Gangliosides as neurotrophic agents: studies on the mechanism of action

During the normal course of neuronal differentiation gangliosides undergo marked changes in both quantity and quality. These changes, i.e. several-fold increase in concentration and appearance of the gangliotetraose family, have been observed both in vivo and in neuronal cell cultures. In addition to these naturally occurring (endogenous) manifestations, exogenously administered gangliosides have been observed to exert neuritogenic and/or neuronotrophic effects on a variety of neuroblastoma cell lines and primary neuronal culture systems. Unlike the endogenous effects, which appear to require gangliotetraose structures, the structural specificity of the exogenous effect is quite broad. Thus, all of 11 different gangliosides proved neuritogenic with neuro-2A neuroblastoma cells. Furthermore, synthetic sialoglycolipids possessing a beta-ketosidic sialic acid linkage and/or a glyceride-like moiety in place of ceramide all caused enhanced neurite outgrowth in neuro-2A, PC12, and embryonic chick dorsal root ganglia. A derivative of GM1 lacking the negative charge was also active in the same 3 systems. These results point to general perturbation of the membrane, probably a physical-chemical effect, in a manner which triggers intracellular events leading to differentiation. In contrast to these in vitro results, use of the above GM1 derivative in two in vivo models proved ineffective in maintaining the level of cholinergic markers that were preserved by GM1 in lesioned brains. These results point to fundamentally different mechanism for the trophic effects of administered gangliosides in vivo and in vitro.