臺灣博碩士論文加值系統

3-nitropropionic acid (3-NP)為粒線體succinate dehydrogenase的不可逆抑制劑，而給予3-NP所引發的病徵和亨丁頓舞蹈症相似，因此近年來此藥物被當作誘發亨丁頓舞蹈症動物模式的神經毒物。另一方面，臨床上亨丁頓舞蹈症病人的下視丘神經元有退化的現象，以及其體重下降的情形。本論文主要去探討當中樞給予3-NP之後是否會對飲食量、體重以及下視丘神經元產生改變。本論文所使用的為Sprague-Dawley雄性大白鼠，利用中樞第三腦室埋管給藥。我們發現在利用中樞給予3-NP (0.1和1 mg/3 μl)都可以使得大鼠的體重和其飲食量有下降的現象出現，但以1 mg/3 μl較為明顯。在1 mg/3 μl此劑量中，同時發現到室旁核的細胞有減少的情形發生。另一方面，我們也試著利用S-nitrosoglutathione（GSNO）此藥物，觀察當共同給予時是否可以具有抑制3-NP所造成的毒性作用。我們發現到當給予高劑量的GSNO (0.84和8.4 nmol)和3-NP時，並無具有保護作用，反而會加強3-NP所造成的毒性作用；反之在低劑量（0.084 nmol）時就具有保護作用的現象出現。綜合以上結果，我們可以知道在中樞給予3-NP此藥物的確會造成大鼠的飲食量、體重有所下降以及使室旁核細胞減少；而在GSNO保護作用方面，在高劑量時會有加強其3-NP毒性效用，反之在低劑量下就具有保護3-NP所造成的毒性效果。

3-Nitropropionic acid (3-NP) is an irreversible succinate dehydrogenase inhibitor and the administration of 3-NP caused neuropathological deficits is similar to these found in Huntington’s disease (HD), including behavioral alteration and cortico-striatal degeneration. HD patients were found the degeneration of the hypothalamic neurons and showed the loss of body weight. The aim in this study is to investigate the change of body weight and food intake after administering 3-NP in adult male Spraque-Dawley rats. The body weight and food intake were significantly decreased in the third cerebroventricular (icv) administration (1 mg/3 μl) or the twice injection per day injections . The neurons in paraventricular nucleus were lost after administering 3-NP through the third cerebroventricule. Additionally, we co-injected S-nitrosoglutathione (GSNO) with 3-NP to test the protective effect. However, high doses of GSNO (0.84, 8.4 nmol, icv) did not show the protective effect. Moreover, high doses of GSNO showed the enhancement of toxicity of 3-NP. Low dose of GSNO (0.084 nmol, icv) exerted the protective effect against the toxicity by 3-NP . In summary, these data showed that the central injection of 3-NP through the third cerebroventricle caused the decline of food intake and body weight in rats, and proper dose of GSNO attenuated this.

