Galantamine-induced behavioral recovery after sublethal excitotoxic lesions to the rat medial septum.
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.
Mulder
Jan
J
Department of Molecular Neurobiology, University of Groningen, Kerklaan 30, NL-9750 AA Haren, The Netherlands.
Harkany
Tibor
T
Czollner
Katalin
K
Cremers
Thomas I F H
TI
Keijser
Jan N
JN
Nyakas
Csaba
C
Luiten
Paul G M
PG
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
D002800:Cholinesterase Inhibitors; D009498:Neurotoxins; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D005702:Galantamine; D016202:N-Methylaspartate; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase