Neuroprotective potential of azilsartan against cerebral ischemic injury: Possible involvement of mitochondrial mechanisms

Gupta, Varun; Dhull, Dinesh K.; Joshi, Jyoti; Kaur, Sukhbir; Kumar, Anil

doi:10.1016/j.neuint.2019.104604

Cited by 32 publications

(45 citation statements)

References 48 publications

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“…Bilateral common carotid artery occlusion (BCCAO) was used to induce cerebral ischemia and reperfusion injury as previously reported. 19 , 20 Under the effect of ketamine (80 mg/Kg; i.p. ) and xylazine (10 mg/Kg; i.p. )…”

Section: Methodsmentioning

confidence: 99%

“…Gross locomotor function in the animals was assessed by using a digital actophotometer and represented as the number of total photo beams crossed in 5 min as previously reported. 20 , 21 …”

Section: Methodsmentioning

confidence: 99%

“…A rota rod apparatus (IMCORP, India) was used to assess motor coordination and grip performance as previously reported. 20 , 21 Fall off time was recorded in each 5 min trial.…”

Section: Methodsmentioning

confidence: 99%

“…Gross locomotor function in the animals was assessed by using a digital actophotometer and represented as the number of total photo beams crossed in 5 min as previously reported. 20,21 Rota Rod Performance A rota rod apparatus (IMCORP, India) was used to assess motor coordination and grip performance as previously reported. 20,21 Fall off time was recorded in each 5 min trial.…”

Section: Behavioral Assessments Locomotor Activitymentioning

confidence: 99%

“…Using a wooden bar of 2 cm width and an inclination of 60° angle from the ground, rats were scored on the basis of their performance when placed on the beam as a measure of gait abnormality and gross vestibular motor function, as reported earlier. 20,22,23 Biochemical Estimations…”

Section: Beam Balance Testmentioning

confidence: 99%

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Possible Pharmacodynamic Interaction of Azelnidipine with Citicoline Against Ischemic Brain Injury: Behavioral, Biochemical and Histological Alterations

Gupta

Bader

Aakriti

et al. 2020

Annals of Neurosciences

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Background: Currently, no drug has been approved for the management of postischemic neuronal damage. Existing studies show that calcium channel blockers have neuroprotective properties, while citicoline is involved in maintaining neuronal integrity. Purpose: This study was envisaged to investigate the effect of azelnidipine (novel calcium channel blocker) alone and in combination with citicoline (phosphatidyl-choline analogue) against ischemic brain damage in Wistar rats. Methods: Previously standardized bilateral common carotid artery occlusion model was used to induce cerebral ischemic injury in Wistar rats. Pretreatment with azelnidipine (1.5 mg/Kg and 3 mg/Kg; p.o.) or citicoline (250 mg/Kg; i.p.) was done every 24 h starting 7 days before the bilateral common carotid artery occlusion surgery. Pharmacological assessments (behavioral, biochemical, mitochondrial, molecular, and histological) were done after 48 h of the reperfusion period. Results: Azelnidipine and citicoline were found to protect the brain from progressive neuronal damage as seen by improved sensorimotor behavior (locomotion, rota rod, and beam balance performance) and reduced oxidative stress (decreased malondialdehyde (MDA), nitrite, increased glutathione (GSH), superoxide dismutase (SOD)). Impairment of mitochondrial enzyme system and increase in the infarct area were found to be arrested by individual treatments with azelnidipine and citicoline. These effects were further potentiated synergistically as the combination of citicoline and azelnidipine was found to decrease glutamate levels, caspase-3 activity and histological alterations as compared to their individual effects. Conclusion: Azelnidipine and citicoline synergistically decrease excitotoxic and oxidative damage against ischemic brain injury in Wistar rats and, therefore, propose a clinically relevant combination for the prevention of postischemic neuronal damage.

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Section: Methodsmentioning

confidence: 99%

“…Gross locomotor function in the animals was assessed by using a digital actophotometer and represented as the number of total photo beams crossed in 5 min as previously reported. 20 , 21 …”

Section: Methodsmentioning

confidence: 99%

“…A rota rod apparatus (IMCORP, India) was used to assess motor coordination and grip performance as previously reported. 20 , 21 Fall off time was recorded in each 5 min trial.…”

Section: Methodsmentioning

confidence: 99%

Section: Behavioral Assessments Locomotor Activitymentioning

confidence: 99%

Section: Beam Balance Testmentioning

confidence: 99%

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Possible Pharmacodynamic Interaction of Azelnidipine with Citicoline Against Ischemic Brain Injury: Behavioral, Biochemical and Histological Alterations

