Investigation of Effect of Carvedilol in Bilateral Common Carotid Artery Occlusion Induced Global Cerebral Ischemia in Neurodegeneration Prone Rats

Abstract

Aim and Objectives: According to WHO, stroke is defined as ‘rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 hours or longer, or leading to death. Stroke is considered as the third leading cause of death in United States. Various studies have associated stroke with Alzheimer’s disease (AD). The risk of developing AD is 2-fold more in patients with stroke. Previous studies have suggested carvedilol to possess anti-oxidant activity in-vitro by preventing the lipid peroxidation & depletion of the anti-oxidants like GSH, SOD. Carvedilol was also known to be a neuroprotective with neuromodulatory action at NMDA receptors. Thus, the aim of the study was to evaluate the effect of pre-treatment of carvedilol on neurodegenerative rats with global ischemic stroke induced by bilateral common carotid arteries occlusion (BCAO). Materials and Methods: Male Wistar rats were selected and divided into eight groups: Normal control (NC), Alzheimer’s control (AC), Alzheimer’s Sham Operated(AS), Alzheimer’s + Carvedilol (AT), BCAO control (BC), BCAO + Carvedilol (BT), BCAO + Alzheimer’s control (BAC), BCAO + Alzheimer’s + Carvedilol (BAT). Alzheimer’s disease was induced by oral administration of Aluminium chloride (AlCl3) (100 mg/kg) for 60 days. Then global cerebral ischemia was induced by occluding both the common carotid arteries on the 50th day followed by reperfusion for 10 days. Carvedilol was also administered 5 mg/kg (p.o) simultaneously for 60 days. The assessment of the Alzheimer’s ischemic stroke was done on the 55th day by performing the cognitive behaviour studies with Morris water maze. Animals were sacrificed on 60th day and estimation of brain damage indicator parameters like infarct size, Na+ K+ ATPase activity, AChE activity was done in the brain homogenate. Estimation of oxidative stress parameters like lipid peroxidation, reduced glutathione (GSH) activity, SOD activity, nitrite level were carried out in brain homogenate. The histopathological evaluation of the brain was done with H & E staining to identify the neurodegeneration.Results: The ischemic control animals, ischemic Alzheimer’s control animals showed increase in the brain damage(infarct size) while the treatment with carvedilol (5 mg/kg, p.o) in both the animals was able to reduce the brain damage (infarct size) as seen by reduction in the brain infarct size. The mean escape latency was increased in the Alzheimer’s control animals, ischemic control animals, ischemic Alzheimer’s control animals with Morris water maze while the treatment with carvedilol (5 mg/kg, p.o) in Alzheimer’s animals, ischemic animals, ischemic Alzheimer’s animals was able to reduce the mean escape latency. The Alzheimer’s control animals, ischemic control animals, Alzheimer’s ischemic control animals showed increase in the AChE activity compared to that of the normal control animals while the treatment with carvedilol (5 mg/kg p.o) in Alzheimer’s animals, ischemic animals and ischemic Alzheimer’s animals showed no significant decrease in AChE levels. The Alzheimer’s control animals, ischemic control animals, Alzheimer’s ischemic control animals showed reduced activity of Na+ K+ ATPase (one of the biochemical parameters) while the treatment with carvedilol (5 mg/kg p.o.) in Alzheimer’s animals, ischemic animals and Alzheimer’s ischemic animals showed significant increase in the Na+ K+ ATPase. The Alzheimer’s control animals, ischemic control animals, ischemic Alzheimer’s control animals showed increased levels of nitrite while the treatment with carvedilol (5 mg/kg p.o.) in Alzheimer’s animals, ischemic animals, ischemic Alzheimer’s animals showed significant reduction in the nitrite levels. The Alzheimer’s control animals, ischemic control animals, ischemic Alzheimer’s control animals showed increased level of MDA while the treatment with carvedilol (5 mg/kg p.o.) in Alzheimer’s animals, ischemic animals, ischemic Alzheimer’s animals showed significant reduction in MDA level by maintaining the anti-oxidant defense. The Alzheimer’s control animals, ischemic control animals, ischemic Alzheimer’s control animals showed reduced activity of SOD, GSH while the treatment with carvedilol (5 mg/kg p.o.) in the Alzheimer’s animals, ischemic animals, ischemic Alzheimer’s animals showed increased activity of SOD, GSH by maintaining the anti-oxidant defense. The Alzheimer’s control, ischemic Alzheimer’s control animals showed neurodegeneration compared to that of the NC group while the treatment with Carvedilol (5 mg/kg p.o) in Alzheimer’s animals, ischemic Alzheimer’s animals showed reduced neurodegeneration. The hippocampal sections of the ischemic control animals showed neurodegeneration however it was not prominent whereas the hippocampal sections of the brain of ischemic treated animals showed reduced neurodegeneration. Conclusion: Our results suggest that the treatment with Carvedilol (5 mg/kg p.o.) showed protective effect against AlCl3 induced neurodegeneration in Alzheimer’s animals as well as the combination of diseases (ischemic and ischemic Alzheimer’s Disease animals) The effect of Carvedilol may be due to it’s anti-oxidant property.