Orally active NGF synthesis stimulators:
potential therapeutic agents in Alzheimer's disease.
Yamada K, Nitta A, Hasegawa T, Fuji K, Hiramatsu
Kameyama T, Furukawa Y, Hayashi K, Nabeshima T.
Department of Neuropsychopharmacology and Hospital Pharmacy
School of Medicine, Japan.
Behav Brain Res 1997 Feb;83(1-2):117-22
The degeneration of cholinergic
neurons may be responsible for cognitive impairment in patients with
Alzheimer's disease (AD). Since nerve growth factor (NGF) plays an important
role in the survival and maintenance of cholinergic neurons in the central
nervous system, this factor may have some beneficial effects on the cognitive
impairment observed in patients with AD. However, since NGF does not cross the
blood-brain barrier and is easily metabolized when administered peripherally,
it can only be used when directly injected into the brain. In this review, we
show that repeated oral administration of the NGF synthesis stimulators,
idebenone and propentofylline, partially restored the age-associated decrease
of NGF in the frontal and parietal cortices. Furthermore, this treatment
attenuated the impairment of performance in the water maze, passive avoidance,
and habituation tasks in rats with bilateral forebrain lesions, and in rats
which had received continuous infusion of anti-NGF antibody into the septum.
The behavioral improvement induced by idebenone and propentofylline was
accompanied by recovery of both the reduced activity of choline
acetyltransferase and the changes in [3H]QNB binding. These results suggest
that the use of NGF synthesis stimulators may provide a novel therapeutic
approach to cholinergic dysfunction.