title: Protective effect of valproic acid in streptozotocin-induced sporadic Alzheimer's disease mouse model: possible involvement of the cholinergic system.
abstract: Sporadic Alzheimer's disease (SAD) is a slowly progressive neurological disorder that is the most common form of dementia. Cholinergic system dysfunction and amyloid beta formation are the two main underlying pathological mechanisms for the disease development. In recent studies, insulin receptor desensitization and disturbances in the downstream effects of insulin receptor signaling were observed in the brains of Alzheimer's patients. Currently, intracereberoventricular (ICV) injection of streptozotocin (STZ) is found to induce behavioral, neurochemical, and structural alterations in animals resembling those found in SAD patients. Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), was recently shown to regulate the transcription of several genes in both in vivo and in vitro models of Alzheimer's disease. The aim of the current study is to investigate the potential effect of different doses of valproic acid, in an ICV-STZ-induced animal model of SAD. Streptozotocin-injected mice showed cognitive and spatial memory dysfunction in the Y-maze, object recognition test, and Morris water maze (MWM) neurobehavioral tests. The mice also exhibited a decrease in acetylcholine (ACh) and neprilysin (NEP) levels accompanied by an increase in acetylcholinesterase (AChE) activity. For the first time to our knowledge, our findings have shown that VPA is capable of restoring ACh levels in ICV-STZ-injected mice, as well as normalizing both NEP levels and AChE activity. Via this mechanism, an enhancement of cognitive functions is observed. Thus, VPA is suggested to be a promising therapeutic approach against SAD.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Main Entrance of Al Tagamoa Al Khames, New Cairo City, 11835, Egypt.
authors.forename: Mirna Ezzat
authors.initials: ME
authors.lastname: Sorial
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Main Entrance of Al Tagamoa Al Khames, New Cairo City, 11835, Egypt. nesrine_salah2002@yahoo.com.|Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Giza, 12613, Egypt. nesrine_salah2002@yahoo.com.
authors.forename: Nesrine Salah El Dine
authors.initials: NSED
authors.lastname: El Sayed
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D003072:Cognition Disorders / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology; D051379:Mice; D015260:Neprilysin / Q000378:metabolism; D013311:Streptozocin / Q000633:toxicity; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D056572:Histone Deacetylase Inhibitors; D013311:Streptozocin; D014635:Valproic Acid; D015260:Neprilysin; D000109:Acetylcholine
keywords: Alzheimer’s disease; Cholinergic system; Intracerebroventricular; Streptozotocin; Valproic acid