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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS021312-01A1
Application #
3402313
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1985-09-16
Project End
1988-08-31
Budget Start
1985-09-16
Budget End
1986-08-31
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Deshpande, S B; Warnick, J E (1994) Analogs of thyrotropin-releasing hormone in potentiating the spinal monosynaptic reflex in vitro. Eur J Pharmacol 271:439-44
Deshpande, S B; Warnick, J E (1994) Thyrotropin-releasing hormone reverses the supersensitively depressed monosynaptic transmission by serotonin in 5,7-dihydroxytryptamine-treated neonatal rats in vitro. Brain Res 655:263-6
Kubek, M J; Knoblach, S M; Sharif, N A et al. (1993) Thyrotropin-releasing hormone gene expression and receptors are differentially modified in limbic foci by seizures. Ann Neurol 33:70-6
Deshpande, S B; Warnick, J E (1993) Thyrotropin releasing hormone-induced potentiation of spinal monosynaptic reflex in rats in vitro. Indian J Exp Biol 31:112-5
Deshpande, S B; Warnick, J E (1990) Interaction of thyrotropin-releasing hormone and methysergide on the monosynaptic reflex in isolated mammalian spinal cord. Neurosci Lett 116:141-8
Sharif, N A; Towle, A C; Burt, D R et al. (1989) Cotransmitters: differential effects of serotonin (5-HT)-depleting drugs on levels of 5-HT and TRH and their receptors in rat brain and spinal cord. Brain Res 480:365-71
Miller, S C; Warnick, J E (1989) Protirelin (thyrotropin-releasing hormone) in amyotrophic lateral sclerosis. The role of androgens. Arch Neurol 46:330-5
Ohno, Y; Warnick, J E (1988) Effects of thyrotropin-releasing hormone on phencyclidine- and ketamine-induced spinal depression in neonatal rats. Neuropharmacology 27:1013-8
Das Gupta, S; Deshpande, S B; Warnick, J E (1988) Segmental synaptic depression caused by diisopropylphosphorofluoridate and sarin is reversed by thyrotropin-releasing hormone in the neonatal rat spinal cord. Toxicol Appl Pharmacol 95:499-506
Deshpande, S B; Warnick, J E (1988) Temperature-dependence of reflex transmission in the neonatal rat spinal cord, in vitro: influence on strychnine- and bicuculline-sensitive inhibition. Neuropharmacology 27:1033-7

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