Recent Advances in the Endogenous Brain Renin-Angiotensin System and Drugs Acting on It

Table 1

Summary of preclinical as well as clinical research work carried using angiotensin enzyme and receptor inhibitors.

Sr. no	Drug	Disease	Disease model used	Results obtained	References
1	Telmisartan	Alzheimer’s Disease (AD); Neuroinflammation	Lipopolysaccharide- (LPS-) induced microglia 5XFAD mouse model	↓ amyloidosis (Aβ (1-40), amyloid plaques); ↑ cerebral blood flow; ↓ neuroinflammation (↓AβO-IL-1β, TNF-α, and NF-κb expression); ↓ microgliosis, ↓ astrogliosis	[97–99]
		Parkinson’s disease (PD)	Rotenone-induced PD	↓ ER stress-mediated neuronal apoptosis	[100]
			MPTP-induced PD; Catalepsy test	Neuroprotection against dopamine cell death (potent PPAR-γ activator); ↑ astroglial functions; Restore dopaminergic function	[76, 101, 102]
		Cognitive impairment and vascular dementia	Chronic cerebral hypoperfusion, MWM	↑ spatial memory and learning; ↓ neuronal loss; ↑ PPARϒ	[103, 104]
		Acute and chronic stress	PAT, ORT, OFT, EPM, FST	HPA axis deactivation; Upregulation of brain-derived neurotrophic factor (BDNF) gene expression	[105, 106]
		Diabetes-induced cognitive decline and depression	FST	Insulin sensitizer; ↓ proinflammatory mediators; Ameliorates the HPA axis function	[70, 107, 108]
		Cerebral ischemia-induced impairment of spatial memory	Eight-arm radial maze	Anti-inflammatory—partial PPARγ agonist	[109]
		Traumatic brain injury (TBI)	Cortical impact injury in mice brain	Reduction in lesion volume and conservation of the hippocampus	[110]
		Epilepsy	Maximal electroshock and PTZ-induced seizure in mice	Antiepileptic	[88, 111, 112]
		PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes); AD (ongoing); NCT02085265; NCT02471833	Patients—20332 (aged 67) (acute mild ischemic stroke and mildly elevated BP)	1360 patients appeared safe	[113, 114]
2	Losartan	AD and cognitive impairment	Aβ peptide oligomerization assay, T maze, MWM, PAT, NOR, FST, EPM, MBT, Hebb-Williams maze (rectangular maze), amyloid-β precursor protein- (APP J20) induced AD	↓ neuroinflammation (↓ astrogliosis, ↓ microgliosis); ↓ plaque number and tau phosphorylation; ↓ oxidative stress and inflammation; ↑ cognition and memory, neurogenesis	[115–122]
		Parkinson’s disease (PD)	MPTP- and 6-OHDA-induced PD in C57BL/6 mice (α-syn-based model)	Protect dopaminergic neurons against MPTP toxicity	[123]
		Learning and memory	OFT, EPM, SPT	Improve cognition function, ↓ oxidative stress and inflammation	[124, 125]
		Epilepsy; Comorbid (hypertension and epilepsy); Cognitive impairment associated with epilepsy	Lithium pilocarpine-induced epilepsy; Neuronal damage in the hippocampus; Wire hang test; Sticky paper test	Attenuate inflammation and oxidative stress, and exhibit neuroprotective effects; Antiepileptic (neuroprotection selectively in the CA1 area of the hippocampus)	[126–128]
			Visual placing response; Lithium pilocarpine-induced status epilepticus in rats	↓ microglial-mediated inflammation; Attenuation of hippocampal neuronal loss	[129]
		Depression and anxiety	OFT; EPM	Antidepressant and anxiolytic	[117, 130–132]
		TBI (traumatic brain injury)	Controlled cortical impact injury; Rotarod test	↓ neuronal apoptosis and ER stress, enhance BBB integrity, PPAR-gamma activation; ↑ cognitive/motor, ↓ cerebral blood flow	[133, 134]
