TY - JOUR
T1 - Orally active NGF synthesis stimulators
T2 - Potential therapeutic agents in Alzheimer's disease
AU - Yamada, Kiyofumi
AU - Nitta, Atsumi
AU - Hasegawa, Takaaki
AU - Fuji, Kazuyuki
AU - Hiramatsu, Masayuki
AU - Kameyama, Tsutomu
AU - Furukawa, Yoshiko
AU - Hayashi, Kyozo
AU - Nabeshima, Toshitaka
N1 - Funding Information:
This work was supported, in part, by an SRF Grant for Biomedical Research, a Gerontological Science Grant from the Sandoz Foundation for Gerontological Research, Grants-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan (05454148 and 07557009), and grants from the Uehara Memorial Foundation, and Japan Research Foundation for Clinical Pharmacology. The authors are grateful to Takeda Chemical Industries, Ltd. (Osaka, Japan) and Hoechst Japan Ltd. (Tokyo, Japan) for the supply of idebenone and propentofylline, respectively.
PY - 1997/2
Y1 - 1997/2
N2 - 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, if 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.
AB - 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, if 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.
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U2 - 10.1016/S0166-4328(97)86054-8
DO - 10.1016/S0166-4328(97)86054-8
M3 - Article
C2 - 9062669
AN - SCOPUS:0031081164
SN - 0166-4328
VL - 83
SP - 117
EP - 122
JO - Behavioural Brain Research
JF - Behavioural Brain Research
IS - 1-2
ER -