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

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.

Potential protective effects of Azelnidipine against cerebral ischemia-reperfusion injury in male rats

“…Azelnidipine-treated groups showed slight brain damage of mild interstitial edema and few dark Eosinophilic neurons. Our results are in accordance with that of Gupta et al (2020) [ 13 ].…”

“…T-AOC provides data on all integrated antioxidants present in the test solution, including enzymatic antioxidants like glutathione peroxidase, catalase, and superoxide dismutase, nonenzymatic antioxidants like glutathione and albumin, enzyme cofactors like coenzyme Q and lipoic acid, metabolites like uric acid and melatonin, and small molecule antioxidants like vitamin C and E and β–carotene. Lukic-Panin et al (2007) [ 17 ], Nada et al (2007) [ 7 ], Yamashita et al (2009) [ 18 ], Omote et al (2014) [ 19 ], and Gupta et al (2020) [ 13 ] observed that Azelnidipine treatment in rats resulted in a great reduction of different markers of oxidative stress such as malondialdehyde (MDA) which is a product of lipid peroxidation. The antioxidant capacity of Azelnidipine is greater than that of other dihydropyridine calcium channel blockers [ 14 , 20 ].…”

“…The results of our work are in line with that of Lukic-Panin et al (2007) [ 17 ], Yamashita et al (2009) [ 18 ], and Omote et al (2014) [ 19 ]. Gupta et al (2020) [ 13 ] supposed that Azelnidipine protection is due to its antioxidative and anti-inflammatory properties.…”

“…The doses of Azelnidipine (purchased from ChemScene/USA, CAS No. 123524-52-7) were prepared immediately before use by suspending in 0.3% CMC and were given through oral gavage in a dose of 3 mg/kg/day [ 12 , 13 ]. A low, non-hypotensive dose of Azelnidipine was used to document that the blood pressure-lowering mechanism is not involved in brain protection.…”

Citicolina: revisión farmacológica y clínica, actualización 2022

“…In a series of conducted studies, citicoline was shown to have a synergistic effect with other drugs in the treatment of cerebral ischemia, such as thrombolytic [ 211 - 215 ] and neuroprotective drugs [ 216 - 224 ]. Andersen et al [ 211 ] conducted an experimental study in a rat model of carotid embolism to evaluate the effect of different doses of citicoline, administered alone or combined with recombinant tissue plasminogen activator (rTPA), on infarction size.…”