Sequelae of biochemical events following photochemical injury of rat sensory-motor cortex: mechanism of ganglioside protection.
In culture the protracted and abusive stimulation of glutamate (GLU) receptors results in neuronal death through a mechanism involving the persistent translocation of PKC and the destabilization of (Ca2+)i homeostasis [(Ca2+)i HD]. In contrast, intermittent GLU receptor use elicits a coordinated expression of immediate early genes (IEG) acting as nuclear third messenger. Brain ischemia also is known to result in the paroxysmal abusive stimulation of glutamate receptors. The glutamate receptive elements in turn degenerate largely as a function of their inability to control homeostatic Ca2+ due to the irreversible translocation of PKC. In the present study we employed an in vivo model of focal brain ischemia using the photosensitive dye, Rose bengal. With this model we sought to determine the neuroprotective actions of MK-801, a noncompetitive blocker of GLU at the NMDA-sensitive receptor and of the semisynthetic gangliosides LIGA 4 and LIGA 20 which in vitro have been demonstrated to block PKC translocation. Moreover, we sought to establish whether the persistent stimulation of ionotropic glutamate receptors would led to a change in ionotropic glutamate expression in the focal and perifocal area. Importantly, the perifocal area (i. e., the region surrounding the area of primary insult) is a region in which profound cellular reorganization occurs including neuronal death and glial proliferation and is a key region to target various neuroprotective drugs aimed at ameliorating the neurodegeneration following stroke. Receptor abuse dependent antagonists (RADA) drugs such as gangliosides selectively curtail the amplification steps that specifically differentiate signal transduction following physiological receptor use from that following pathological receptor abuse.(ABSTRACT TRUNCATED AT 250 WORDS)
Costa
E
E
Fidia-Georgetown, Institute for the Neurosciences, Georgetown University, Washington.
Kharlamov
A
A
Guidotti
A
A
Hayes
R
R
Armstrong
D
D
D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005732:Gangliosides / Q000037:antagonists & inhibitors*; D009044:Motor Cortex / Q000502:physiology*; D010777:Photochemistry; D051381:Rats; D017470:Receptors, Glutamate / Q000187:drug effects
D005732:Gangliosides; D017470:Receptors, Glutamate; D016291:Dizocilpine Maleate