Gangliosides' dual mode of action: a working hypothesis.

Using in vitro preparations, we have tested the hypothesis that gangliosides, and more specifically GM1, may prevent progressive neural damage following a trauma by means of complex intracellular mechanisms that might be triggered originally by ganglioside interaction with neuronal membranes. We have recently shown that 2-hr ganglioside incubation in vitro stimulates the membrane Na/K pump in neuromuscular preparations. However, 5-6-hr incubation or in vivo treatment for 3 days with a daily injection of gangliosides at a dose of 1 or 10 mg/kg prevents the depolarization that normally occurs after several hours of exposure to K+-free solutions. In such undepolarized muscles, the electrogenic Na+/K+ pump does not seem to be activated. Hippocampal slices subjected to hypoxia undergo depolarization, which is reversed after oxygen readmission. The recovery phase is characterized by a huge hyperpolarization, probably reflecting electrogenic pump activity. In control preparations the depolarization occurs after 3.15 +/- 0.4 min and has a value of 48.7 +/- 5.7 mV; GM1 treatment for at least 4-5 hr increases the latency to 7.3 +/- 2.3 min, and the depolarization is reduced to 31.8 +/- 4.5 mV. This protective effect is accompanied by a reduced hyperpolarization in treated preparations. The ionic studies performed on neuromuscular preparations indicate that the protective effect may not be solely dependent on K+ leakage; however, the experiments are not conclusive and must be repeated with more direct methods. The results obtained indicate a dual mode of action for gangliosides. The early one seems characterized by membrane-enzyme activation, perhaps in relationship to their incorporation in the membrane, which could be compatible with previously described effects, such as enhancement of neuronal sprouting and neuritogenesis. The late one, occurring 4-5 hr after ganglioside addition in vitro, might reflect intracellular events and be compatible with the protective action exhibited by gangliosides against neural damage.