Globoid cell leukocystorophy (Krabbe's Disease) is an autosomal metqabolic disordear of beta-galactocerebrosidase deficiency with progressive pathognomonic accumulation of psychosine (galactosylsphingosine) which subsequently becomes a neuroinflammatory disease resulting in demyelination, olidogendrocyte loss and death. The objectives of the proposed studies are to elucidate the possible role of psychosine in neuroinflammatory response and in the mechanism of oligodendrocyte loss by using twitcher mice, a murine model of globoid cell leukodystrophy (GLD). Studies from our laboratory have demonstrated the psychosine potentiates the cytokine-induced induction of iNOS and also the psychosine when incubated with C6 glial cells in culture, induces apoptotic cell loss. Achievement of these goals will be facilitated by understanding the molecular mechanism of induction of inducible nitric oxide synthase (iNOS) and inflammatory cytokines (e.g. TNFalpha and IL-6) and psychosine-induced apoptotic loss of oligodendrocytes. Studies are also proposed to investigate the psychosine-induced electrophysiological alterations in brain cells/brain slices form twitcher mice. We also propose to test the efficacy of antioxidants (N-acetyl cysteine, alpha-lipoic acid) and the compounds that are known to block the induction of inflammatory cytokines (lovastatin, sodium phenylacetate) for halting/delaying the disease process in twitcher mice. The proposed studies will provide a better understanding of the disease process in GLD/twitcher mice and the demonstration of beneficial effects of the drugs in twitcher mice) may help in the identification of an ideal candidate drug for subsequent use in clinical trials involving GLD patients.
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