title: Free chelatable zinc modulates the cholinergic function during hypobaric hypoxia-induced neuronal damage: an in vivo study.
abstract: The deregulation of cholinergic system and associated neuronal damage is thought to be a major contributor to the pathophysiologic sequelae of hypobaric hypoxia-induced memory impairment. Uniquely, the muscarinic receptors also play a role in zinc uptake. Despite the potential role of muscarinic receptors in the development of post hypoxia cognitive deficits, no studies to date have evaluated the mechanistic relationship between memory dysfunction and zinc homeostasis in brain. In the present study, we evaluated the effect of Ca(2)EDTA, a specific zinc chelator in the spatial working and associative memory deficits following hypobaric hypoxia. Our results demonstrate that accumulation of intracellular free chelatable zinc in the hippocampal CA3 pyramidal neurons is accompanied with neuronal loss and memory impairment in hypobaric hypoxic condition. Chelation of this free zinc with Ca(2)EDTA (1.25 mM/kg) ameliorated the hippocampus-dependent spatial as well as associative memory dysfunction and neuronal damage observed on exposure to hypobaric hypoxia. The zinc chelator significantly alleviated the downregulation in expression of choline acetyltransferase, muscarinic receptor 1 and 4, and acetylcholinesterase activity due to hypobaric hypoxia. Our data suggest that the free chelatable zinc released during hypobaric hypoxia might play a critical role in the neuronal damage and the alteration in cholinergic function associated with hypobaric hypoxia-induced memory impairment. We speculate that zinc chelation might be a potential therapy for hypobaric hypoxia-induced cognitive impairment.
authors.affiliation: Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi-110007, India.
authors.forename: M
authors.initials: M
authors.lastname: Udayabanu
authors.forename: D
authors.initials: D
authors.lastname: Kumaran
authors.forename: A
authors.initials: A
authors.lastname: Katyal
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000399:Air Pressure; D000818:Animals; D001245:Association Learning / Q000502:physiology; D056654:CA3 Region, Hippocampal / Q000737:chemistry / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology*; D020552:Comet Assay; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000473:pathology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000473:pathology*; D010275:Parasympathetic Nervous System / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D043643:Receptor, Muscarinic M1 / Q000378:metabolism; D043588:Receptor, Muscarinic M4 / Q000378:metabolism; D015032:Zinc / Q000097:blood / Q000502:physiology*
chemical_list: D002614:Chelating Agents; D043643:Receptor, Muscarinic M1; D043588:Receptor, Muscarinic M4; D012313:RNA; D004492:Edetic Acid; D007770:L-Lactate Dehydrogenase; D000110:Acetylcholinesterase; D015032:Zinc