Pelligrini-Giampietro et al, TiPS (2003) 24 461-470
POSSIBLE EXPLANATION FOR THE NEUROPROTECTIVE EFFECTS OF
METABOTROPIC GLUTAMATE 1 RECEPTOR ANTAGONISTS
(1) Excessive activation of postsynaptic AMPA and
NMDA
receptors by glutamate produces a sustained depolarizing influx of
Na+ and Ca2+, which eventually leads to neurodegeneration
(2) Activation of
postsynaptique GABAA receptors produces an influcx of
Cl-, hyperpolarization and neuroprotection
(3) GABA can also
interact with presynaptic GABAB receptors that negatively control
the release of glutamate, thus leading to reduced excitation of postsynaptic
neurons
(4) The release of GABA
is negatively-controlled by mGlu1 receptors and cannabinoid CB1 receptors, via suppression of Ca2+ currents through N-type channels or activation of K+ channels
Antagonists of mGlu1 receptors can lead to increased release of GABA and therefore to neuroprotective hyperpolarization
• Direct blockade of presynaptic mGLU1
receptor on GABAergic terminals
• Indirect inhibition of CB1
receptors located on GABAergic terminals promted by mGlu1 receptors located postsynapically
(1)
(2)
(3)
(4)
(4)
FARM 2146 - 2003-2004