This proposal focuses studies on the acute effects of GM1 ganglioside on CNS injury processes in stroke. We have already found that ganglioside injections can decrease functional deficits and reduce mortality within 24-48hrs in rats that sustained substantial brain ablations. Subsequently we found that ganglioside treatment limited cerebral edema, and reduced associated losses of CNS membrane Na,KATPase activity and intracellular K+ following cerebral trauma, as well as after denervation of subcortical regions. We have hypothesized that gangliosides reduce the extent of local CNS damage at the time of injury by preventing membrane failure, subsequent cell loss and fiber degeneration. By limiting the extent of CNS tissue damage at the time of injury conditions may be optimized for CNS regeneration and functional recovery. Most recently we have begun studying the effects of ganglioside treatment on ischemia. Completed studies show that, after 48hrs. ganglioside treatment of gerbils with global ischemia results in a 48% decrease in mortality and protection from associated losses of membrane Na,K-ATPase activity. Using the rat model of focal cerebral ischemia (MCAo) this proposal examines in greater detail the phenomena and molecular mechanisms by which gangliosides reduce pathological membrane events associated with CNS injury, and whether such acute effects result in reduced functional losses. In order to determine whether ganglioside treatment reduces functional losses immediately (1-72hrs) after the induction of ischemia, rats will be assessed on behavioral tests sensitive to cortical parietal damage (locus of primary infarct). Using light microscopy AND tissue analyses, in vivo localization of (H3)GM1 ganglioside will provide morphological evidence indicating where the CNS locus of action for these injected glycolipids might be. In vivo analyses of membrane components (ATPases & membrane fatty acids), and ions, which undergo changes during ischemia will be assayed to focus on processes in the pathophysiology of membrane events associated with stroke and how these are affected by GM1 treatment. Studying these membrane events as a function of time will indicate whether the treatment prevents further spread of the ischemic damage. Aside from the therapeutic clinical implications, this proposal will provide insight into ischemic injury processes and the mechanisms by which ganglioside treatment is effective.
| Mahadik, S P; Makar, T K; Murthy, J N et al. (1993) Temporal changes in superoxide dismutase, glutathione peroxidase, and catalase levels in primary and peri-ischemic tissue. Monosialoganglioside (GM1) treatment effects. Mol Chem Neuropathol 18:1-14 |
| Mahadik, S P; Bharucha, V A; Stadlin, A et al. (1992) Loss and recovery of activities of alpha+ and alpha isozymes of (Na(+) + K+)-ATPase in cortical focal ischemia: GM1 ganglioside protects plasma membrane structure and function. J Neurosci Res 32:209-20 |
| Bharucha, V A; Wakade, C G; Mahadik, S P et al. (1991) GM1 ganglioside treatment reduces functional deficits associated with cortical focal ischemia. Exp Neurol 114:136-9 |
