Brain content of glycosphingolipids after oral administration of monosialogangliosides GM1 and LIGA20 to rats

Abstract

Natural (GM1) and semisynthetic [113-Neu-5-AcGgOse4-2-D-erythro-1,3- dihydroxy-2-dichloroacetylamide-4-trans-octadecene (LIGA20)] glycosphingolipids, given parenterally, protect neurones against glutamate-induced death without producing the side effects typical of glutamate receptor antagonists. Chronic glutamate-related neurotoxicity (e.g., in recurring strokes in elderly hypertensive patients, and in Parkinson disease) could be prevented also by glycosphingolipids treatment, but this therapeutic intervention will require a protracted administration of orally active glycosphingolipids. Here we demonstrate that 3-6 h after oral administration of 68 mumol/kg of LIGA20 and GM1 to rats, the brain content of LIGA20 is 50-fold higher than that of GM1. The brain concentration of LIGA20 remains elevated for at least 12-24 h. Because the LIGA20 that reaches the brain is slowly metabolized, repeated oral administrations of this glycosphingolipid can yield to its accumulation in brain, and can yield various brain levels depending on the dose and frequency of drug administration. In contrast this is not possible with GM1, which given orally for 7 d, cannot accumulate in brain in pharmacologically significant concentrations.

LIGA20, a lyso derivative of ganglioside GM1, given orally after cortical thrombosis reduces infarct size and associated cognition deficit.

“…Since the LIGA20 plasma levels are 4-to 6-fold greater than that of brain (22,23), one can presume that the drug concentration in the brain may not be uniform and perhaps may be higher in the surroundings of the infarcted area due to local changes in the blood-brain barrier. A protracted treatment combining i.v.…”

“…Thus, the bioavailability of LIGA20 given orally to rats is at least 2 orders of magnitude greater than that of GM1 (22). Moreover, recent studies demonstrated that LIGA20 is slowly metabolized, and after a single oral administration a measurable brain content of this drug is maintained for longer than 48 hr (22). In addition, the parenteral or oral administration of LIGA20 to rats, before the induction of a photochemical brain infarct, exerts a strong neuroprotective action against glutamateinduced neurotoxicity in the areas that surround the region of maximal ischemic damage (10).…”

“…These properties reduce the probability of molecular self-aggregation and thus limit the molecular volume ofthese aggregates, thereby facilitating and accelerating their insertion in the lipid monolayer (20). Thus, the bioavailability of LIGA20 given orally to rats is at least 2 orders of magnitude greater than that of GM1 (22). Moreover, recent studies demonstrated that LIGA20 is slowly metabolized, and after a single oral administration a measurable brain content of this drug is maintained for longer than 48 hr (22).…”

“…The total infarct volume was calculated by numerical summation of the volume calculated in each slice. (22). LIGA and GM1 were dissolved in saline and administered using an enteral feeding tube in a volume of 1 ml/150 g ofbody weight, in rats deprived of food for 6-8 hr.…”

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

“…Oral administration of LIGA 20 protects neurons against glutamate-induced neuronal death in rats without producing the side effects typical of glutamate receptor antagonists (173) and in mice subject to kainate-induced seizures and apoptosis (174). The level of LIGA 20 in brains of treated animals can reach a significantly higher level than can GM1; moreover, animals treated with LIGA 20 showed no apparent biochemical or behavioral adverse effects (173,175), suggesting that this compound may be useful as a neuroprotective agent in neuronal cell death in AD.…”