		Neurocognitive alteration affecting long-term memory	Amphetamine-induced neurocognitive alteration in rats	Antipsychotic (↓ KYNA production)	[135]
		RADAR; AD (ongoing); NCT02913664	Patients—228 (55 years with mild to moderate AD)	Assessment of rate of whole-brain atrophy, memory, cognitive function	[136]
3	Valsartan	AD	Tg 2576 mouse model	↓ amyloidosis (↓ plaque load, Aβ oligomerization); Improves spatial learning	[98, 115, 137]
			APP/PS1 transgenic mouse model (intranasal)	↓ Aβ-inflammatory effects	[121]
		Cognitive impairment and amnesia	Icv STZ-induced cognitive impairment	Hippocampal neurogenesis; Improves spatial learning; ↓ acetylcholinesterase activity (increased acetylcholine)	[138]
		Depression and anxiety	CUMS, FST, OFT, NSF; SPT	Antidepressant (↑ BDNF protein, ↓ noradrenaline and cortisone)	[139]
4	Candesartan	AD and cognitive impairment	LPS-induced microglia activation (5FXAD mouse model); Tg 2576 mouse model; MWM	Anti-inflammatory, neuroprotective; ↓ Aβ oligomerization; ↓ neuroinflammation (↓ astrogliosis, ↓ microgliosis); Improved cognitive function (spatial memory, ↑ neurogenesis); Improved dementia	[99, 140, 141]
		PD	6-OHDA-induced PD in rats	Protection of dopaminergic neurons; Inhibition of the synergetic action between Ang II and 6-OHDA	[142]
			Rotenone-induced PD in rats	Reduced neuronal loss and restored motor functioning.	[143]
			MPTP-induced PD in mice	PPAR-γ activation (partial agonism); Anti-inflammatory	[76]
		Cognitive impairment	Long-term repeated amphetamine administration	Neurorestorative effect; ↑ expression of BDNF and TrkB	[135]
		Stress	Tight plastic tubes stress; Inhibitory avoidance (IA) and object recognition (OR)	↓ stress; ↑ memory	[144]
		TBI	Cortical impact injury in mice brain; Hypertensive rat stroke model	↓ lesion volume and conservation of the hippocampus; Upregulation of iNOS	[110, 145]
		Cognitive impairment postischemic stroke	NOR, SAP, PAT	Neurorestorative effect; ↓ nonfatal stroke	[146–148]
		Depression and anxiety	LPS-induced brain injury in rats; EPM	Anxiolytic and antidepressant	[131]
		CALIBREX (NCT01984164)	Participants—176 (55 years or older) with mild cognitive impairment (MCI) and hypertension	Lower risk of dementia and AD	[149]
		SCOPE; AD (ongoing); NCT02646982	Participants—4937 (70 to 89 years), evaluation of cognitive state by specific tests with mild-to-moderate hypertension	Hampered initiated cognitive decline	[150, 151]
5	Olmesartan	AD and cognition	MWM	Anti-inflammatory and antioxidative; Prevent β-amyloid-induced vascular dysregulation (↓ ROS, MDA level); Improved Aβ-induced cognitive dysfunction	[98, 152]
		Cognitive impairment	PAT	↓ microvessel leakage (hippocampus and corpus callosum); Restored cognitive decline	[153]
		Epilepsy	MES- and PTZ-induced seizure in mice	Antiepileptic	[88]
6	Irbesartan	Schizophrenia	In vitro model using brain cortex slices	↓ KYNA production and KAT II activity in the rat brain cortex	[154]
		Depression	CUMS, FST, SPF	Antidepressant	[155]
7	Eprosartan	Early AD	C57bl/6j and AβPP/PS1/Alzheimer's disease mice; Ang II infusion in the brain of AD mice	Improved cerebral blood flow and connectivity	[156]
		OSCAR	Patients—25745 (aged 50 yrs) with cognitive decline	Improvement of cognitive function	[157, 158]
