model	Age associated cognitive decline
Treatment/Intervention	PO candesartan (0.1 mg kg/d) or vehicle for 21 days
Results/Conclusion	Candesartan significantly improved recognition memory in both young and aged animals. The degree of improvement in older rats was far more pronounced than in young rats. Candesartan significantly (P < 0.01) reversed age associated recall memory impairments and cognitive declines in aged rats.

26.Pleiotropic Benefits of the angiotensin receptor blocker candesartan in a mouse model of Alzheimer disease [92].
Animals:	3–4 mo old male and female C57BL6 APP mice
Model	Transgenic AD model of cognitive impairment
Treatment/Intervention	Cohort 1: SQ Candesartan (1 mg/kg/d) or vehicle for 2 mos Cohort 2: PO Candesartan (10 mg/kg/d) or vehicle for 5 mos
Results/Conclusion	Candesartan exerted potent anti-inflammatory effects, increased markers of neurogenesis & restored cerebrovascular reactivity, but unlike losartan had limited benefits on cognition. The authors suggest that PPAR-γ agonist properties are not needed for cognitive recovery with ARBs

27.Effects of enalapril and losartan alone and in combination with sodium valproate on seizures, memory, and cardiac changes in rats [116].
Animals	200–250g male wistar rats
Model	Sodium valproate induced cognitive impairment
Treatment/Intervention	IP enalapril (20 mg/kg/d), IP losartan (10 mg/kg/d) or vehicle
Results/Conclusion	Both ACEI (enalapril) and ARB (losartan) effectively prevented Sodium valproate induced cognitive impairment in seizure affected animals

28.A Comparative Study on the Memory-Enhancing Actions of Oral Renin-Angiotensin System Altering Drugs in Scopolamine-Treated Mice [113].
Animals	20–30g male Swiss mice given IP scopolamine
Model	Anticholinergic (scopolamine)-induced memory impairment
Treatment/Intervention	PO Captopril 25 mg/kg/d, Ramipril 4 mg/kg/d, Losartan 20 mg/kg/d, an hour before cognitive test
Results/Conclusion	All 3 RAS modulators showed a protective effect against scopolamine-induced memory impairment. These agents decreased the number of working and reference memory errors and spared short term and long term spatial memory.

29.Angiotensin Receptor Type 2 Activation Induces Neuroprotection and Neurogenesis After Traumatic Brain Injury [117].
Animals	9–10 wk old Mice
Model	TBI induced cognitive impairment
Treatment/Intervention	ICV infusion of CGP42112A (0.1, 1.0, or 10.0 ng/kg/min) or saline for 3d post-TBI
Results/Conclusion	CGP42112A attenuated TBI induced cognitive impairment (dose-dependent improvement in functional recovery& cognitive performance) accompanied by reduced lesion volume and induced neurogenesis

30.Direct stimulation of angiotensin II type 2 receptor enhances spatial memory [62].
Animals:	10–12 wk old male (WT, AT2R KO) C57BL/6 mice ICV Aβ (for 4 wks)
Model	Amyloid induced cognitive impairment
Treatment/Intervention	IP C21 (1, 3 or 10 mg/kg/d) for a duration of 2 wks administered with or without the bradykinin B2 receptor antagonist icatibant (70 mg/kg/d), IP infused via implanted osmotic mini-pump
Results/Conclusion	Treatment with C21 significantly enhanced cognitive function (spatial learning and memory) in WT, but not AT2RKO mice. This cognitive enhancement was attenuated by coadministration of icatibant. C21 also increased CBF in WT, but not AT2RKO mice. This increase was not observed in the icatibant co-treated group.

