INVESTIGATION OF PHARMACOLOGICAL ACTIONS OF WITHAFERIN-A IN ALUMINIUM CHLORIDE INDUCED ALZHEIMER’S DISEASE

Abstract

BACKGROUND AND OBJECTIVES: Alzheimer’s disease (AD) is a progressive irreversible condition where there is complete destruction of the brain cells leading to dementia. The disease is termed as progressive as there is worsening of the condition with the loss of brain function as the time passes. This clinical condition is becoming more common in the western part of the world. From the collected data over the period of time it is observed that it affects the Aged population as compared to the younger population. According to the reports from national institute on aging AD prevalence doubles every five years above the age of 65.In the present situation in U.S someone develops AD every 66 seconds and the prevalence estimated is as high as up to 16million by 2050. Amongst the various proposed hypothesis, the AB hypothesis is proven to be more explaining and simplified. The insoluble fibrils formed as an aberrant processing of amyloid beta causes its accumulation in the senile plaques and exerts oxidative stress as well as leads in the hyper phosphorylation of tau protein which causes neurotoxicity. The origin of disease may be genetic and also due to exposure to toxins such as aluminum chloride hence leading to neurodegenerative condition. Treatment options available are NMDA receptor antagonists (mementine) cholinesterase inhibitor (donepezil) and rivastigmine. The currently available treatment for AD only prevents the worsening of the condition and is unable to reverse the conditions. Also Due to the reported side effects of the current treatment patients remains unsatisfied with the available treatment options hence an approach towards herbal treatment may prove to be beneficial. The herbal constituent withaferin-A, an active component of withania somniferous, is proven to have anticancer properties and also poses anti-inflammatory activity. The reported actions of withania somniferous suggests the neuroprotective actions. Hence our objective is to investigate actions of Withaferin-A in AD induced with aluminum chlorideMATERIALS AND METHODS. The Alzheimer’s dementia like conditions were generated in the Disease control (DC) group with the induction of aluminum chloride with the dose of 17mg/kg given orally for the period of 30 days. The treatment groups were exposed to aluminum chloride (17mg/kg) and withaferin-A simultaneously with one of the groups treated with the dose of 50mg/kg(DW50) and other group treated with 100mg/kg(DW100) of withaferin-A. Donepezil (10mg/kg) (cholinesterase inhibitor) was used as a standard treatment. To evaluate the dementia and behavior in the animals Y-maze and water maze were carried out, For Y maze animals were trained for 5 days prior to treatment and after the period of 30 days again the behavior was evaluated for all the groups, whereas in water maze the animals were evaluated for their behavior after completion of treatment without any prior training. After the behavioral parameters animals were sacrificed. The brain tissue was subjected to the analysis of oxidative stress parameters, acetylcholinesterase assay, Histopathological studies and evaluation of levels of ß amyloid and tau protein. RESULTS Y-maze: Percent alternation: - There was significant reduction in the % alternation score in the DC group as compared to NC, whereas the percent score in the treatment groups were elevated significantly. Compared to the group treated with 50mg/kg withaferin-A the group treated with 100mg/kg shows the elevated percent alternation score. Total arm entry:-The results of total arm entry gives the significant decline in the disease control group compared to Normal control. Whereas in the DW100 group there was significant elevation in the total no. of entries as compared to DC and DW50. Morris water maze:- There was significant change found in the DC group when compared with NC on the third day. but on probe trail all the groups reveled significant reduction in escape latency time.Acetylcholinesterase assay: There was marked decline in the levels of cholinesterase in the DW100 group as compared to the disease control group but the difference was found to be insignificant. DW50 and the standard treatments also showed the nonsignificant decline. Histopathological evaluation:- The alignment of the granular cells were found to be disturbed in DC group as compared to NC. The cell death was observed in the sub granular zone in DC while the arrangement of cell was found to be intact in the NC and the treated groups. Biomarkers for Alzheimer’s disease:- The ELISA showed the rise in the Abeta and hyper phosphorylated tau protein in the DC group whereas those were found to be decline in the treated groups but changes found were insignificant. Oxidative stress parameters: The MDA levels were found to be significantly elevated in the disease control group as compared to normal. It was found to be lowered in the DW100 group as compared to the DC group. SOD, GSH and catalase levels were significantly reduced in the DC group as compared to the NC. In the DW100 group there was significant increase in the SOD, GSH and catalase. There was marked increase in the DW50 but rise in the level was insignificant. CONCLUSION. From the above mentioned data our study suggest that the Withaferin-A(100mg/kg) reduces the biomarkers for Alzheimer’s disease and is also useful in reducing the oxidative stress and hence withaferin-A(100mg/kg) can be significantly used as a neuroprotective agent in Alzheimer’s disease.