8	Perindopril	AD and cognitive impairment	Icv administration of amyloid-β (Aβ)1-40, induced AD mice; Y-maze test	↓ oxidative stress; Suppression of microglia/astrocyte activation	[82]
		PD	MPTP mouse model	Neuroprotection (inhibition of dopamine cell loss)	[159, 160]
		Vascular cognitive impairment	Chronic cerebral hypoperfusion in rats	Modulate BDNF; Protect against neuroinflammation and oxidonitrosative stress	[161, 162]
		PROGRESS (Perindopril Protection against Recurrent Stroke Studies)	Participants—6105 (previous stroke or transient ischemic attack); Evaluation of cognitive state by specific tests	Improved cognition; Reduced risk of AD	[163–166]
		CANTAB (Cambridge Neuropsychological Test Automated Battery)	Measurement of visuospatial, attention, and verbal memory, problem solving, learning, and reasoning	Improved cognitive function	[167, 168]
9	Captopril	AD	LPS-induced microglia activation; T-maze test	↓ amyloidogenic processing; Antioxidant (↓ oxidative/nitrosative stress); ↓ inflammation, ↓ Aβ plaque accumulation	[169]; [170]
		PD	MPTP-induced PD model	Protect dopamine cell from degeneration	[78, 171]
		Epilepsy	PTZ-induced seizures	↓ seizures and protection against postseizure neuronal injury in the hippocampus	[172]
		Depression	CUMS, chronic social defeat stress model	Antidepressant (BK-dependent activation of mTORC1)	[173]
10	Lisinopril	AD	STZ-induced dementia	PPAR-γ modulation	[174]
		Tardive dyskinesia	Haloperidol-induced stereotypic behavior	↓ oxidative damage and neuroinflammation	[175]
11	Trandolapril	Huntington’s disease	3-Nitropropionic acid-induced Huntington’s disease; EPM, MWM, narrow beam test, locomotor activity	Neuroprotection	[176]
12	Zofenopril	Cerebral ischemia	Bilateral coronary artery occlusion in rats. Biochemical analysis for the level of NO, SOD, and TAC	↓ TOS and MDA levels	[177]
		Epilepsy	Auditory stimulation model	Antiepileptic activity	[178]
13	Fosinopril	Amnesia	Scopolamine amnesia in rats, SPA, EPM, MWM	Antiamnesic activity	[179]
		Epilepsy	Audiogenic seizures	Antiepileptic	[178]
14	Ramipril	Cognitive impairment	Radiation-induced cognitive impairment, NOR	Potentiated ACE2/Ang-MasR axis; ↓ microglial activation	[180]
		HOPE; Stroke	Women with Vascular/Diabetic disorder—2480 (age—55 yrs and more) with vascular disease or diabetes	↓ incidence of fatal and nonfatal stroke	[181]
15	Aliskiren	Ischemic stroke	Middle cerebral artery occlusion in mice	Neuroprotection, reduced infarct volume, and brain edema formation	[182] (Panahpour, 2019 #5)
		Epilepsy	MES-induced seizures in mice	Enhances the anticonvulsant effect of AEDs in mice	[183] (Panahpour, 2019 #5)
16	EMA 300, EMA 200 molecule 20	Pain	Unilateral chronic constriction injury of the sciatic nerve	Inhibit P38 and p42/p44 MAPK (inhibition of metabolism of bradykinin and substance P)	[184]
	EMA 401	EMPHENE trial	Patients with postherpetic neuralgia	No beneficialeffects of AT2R are observed in pain	[185]

Abbreviations: AD: Alzheimer’s disease; PD: Parkinson’s disease; MPTP: 1-methyl-4-phenyl-1;2;3;6-tetrahydropyridine; PAT: passive avoidance test; ORT: object recognition test; OFT: open field test; EPM: elevated plus maze; FST: forced swim test; MES: maximal electroshock; MWM: Morris water maze; CUMS: chronic unpredictable model of stress; PTZ: pentylenetetrazol; NOR: novel object recognition; SPT: sucrose preference test; 6-OHDA: 6-hydroxyl dopamine.