Ganglioside-mediated protection from glutamate-induced neuronal death.
Glutamate, an excitatory amino acid (EAA), plays an important role in neuron to neuron signaling by binding to specific receptors. When, during neuronal firing, quanta of glutamate are released from the nerve terminal, they interact with the receptors for a few milliseconds and, thereafter, glutamate is promptly cleared by appropriate mechanisms. The neurotoxic action of glutamate arises from its capacity to trigger a pathophysiological chain of events when it acts continuously and abusively on its receptors (e.g., during cerebral edema associated with trauma, ischemia, stroke). In primary cultures of cerabellar granule neurons the abusive stimulation of EAA receptors by glutamate amplifies pathologicaly two early intracellular signals: free cytosolic Ca++ and the translocation of protein kinase C (PKC) from cytosol to neuronal membrane. Both of these signals persist unabated even after removal of glutamate from the incubation medium. Natural gangliosides and their semisynthetic derivatives protect neurons from glutamate toxicity by blocking the consequences of receptor abuse but they leave physiological responses to glutamate unaffected; hence they represent a prototype of a "receptor abuse dependent antagonist" (RADA).
Manev
H
H
Fidia Georgetown Institute for the Neurosciences, Georgetown University, Washington, DC 20007.
Favaron
M
M
Vicini
S
S
Guidotti
A
A
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D005732:Gangliosides / Q000494:pharmacology*; D005971:Glutamates / Q000633:toxicity*; D018698:Glutamic Acid; D009474:Neurons / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D009498:Neurotoxins / Q000633:toxicity*; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter / Q000502:physiology*
D005732:Gangliosides; D005971:Glutamates; D009498:Neurotoxins; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter; D018698:Glutamic Acid