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Anti-Excitotoxic and Antioxidant TGF-Beta Family Neurotrophic Factors: In Vitro Screening Models of Motor Neuron Degeneration
Final rept. 1 Jun 1999-31 May 2002
JOHNS HOPKINS UNIV BALTIMORE MD
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TGFbeta-like trophic factors have been shown to be protective in acute neuronal injury paradigms. In the current studies, we analyzed and compared members of this growing family, including GDNF, neurturin, nodal, persephin, TGFbeta1 as well as neuroimmunophilin ligand GPl-1O46, for protection against chronic glutamate toxicity and the mechanisms for protection. In parallel, we developed a novel organotypic spinal cord culture system to study the ability of these factors to promote motor axon outgrowth. Using these systems, we were able to differentiate the neuroprotective effect of the TGFbeta-like factors from their motor axon outgrowth-promoting activity. GDNF, neurturin, persephin, and nodal all protect against excitotoxic motor neuron degeneration. Low amounts of GDNF 1 ngml and high concentrations of neurturin induced vigorous motor axon outgrowth. In contrast, nodal, persephin and TGFbetal did not induce motor axon outgrowth. Finally, we have ascertained that the neuroprotective properties of some of these compounds GDNF and GPl-1 046 may lie in their ability to induce rapidly synthesis of the glutamate transporter EAAT2.
APPROVED FOR PUBLIC RELEASE