致謝
英文摘要
中文摘要
前言
材料與方法
實驗目的
實驗材料
實驗方法
實驗步驟
結果
討論
參考文獻
圖表與說明

A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell 72, 971-983, 1993.
Aylward E. H., Brandt J., Codori A. M., Mangus R. S., Barta P. E. and Harris G. J. Reduced basal ganglia volume associated with the gene for Huntington's disease in asymptomatic at-risk persons. Neurology 44, 823-828, 1994.
Aylward E. H., Li Q., Stine O. C., Ranen N., Sherr M., Barta P. E., Bylsma F. W., Pearlson G. D. and Ross C. A. Longitudinal change in basal ganglia volume in patients with Huntington's disease. Neurology 48, 394-399, 1997.
Beal M. F. Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci 23, 298-304, 2000.
Blum D., Galas M. C., Cuvelier L. and Schiffmann S. N. Chronic intoxication with 3-nitropropionic acid in rats induces the loss of striatal dopamine terminals without affecting nigral cell viability. Neurosci Lett 354, 234-238, 2004.
Brouillet E., Conde F., Beal M. F. and Hantraye P. Replicating Huntington's disease phenotype in experimental animals. Prog Neurobiol 59, 427-468, 1999.
Browne S. E., Bowling A. C., MacGarvey U., Baik M. J., Berger S. C., Muqit M. M., Bird E. D. and Beal M. F. Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia. Ann Neurol 41, 646-653, 1997.
Carlson, N. R. Physiology of behavior, 4th edition, pp401-433. Allyn and Bacon, U.S.A , 1991.
Chiueh C. C. Neuroprotective properties of nitric oxide. Ann N Y Acad Sci 890, 301-311, 1999.
Chiueh C. C. S-nitrosoglutathione (GSNO) mediates brain response to hypoxia. Pediatr Res 51, 414, 2002.
Chiueh C. C. and Rauhala P. The redox pathway of S-nitrosoglutathione, glutathione and nitric oxide in cell to neuron communications. Free Radic Res 31, 641-650, 1999.
Davies S. W., Turmaine M., Cozens B. A., DiFiglia M., Sharp A. H., Ross C. A., Scherzinger E., Wanker E. E., Mangiarini L. and Bates G. P. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537-548, 1997.
Elmquist J. K. CNS regulation of energy balance and body weight: insights from rodent models. Lab Anim Sci 48, 630-637, 1998.
Elmquist J. K., Elias C. F. and Saper C. B. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22, 221-232, 1999.
Elmquist J. K., Maratos-Flier E., Saper C. B. and Flier J. S. Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci 1, 445-450, 1998a.
Elmquist J. K., Bjorbaek C., Ahima R. S., Flier J. S. and Saper C. B. Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol 395, 535-547, 1998b.
Fink J. S., Kalda A., Ryu H., Stack E. C., Schwarzschild M. A., Chen J. F. and Ferrante R. J. Genetic and pharmacological inactivation of the adenosine A2A receptor attenuates 3-nitropropionic acid-induced striatal damage. J Neurochem 88, 538-544, 2004.
Greene J. G., Sheu S. S., Gross R. A. and Greenamyre J. T. 3-Nitropropionic acid exacerbates N-methyl-D-aspartate toxicity in striatal culture by multiple mechanisms. Neuroscience 84, 503-510, 1998.
Gu M., Gash M. T., Mann V. M., Javoy-Agid F., Cooper J. M. and Schapira A. H. Mitochondrial defect in Huntington's disease caudate nucleus. Ann Neurol 39, 385-389, 1996.
Hillebrand J. J., de Wied D. and Adan R. A. Neuropeptides, food intake and body weight regulation: a hypothalamic focus. Peptides 23, 2283-2306, 2002.
Ju T. C., Yang Y. T. and Yang D. I. Protective effects of S-nitrosoglutathione against neurotoxicity of 3-nitropropionic acid in rat. Neurosci Lett 362, 226-231, 2004.
Ju T. C., Chen S. D., Liu C. C. and Yang D. I. Protective effects of S-nitrosoglutathione against amyloid beta-peptide neurotoxicity. Free Radic Biol Med 38, 938-949, 2005.
Kremer H. P., Roos R. A., Dingjan G., Marani E. and Bots G. T. Atrophy of the hypothalamic lateral tuberal nucleus in Huntington's disease. J Neuropathol Exp Neurol 49, 371-382, 1990.
Kremer H. P., Roos R. A., Dingjan G. M., Bots G. T., Bruyn G. W. and Hofman M. A. The hypothalamic lateral tuberal nucleus and the characteristics of neuronal loss in Huntington's disease. Neurosci Lett 132, 101-104, 1991.
Leibowitz S. F. Differential functions of hypothalamic galanin cell grows in the regulation of eating and body weight. Ann N Y Acad Sci 863, 206-220, 1998.
Leibowitz S. F. and Alexander J. T. Hypothalamic serotonin in control of eating behavior, meal size, and body weight. Biol Psychiatry 44, 851-864, 1998.
Li C. Y., Chin T. Y. and Chueh S. H. Rat cerebellar granule cells are protected from glutamate-induced excitotoxicity by S-nitrosoglutathione but not glutathione. Am J Physiol Cell Physiol 286, C893-904, 2004.
Li S. H., Yu Z. X., Li C. L., Nguyen H. P., Zhou Y. X., Deng C. and Li X. J. Lack of huntingtin-associated protein-1 causes neuronal death resembling hypothalamic degeneration in Huntington's disease. J Neurosci 23, 6956-6964, 2003.
Lipton S. A. and Rosenberg P. A. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 330, 613-622, 1994.
Ludolph A. C., He F., Spencer P. S., Hammerstad J. and Sabri M. 3-Nitropropionic acid-exogenous animal neurotoxin and possible human striatal toxin. Can J Neurol Sci 18, 492-498, 1991.
Pratley R. E., Salbe A. D., Ravussin E. and Caviness J. N. Higher sedentary energy expenditure in patients with Huntington's disease. Ann Neurol 47, 64-70, 2000.
Rauhala P., Lin A. M. and Chiueh C. C. Neuroprotection by S-nitrosoglutathione of brain dopamine neurons from oxidative stress. FASEB J 12, 165-173, 1998.
Saydoff J. A., Liu L. S., Garcia R. A., Hu Z., Li D. and von Borstel R. W. Oral uridine pro-drug PN401 decreases neurodegeneration, behavioral impairment, weight loss and mortality in the 3-nitropropionic acid mitochondrial toxin model of Huntington's disease. Brain Res 994, 44-54, 2003.
Schilling G., Becher M. W., Sharp A. H., Jinnah H. A., Duan K., Kotzuk J. A., Slunt H. H., Ratovitski T., Cooper J. K., Jenkins N. A., Copeland N. G., Price D. L., Ross C. A. and Borchelt D. R. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet 8, 397-407, 1999.
Singh R. J., Hogg N., Joseph J. and Kalyanaraman B. Mechanism of nitric oxide release from S-nitrosothiols. J Biol Chem 271, 18596-18603, 1996.
Vonsattel J. P., Myers R. H., Stevens T. J., Ferrante R. J., Bird E. D. and Richardson E. P., Jr. Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol 44, 559-577, 1985.
Williams G., Bing C., Cai X. J., Harrold J. A., King P. J. and Liu X. H. The hypothalamus and the control of energy homeostasis: different circuits, different purposes. Physiol Behav 74, 683-701, 2001.