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A Computerized Test Battery to Study Pharmacodynamic Effects on the Central Nervous System of Cholinergic Drugs in Early Phase Drug Development
07:02

A Computerized Test Battery to Study Pharmacodynamic Effects on the Central Nervous System of Cholinergic Drugs in Early Phase Drug Development

Published on: February 11, 2019

Decrease in GTP-sensitive high affinity agonist binding of muscarinic acetylcholine receptors in autopsied brains of

Kazumasa Shiozaki1, Eizo Iseki

  • 1Department of Psychiatry, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama 236-0004, Japan. NBG01035@nifty.com

Journal of the Neurological Sciences
|September 1, 2004
PubMed

Insights

Signal transduction from muscarinic acetylcholine receptors (mAChR) to G protein is impaired in the frontal lobe of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) patients. This study found reduced mAChR-G protein complex concentration in affected brain regions.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pathology

Background:

  • Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are neurodegenerative disorders.
  • Muscarinic acetylcholine receptors (mAChR) play crucial roles in cognitive function.
  • Dysregulation of G protein-coupled receptor signaling is implicated in neurodegeneration.

Purpose of the Study:

  • To investigate alterations in signal transduction from mAChR to G protein in the brains of DLB and AD patients.
  • To assess the formation of the mAChR-G protein complex as an index of signal transduction.
  • To compare these changes between DLB, AD, and control groups.

Main Methods:

  • Utilized post-mortem brain tissue from DLB, AD, and control subjects.
  • Prepared membrane fractions from frontal and temporal cerebral tissues.
  • Analyzed GTP-sensitive high-affinity binding of radiolabeled ligands to mAChR using nonlinear regression.

Main Results:

  • Significantly decreased GTP-sensitive agonist high-affinity binding was observed in the frontal lobe of both DLB (P<0.01) and AD (P<0.05) patients compared to controls.
  • No significant differences were found in the temporal lobe.
  • The affinity ratio of the agonist did not differ significantly among the groups in either brain region.

Conclusions:

  • The concentration of the mAChR-G protein complex is reduced in the frontal lobe in DLB and AD.
  • Signal transduction from mAChR to G protein is disturbed in the frontal lobe in these neurodegenerative diseases.
  • These findings highlight a specific molecular deficit in the frontal cortex relevant to DLB and AD pathophysiology.

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