LIGA20, A LYSO DERIVATIVE OF GANGLIOSIDE GM1, GIVEN ORALLY AFTER CORTICAL THROMBOSIS REDUCES INFARCT SIZE AND ASSOCIATED COGNITION DEFICIT

A bilateral photochemically induced thrombotic lesion of rat sensorimo tor cortex (approximate to 3 mm in diameter and 25 mm(3) in volume) is associated with a persistent cognition (learning and memory) deficit, which was evaluated with water maze tasks. The N-dichloroacetylsphing osine derivative of lysoGM1 (LIGA20) administered after the lesion eit her i.v., or per os reduces the infarct size by 30-40% and attenuates the associated cognition deficits, presumably by limiting the extent o f damage of neurons at risk located in the surroundings of the infarct ed core (i.e., area penumbra). The LIGA20 protection is dose and time dependent. Maximal protection is afforded by a single dose of LIGA20 o f 34 mu mol/kg i.v. 1 hr after lesion or by a dose of 270 mu mol/kg pe r os when administered 1 hr and 24 hr after the lesion. The protective effect of LIGA20 can be observed when the drug is administered i.v. u p to 6 hr after the lesion. The protective efficacy of the oral admini stration of LIGA20 is related to its physicochemical properties, which , unlike those of GM1, allow absorption from the gastrointestinal trac t. LIGA20 given orally reaches the brain promptly and rapidly inserts into the neuronal membranes. Here, by an unknown molecular mechanism, LIGA20 selectively reduces the pathological amplification of Ca2+ sign aling elicited by persistent stimulation of ionotropic glutamate recep tors in the area penumbra.