Protection by Natural and Semisynthetic Gangliosides from Ca2+-Dependent Neurotoxicity Caused by Excitatory Amino Acid (EAA) Neurotransmitters

Abstract

Neuronal death is a frequent occurrence during nervous system ontogenesis and continues, though at a slower rate, throughout life. EAA neurotransmitters, when added (in appropriate concentrations) to primary neuronal cultures, are the only neurotransmitters known to cause neuronal death by destabilizing homeostasis of free Ca2+ (Olney, 1969; Coyle, 1987; Vaccarino et al., 1987; Favaron et al., 1988; Connor et al., 1988). In neurons, EAA increase Ca2+ influx through specific cationic channel activation, thereby stimulating Ca2+-dependent enzymes, including protein kinase C (PKC) (Wroblewski and Danysz, 1989). Presumably, these actions of EAAs can be mediated at NMDA-, kainate- or quisqualate-sensitive synaptic receptors (Wroblewski and Danysz, 1989). Normally, intraneuronal Ca2+ homeostasis is maintained by the equilibration of free Ca2+, with Ca2+ compartmentalized in endoplasmic reticulum and mitochondria and the operation of channels and pumps allowing Ca2+ influx (cationic channels) and efflux (Nat-Ca2+ exchanger and ATPase-operated Ca2+ pumps) (Carafoli, 1987). It is, therefore, not surprising that many have attempted to evaluate whether EAA receptors are also operative in physiologically programmed neuronal death. In central nervous system, an alteration of EAA transmission may occur in a variety of acute (stroke, ischemia, and CNS traumas) or chronic (autoimmune responses, Huntington’s chorea, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, lathyrism, and the Guamanian complex) neuropathological processes (Rothman, 1984; Kostic et al., 1989; Spencer et al., 1987; Plaitakis et al., 1988).