31.Direct angiotensin II type 2 receptor stimulation by compound 21 prevents vascular dementia [65].
Animals	10 wk old male C57BL6 (WT/ AT2KO) mice- BCAS induced CCH
Model	CCH induced cognitive impairment/VCI
Treatment/Intervention	IP C21 (0.01 mg/kg/d), vehicle or azilsartan (0.1 mg/kg/day) with or without PD123319 starting 1 wk before BCAS continued 6 wks
Results/Conclusion	C21and azilsartan treatments prevented BCAS induced cognitive impairment. These positive effects were attenuated with PD123319 and AT2KO in azilsartan treated and abolished in C21 treated animals. C21 also preserved CBF and reduced inflammatory cytokine expression with BCAS. The authors concluded that direct AT2R stimulation by C21 attenuates ischemic vascular dementia induced by hypoperfusion at least in part by an increase in CBF and reduced inflammation

32.RAS modulation prevents progressive cognitive impairment after experimental stroke: a randomized, blinded preclinical trial [60].
Animals	4 mo old male SHRs, t-MCAO induced cognitive impairment
Model	Post Stroke cognitive impairment (PSCI) in hypertensive animals
Treatment/Intervention	4 Groups: Sham, t-MCAO, IP C21(0.03 mg/kg/d 30d) t-MCAO, IP C21(0.03 mg/kg/d 7d) then IP candesartan (0.3 mg/kg/d) for the remainder of the study t-MCAO, IP saline 7d then IP candesartan (0.3 mg/ kg/d) for the remainder of the study
Results/Conclusion	Treatment with RAS modulators effectively preserved cognitive function, reduced cytotoxicity, and prevented chronic-reactive microgliosis in SHRs, poststroke. These protective effects were apparent even when treatment was delayed up to 7 days post-stroke and were independent of blood pressure and β-amyloid accumulation.

33.Angotensin receptor (AT2R) agonist C21 prevents cognitive decline after permanent stroke in aged animals-A randomized double- blind pre-clinical study [36].
Animals	14-mo old Male Wistar rats subjected to tandem d-MCAO
Model	Post Stroke cognitive impairment (PSCI) in aged animals
Treatment/Intervention	PO C21 (0.12 mg/kg/d 30d) or vehicle started 24h post ischemic insult and continued for 30d
Results/Conclusion	AT2R agonist, C21, effectively prevented development of PSCI and reduced cortical accumulation of Aβ1–42 in aged animals post-stroke

34.Delayed Administration of Angiotensin II Type 2 Receptor (AT2R) Agonist Compound 21 Prevents the Development of Post-stroke Cognitive Impairment in Diabetes Through the Modulation of Microglia Polarization [127].
Animals	12 wk old male Wistars +/− diabetes, subjected to t-MCAO
Model	Post Stroke cognitive impairment (PSCI) in diabetic animals
Treatment/Intervention	PO C21 (0.12 mg/kg/d) or vehicle started 3d post stroke for 8wks
Results/Conclusion	C21 resulted in a net cognitive improvement from baseline- 8 wks post- stroke in diabetic animals which may have been through modulation of the M1:M2 ratio.

35.Possible synergistic effect of direct angiotensin II type 2 receptor stimulation by compound 21 with memantine on prevention of cognitive decline in type 2 diabetic mice [129]
Animals	10-wk old KKAy mice
Model	Diabetes induced cognitive impairment
Treatment/Intervention	Four groups: (1) Control, (2) IP C21(10 μg/ kg/day), (3) PO Memantine (20mg/kg/day),(4) IP C21(10 μg/ kg/day) + PO Memantine (20mg/kg/day) for 4 wks
Results/Conclusion	Memantine and C21 had a synergistic beneficial effect in preventing diabetesinduced cognitive impairment. This synergistic effect may have occured through an increase in CBF and or ACh level.

36.Role of angiotensin system modulation on progression of cognitive impairment and brain MRI changes in aged hypertensive animals – A randomized double- blind pre-clinical study [34].
Animals	14-mo old male SHRs with UCCAO induced CCH, (aged SHRs)
Model	CCH induced cognitive impairment /VCI in aged hypertensive animals
Treatment/Intervention	PO candesartan (1 mg/kg/d 8wks), PO C21 (0.12 mg/kg/d 8wks) or vehicle started 24h post ischemic insult
Results/Conclusion	RAS modulators, Candesartan & C21 preserved cognitive function & prevented progression of VCI but only candesartan prevented loss of brain volume in aged hypertensive animals with chronic cerebral hypoperfusion.