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

Varun Gupta; Zein Eddin Bader; Aakriti; Anil Kumar

doi:10.1177/0972753120932475

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

Ann Neurosci. 2020 Jan;27(1):9-17. doi: 10.1177/0972753120932475. Epub 2020 Jul 15.

Authors

Varun Gupta¹, Zein Eddin Bader^{1

2}, Aakriti¹, Anil Kumar¹

Affiliations

¹ Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh, India.
² Palestine-Korea Biotechnology Centre, Palestine Polytechnic University, Hebron, Palestine.

Abstract

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.

Keywords: Ischemia; azelnidipine; citicoline; excitotoxicity; oxidative stress.