Donepezil induces a cholinergic sprouting in basocortical degeneration.
One of the few currently approved therapies for Alzheimer's disease (AD) consists in the administration of acetylcholinesterase inhibitors, which enhances the lifetime of the neurotransmitter acetylcholine. Despite numerous studies on the symptomatic effect of acetylcholinesterase inhibitors, there is as yet no direct morphological evidence to indicate that they have a neurorestorative action. We investigated the effect of the acetylcholinesterase inhibitor donepezil administered subcutaneously in a rat model of partial unilateral cortical devascularization that induces a loss of the cortical cholinergic terminal network and a retrograde degeneration of the cholinergic projections that originate in the nucleus basalis. For 6 weeks, lesioned and sham-operated rats received a subcutaneous infusion of donepezil (2 mg/kg/day) or vehicle, delivered by osmotic minipumps implanted 2 weeks before the cortical devascularization. In lesioned rats, donepezil treatment increased the number and the size of vesicular acetylcholine transporter immunoreactive boutons in comparison to vehicle treatment. Donepezil had no observable effect on any of these parameters in sham-operated animals. These results show that donepezil mitigates cholinergic neuronal degeneration in vivo. This suggests a neuroplastic activity of this drug and provides evidence for a potential use of donepezil as a disease modifier in neurodegenerative diseases such as AD.
Ginestet
Laure
L
INSERM, UMR-679, Neurology and Experimental Therapeutics, Hôpital de la Salpêtrière, Université Pierre et Marie Curie-Paris 6, Paris, France.
Ferrario
Juan E
JE
Raisman-Vozari
Rita
R
Hirsch
Etienne C
EC
Debeir
Thomas
T
D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D020532:Basal Nucleus of Meynert / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D000077265:Donepezil; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; C493461:Slc18a3 protein, rat; D050494:Vesicular Acetylcholine Transport Proteins; D000077265:Donepezil; D000109:Acetylcholine