Development of cholinergic drugs for the treatment of Alzheimer's disease
作者:
Celeste A. Johns,
Vahram Haroutunian,
Blaine S. Greenwald,
Richard C. Mohs,
Bonnie M. Davis,
Phil Kanof,
Tom B. Horvath,
Kenneth L. Davis,
期刊:
Drug Development Research
(WILEY Available online 1985)
卷期:
Volume 5,
issue 1
页码: 77-96
ISSN:0272-4391
年代: 1985
DOI:10.1002/ddr.430050108
出版商: Wiley Subscription Services, Inc., A Wiley Company
关键词: Alzheimer's Disease;cholinergic system;nucleus basalis of Meynert;physostig‐mine;hypocholinergic animal model
数据来源: WILEY
摘要:
AbstractAlzheimer's Disease (AD) is characterized neurochemically by a profound loss of choline acetyl transferase activity and histologically by a selective degeneration of cholinergic neurons originating in the nucleus basalis of Meynert (nbM). The clinical relevance of this cholinergic deficit and its implications for the development of treatment strategies was explored in animal studies and in patients with carefully diagnosed AD. A hypocholinergic animal model was developed by chemical ablation of the nbM in rats. These rats demonstrated significant impairment of learning and memory as measured by long‐term habituation of locomotor activity and retention of a one‐trial passive avoidance task, which was substantially improved after the administration of the cholinergic drug physostigmine. In AD patients, in vivo assessment of cholinergic markers in cerebrospinal fluid showed decreased acetylcholine and choline activity in proportion to the patient's degree of cognitive impairment. Physostigmine was administered to AD patients both intravenously and orally in an attempt to enhance central cholinergic activity. Significant improvement of long‐term memory encoding followed administration of intravenous physostigmine, and modest improvements in cognition and behavior resulted when oral physostigmine was given to some AD patients. These results support the hypothesis that cholinergic deficits are manifested in symptoms of AD and suggest that administration of cholinomimetic agents is a rational treatment strategy
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