Pharmacological Evaluation of Gallic Acid and Saroglitazar against Experimentally induced Alzheimer’s Disease Model in Rats

Abstract

Title: Pharmacological evaluation of anti-diabetic agents against experimentally induced Alzheimer’s Disease. BACKGROUND Alzheimer’s disease (AD) is a progressive, irreversible neurodegenerative disorder that gradually deteriorates memory and cognitive skills eventually affecting normal independent daily living in affected individuals. Amyloid beta (Aβ) peptide, neurofibrillary tangles and neuronal loss in distinct brain regions are the major pathological changes that occur in AD. Recent studies report that adults who develop type 2 diabetes mellitus (T2DM) at later stages in life are at higher risk of developing AD. Interestingly, T2DM shares many of the features of AD, including Aβ aggregation, increased glycogen synthase kinase-3 (GSK-3) activity, deregulated protein phosphorylation, aging-related processes, high cholesterol levels, metabolic disorders, blood vessel abnormalities, increased oxidative stress, increased inflammatory response, correlation with apolipoprotein E ε4 allele and glyceraldehydederived advanced glycation end-products. These similarities thus provide a plethora of opportunities to develop common effective pharmacological interventions to treat both T2DM and AD. Gallic acid plays a neuroprotective role through involving the antioxidant and inflammation pathways in the animal models of neurodegenerative disease. Saroglitazar is a novel nonthiazolidinediones (TZD) and nonfibric acid derivative designed to act as dual regulator of lipids and glucose metabolism by activating peroxisome proliferator-activated receptors (PPARs). Objectives:1. To evaluate neuropharmacological actions of antidiabetic agents against Alzheimer’s disease. 2. To investigate mechanism of action of neuroprotective action of antidiabetic agents in experimentally induced Alzheimer’s disease.MATERIALS & METHODS In present protocol after acclimatization and training, animals were divided in nine groups as Group 1: Normal control (NC), Group 2: Sham Control (SC), Group 3: Diabetic Control (Streptozotocin, 35mg/kg, i.p.) (DM), Group 4: Alzheimer’s disease Control (AD) (Streptozotocin, 3mg/kg, i.c.v.). Group 5: Alzheimer’s disease together with diabetes mellitus disease control group (DM+AD) (High Fat Diet, Streptozotocin, 35mg/kg,i.p. and Streptozotocin, 3mg/kg,i.c.v), Group 6: : Alzheimer’s disease With Donezepil (5mg/kg) , Group 7: DM+AD With Gallic acid (50mg/kg), Group 8: DM+AD With saroglitazar (4mg/kg), Group 9: DM+AD With sarogliotazar (10mg/kg). Rats were anesthetized with80 mg/kg ketamine and 15 mg/kg Xylazine and streptozotocin (not more than 5 μl once) was administered by intracerebroventricular (i.c.v) route in rat brain with the help of stereotaxic device. Surgery was performed in Sham control animal but Streptozotocin was not administered. The animals were tested for behavioural tests like Morris water maze, novel object preference and modified Y-maze. Biochemical estimations included oxidative stress Parameters (SOD, Catalase, Glutathione, MDA Content and Acetylcholinesterase Activity. Histopathological examination was performed at the end. Results: Glucose levelsThere was increase in blood glucose levels in all the three disease control groups as compared to normal control group and significant decrease in blood glucose levels all the treatment groups as compared to disease control group. Neurobehavioral Studies: In Y Maze, Total number of entries in closed arm were reduced which indicated that behavior for exploration was decreased in the disease control groups as compared to the normal and sham control groups. Progressive decrease in total number of entries in closed arm was seen with respect to time in the Y-maze in the Streptozotocin induced Alzheimer’s disease group, as well as Diabetes plus Alzheimer’s disease induced groups as compared to normal control group. There was insignificant increase in total number of entries in closed arm in all the treatment groups as compared to Disease control group. In Morris water maze, as the animalsConclusion: Our data suggests neuroprotective activity of Gallic acid as well as Saroglitazar against experimentally induced Alzheimer’s disease model in rats. This effect might be due to their antioxidant and anticholinesterase activity. Further studies are warranted to confirm these preliminary studies.