title: Galantamine-induced behavioral recovery after sublethal excitotoxic lesions to the rat medial septum.
abstract: Clinical trials show beneficial effects of acetylcholinesterase (AChE) inhibitors, including galantamine, on cognitive functions in patients with mild to moderate Alzheimer's disease. Galantamine shows a dual action profile by also acting as an allosteric modulator of nicotinic acetylcholine receptors. Nevertheless, its in vivo mechanism of action is only partly understood. Here, we first established a novel lesion model provoking significant functional impairment of the septo-hippocampal projection system without triggering massive neuronal death in the rat medial septum. Next, we studied whether galantamine, administered in doses of 1 and 3mg/kg post-lesion, promotes functional recovery of spatial navigation behaviors, and affects the output of septal cholinergic projections. Infusion of N-methyl-d-aspartate (NMDA; 30nmol/1microl) in the medial septum resulted in spatial learning deficits associated with significant shrinkage of cholinergic neurons and reduced AChE activity in the hippocampus at 7 days post-lesion. Galantamine treatment alone significantly increased the hippocampal acetylcholine concentration and attenuated the NMDA-induced spatial learning impairment. Galantamine post-treatment also affected NMDA-induced changes in AChE and choline-acetyltransferase activities. In conclusion, our data show that galantamine attenuates experimentally-induced cognitive impairments underscored by mild neuronal damage.
authors.affiliation: Department of Molecular Neurobiology, University of Groningen, Kerklaan 30, NL-9750 AA Haren, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Mulder
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
authors.forename: Katalin
authors.initials: K
authors.lastname: Czollner
authors.forename: Thomas I F H
authors.initials: TI
authors.lastname: Cremers
authors.forename: Jan N
authors.initials: JN
authors.lastname: Keijser
authors.forename: Csaba
authors.initials: C
authors.lastname: Nyakas
authors.forename: Paul G M
authors.initials: PG
authors.lastname: Luiten
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002795:Choline O-Acetyltransferase / Q000187:drug effects / Q000378:metabolism; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005702:Galantamine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D023421:Models, Animal; D016202:N-Methylaspartate; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology; D009434:Neural Pathways / Q000187:drug effects / Q000201:enzymology; D009498:Neurotoxins; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D012686:Septal Nuclei / Q000187:drug effects* / Q000201:enzymology; D013028:Space Perception / Q000187:drug effects
chemical_list: D002800:Cholinesterase Inhibitors; D009498:Neurotoxins; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D005702:Galantamine; D016202:N-Methylaspartate; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase