The goal of the proposed research is to discover how thyrotropin-releasing hormone (TRH,pGLU-His-Pro-NH2) produces therapeutically-useful effects in motor neuron disease, notably amyotrophic lateral sclerosis (ALS). Two animal models of motor neuron disease will be used, one viral and one hereditary, both in mice. The first is infection with a retrovirus (murine leukemia virus, MuLV) leading to paralysis in the hind limbs with a time course depending on dose and the second (primarily for confirmation of results in the virus model) is the wobbler (wr) mutant, an autosomal recessive condition leading to variable and progressive forelimb paralysis starting at several weeks of age. Biochemical measurements in the spinal cords of affected mice will concentrate on receptors for TRH as a possible site involved in the pathophysiology of motor neuron disease. They represent the first step in translating the presence of TRH into a response and are readily detected by binding measurements. Previous work has developed an improved ligand,(H3)(3-Me-His2)TRH([H]3MeTRH), to study such receptors and, using it and (H3)TRH, has established their presence and identity in the spinal cord and other areas of the central nervous system, the existence of species differences in their density, their localization in rabbit spinal cord by dissection and autoradiography, their """"""""up-regulation"""""""" following destruction of TRH-containing nerve terminals, and their modulation in the test tube by substance P and certain benzodiazepines. Other measurements will include levels of TRH (by radioimmunoassay) and various cholinergic markers (choline acetyltransferase, etc.) as indices of motor neuron survival. Results of biochemical measurements will be correlated with electrophysiological measurements on the isolated spinal cord preparation from affected mice, looking for changes in responses to TRH which accompany biochemical changes. Further experiments will examine changes in biochemical markers and responses to TRH in spinal cords of normal and MuLV-infected mice after treatment with 5,7-dihydroxytryptamine (destroys neurons containing serotonin and colocalized TRH), seeing if TRH depletion speeds the progression of motor neuron disease, and effects of treatment with TRH and its analogs on motr performance in the two murine models of motor neuron disease.
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