Excitotoxicity and neurodegenerative diseases

Area of Science:

• Neuroscience
• Neurobiology
• Neurochemistry

Background:

• Glutamate acts as an excitatory neurotransmitter and a neurotoxin (excitotoxin) in the mammalian central nervous system.
• Established links exist between glutamate excitotoxicity and neuronal death in acute conditions like hypoxia/ischaemia, but not chronic neurodegenerative disorders.
• Impaired energy metabolism enhances neuronal susceptibility to glutamate excitotoxicity.

Purpose of the Study:

• To establish a link between excitotoxicity and neuronal death in chronic neurodegenerative disorders.
• To investigate the mechanism by which impaired energy metabolism increases neuronal vulnerability to glutamate.
• To explore the therapeutic potential of glutamate antagonists for chronic neurodegenerative diseases.

Main Methods:

• The study discusses the mechanism involving the attenuation of the Mg2+ blockade of N-methyl-D-aspartate (NMDA) receptors.
• Physiological extracellular glutamate concentrations and persistent receptor activation are examined.
• The concept of increased neuronal vulnerability to excitotoxic injury is explored.

Main Results:

• Impaired energy metabolism leads to reduced Mg2+ blockade of NMDA receptors.
• This reduction results in persistent activation of NMDA receptors by physiological glutamate levels.
• Neuronal vulnerability to excitotoxic injury is increased under conditions of impaired energy metabolism.

Conclusions:

• A link is established between slow neuronal degeneration in chronic diseases and excitotoxicity.
• Increased neuronal vulnerability to excitotoxic injury is a key factor in neurodegeneration.
• Glutamate antagonists may represent a promising therapeutic avenue for treatment-resistant chronic neurodegenerative diseases.