Nerve growth factor strategy and preparation of animal model for Alzheimer-type senile dementia

Research output: Contribution to journalReview article

8 Citations (Scopus)

Abstract

Nerve growth factor (NGF) plays an important role in the survival and maintenance of cholinergic neurons in the central nervous system. In senile dementia of the Alzheimer type (SDAT), learning and memory are impaired by the loss of neurons in the magnocellular cholinergic neuronal system. It is, therefore, of interest to investigate the role of NGF in this degenerative disorder. Since NGF does not cross the blood-brain barrier and is easily metabolized by peptidases when administered peripherally, it can be used for medical treatment only when directly injected into the brain. We tried to develop drugs which could be taken orally and stimulate the NGF synthesis in the brain. In addition, we attempted to develop a SDAT animal model using osmotic minipump to infuse β-amyloid protein into cerebral ventricle, since there are no SDAT model animals accompanied with various pathophysiological changes. We demonstrate here that the oral administration of propentofylline, idebenone and trimethylquinone derivative, potent in vitro NGF synthesis stimulators, induced the increase in NGF protein and mRNA, and in choline acetyltransferase activity, in basal forebrain-lesioned and aged rats, but not in intact young rats. These drugs also ameliorated the behavioral deficits in habituation, water maze, and passive avoidance tasks in these animals. These results suggest that these drugs stimulated NGF synthesis in vivo and ameliorated the behavioral deficits which were accompanied with the reduced choline acetyltransferase activity in the basal forebrain-lesioned and aged rats. In terms of the SDAT animal model, the performance of the water maze and passive avoidance tasks was impaired and choline acetyltransferase activity significantly decreased in β-amyloid protein- treated rats. Histochemical results showed the deposition of β-amyloid protein in the cortex and hippocampus and atrophy and loss of hippocampal neurons. These results suggest that the deposition of β-amyloid protein in the brain is related to the impairment of learning and cholinergic neuronal degeneration, and that β-amyloid protein-treated rats could be an animal model for SADT and used for the screening of drugs for SDAT.

Original languageEnglish
Pages (from-to)499-512
Number of pages14
JournalYakugaku Zasshi
Volume115
Issue number7
DOIs
Publication statusPublished - 01-01-1995
Externally publishedYes

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Nerve Growth Factor
Amyloidogenic Proteins
Alzheimer Disease
Animal Models
Choline O-Acetyltransferase
Cholinergic Agents
Brain
Learning
Pharmaceutical Preparations
Neurons
Cerebral Ventricles
Preclinical Drug Evaluations
Cholinergic Neurons
Water
Memory Disorders
Blood-Brain Barrier
Atrophy
Oral Administration
Hippocampus
Peptide Hydrolases

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

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title = "Nerve growth factor strategy and preparation of animal model for Alzheimer-type senile dementia",
abstract = "Nerve growth factor (NGF) plays an important role in the survival and maintenance of cholinergic neurons in the central nervous system. In senile dementia of the Alzheimer type (SDAT), learning and memory are impaired by the loss of neurons in the magnocellular cholinergic neuronal system. It is, therefore, of interest to investigate the role of NGF in this degenerative disorder. Since NGF does not cross the blood-brain barrier and is easily metabolized by peptidases when administered peripherally, it can be used for medical treatment only when directly injected into the brain. We tried to develop drugs which could be taken orally and stimulate the NGF synthesis in the brain. In addition, we attempted to develop a SDAT animal model using osmotic minipump to infuse β-amyloid protein into cerebral ventricle, since there are no SDAT model animals accompanied with various pathophysiological changes. We demonstrate here that the oral administration of propentofylline, idebenone and trimethylquinone derivative, potent in vitro NGF synthesis stimulators, induced the increase in NGF protein and mRNA, and in choline acetyltransferase activity, in basal forebrain-lesioned and aged rats, but not in intact young rats. These drugs also ameliorated the behavioral deficits in habituation, water maze, and passive avoidance tasks in these animals. These results suggest that these drugs stimulated NGF synthesis in vivo and ameliorated the behavioral deficits which were accompanied with the reduced choline acetyltransferase activity in the basal forebrain-lesioned and aged rats. In terms of the SDAT animal model, the performance of the water maze and passive avoidance tasks was impaired and choline acetyltransferase activity significantly decreased in β-amyloid protein- treated rats. Histochemical results showed the deposition of β-amyloid protein in the cortex and hippocampus and atrophy and loss of hippocampal neurons. These results suggest that the deposition of β-amyloid protein in the brain is related to the impairment of learning and cholinergic neuronal degeneration, and that β-amyloid protein-treated rats could be an animal model for SADT and used for the screening of drugs for SDAT.",
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Nerve growth factor strategy and preparation of animal model for Alzheimer-type senile dementia. / Nabeshima, Toshitaka.

In: Yakugaku Zasshi, Vol. 115, No. 7, 01.01.1995, p. 499-512.

Research output: Contribution to journalReview article

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