Gupta

Bader

Aakriti

et al. 2020

Annals of Neurosciences

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Cardioprotective effects of azilsartan compared with that of telmisartan on an in vivo model of myocardial ischemia‐reperfusion injury

Garg

Khan

Malhotra

et al. 2021

J Biochem & Molecular Tox

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Azilsartan is found to be more potent than other angiotensin receptor blockers in reducing blood pressure. However, its effect on the heart following myocardial infarction remains to be established. For the first time, we investigated the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonistic and cardioprotective properties of azilsartan. Computational modeling studies of interactions between azilsartan and PPAR-γ revealed azilsartan as an agonist of PPAR-γ and showed the mechanism of azilsartan in cardioprotection. Our study compared the cardioprotective potential of telmisartan to that of azilsartan in a murine model of myocardial ischemia-reperfusion injury by comparing their antioxidant, ant apoptotic, antiinflammatory, mitogen-activated protein kinase (MAPK)-modulating ability, and PPAR-γ agonistic activity. Male Wistar rats were grouped into four to receive vehicle (dimethyl sulfoxide [0.05%] 2 ml/kg) telmisartan (10 mg/kg p.o.), azilsartan (10 mg/kg p.o.) or azilsartan with specific PPAR-γ blocker, GW 9662 for 28 days.Ischemia was induced for 45 min on the 29th day followed by 60 min of reperfusion.Telmisartan and azilsartan pretreatment significantly nearly normalized cardiac parameters and preserved structural changes. Both drugs inhibited oxidative burst, inflammation, as well as cell death by modulating apoptotic protein expression along with reduction in 4′,6-diamidino-2-phenylindole/terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. An increment in pro-survival kinase ERK paralleled with a reduction in p38 and JNK was also revealed by MAPK pathway studies, after administration of these drugs. Interestingly, the aforementioned changes induced by both drugs were reversed by administration of the specific PPAR-γ antagonist, GW9662. However, we found that azilsartan upregulated PPAR-γ to a lesser extent as compared to telmisartan and the latter may be preferred in hypertensive patients at risk of myocardial infarction.

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The role of angiotensin II type 1 receptor pathway in cerebral ischemia‒reperfusion injury: Implications for the neuroprotective effect of ARBs

Huang,

Zhang

2024

Neuroprotection

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Cerebral ischemia–reperfusion (I/R) injury is a crucial factor that impacts the prognosis of recanalization therapy for acute ischemic stroke (AIS). It has been found that the brain renin–angiotensin system, especially the angiotensin II type 1 receptor (AT1R) pathway, plays a significant role in cerebral I/R injury. This pathway is involved in processes such as oxidative stress, neuroinflammation, apoptosis, and it affects cerebrovascular autoregulation and the maintenance of blood–brain barrier. AT1R blocker (ARB), widely used as an antihypertensive agent, has demonstrated stroke prevention capabilities in numerous prospective studies, independent of its antihypertensive characteristics. Studies focusing on neurological diseases like Alzheimer's disease, Parkinson's disease, and cognitive impairment have confirmed that ARBs exhibit neuroprotective effects and aid in improving neurological functions. Preclinical studies have shown that ARBs can reduce infarct volume and brain edema, inhibit multiple signaling pathways associated with I/R injury, restore energy levels in damaged brain regions, and rescue the penumbra by promoting neovascularization in cerebral I/R models. These findings suggest that ARBs have potential to become a novel category of neuroprotecting agents for clinical treatment of AIS. Therefore, this review primarily provides a theoretical foundation and practical evidence for the future clinical utilization of ARBs as neuroprotective agents following reperfusion therapy for AIS. It outlines the role of cerebral I/R injury through the AT1R pathway and highlights the research progress made on ARBs in I/R models.

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Neuroprotective potential of azilsartan against cerebral ischemic injury: Possible involvement of mitochondrial mechanisms

Cited by 32 publications

References 48 publications

Possible Pharmacodynamic Interaction of Azelnidipine with Citicoline Against Ischemic Brain Injury: Behavioral, Biochemical and Histological Alterations

Possible Pharmacodynamic Interaction of Azelnidipine with Citicoline Against Ischemic Brain Injury: Behavioral, Biochemical and Histological Alterations

Cardioprotective effects of azilsartan compared with that of telmisartan on an in vivo model of myocardial ischemia‐reperfusion injury

The role of angiotensin II type 1 receptor pathway in cerebral ischemia‒reperfusion injury: Implications for the neuroprotective effect of ARBs

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