본문 바로가기
KERD
논문KCI 등재

알코올 의존과 파킨슨병 병태생리에서의 살소리놀(Salsolinol)

Salsolinol in the Pathophysiology of Alcohol Dependence and Parkinson’s Disease

김진영|정성훈|정인원
대한신경정신의학회 (Korean Neuropsychiatric Association)|2008.05|신경정신의학 (JOURNAL OF THE KOREAN NEUROPSYCHIATRIC ASSOCIATION)|제47권 제3호|pp. 217-224

2

조회

0

다운로드

1

인용

0

참고문헌

키워드

살소리놀·도파민·아세트알데히드·신경독성효과·알코올 의존·파킨슨병.Salsolinol· Dopamine· Acetaldehyde· Neurotoxicity· Alcoholism· Parkinsons disease.
주제분류정신과학

초록

Salsolinol, a dopamine-derived tetrahydroisoquinoline, is one of the endogenous alkaloids structurally related to morphine. It has been implicated in the pathophysiology of alcohol dependence and Parkinson’s disease since it’s first discovery in 1970’s. Salsolinol is involved in many neurophysiological processes, including modulation of dopamine activity, facilitation of prolactin release and reinforcement of additive substance craving. In addition, salsolinol exerts highly neurotoxic effects on dopaminergic neurons ultimately leading to apoptosis, which is mediated by inhibition of endogenous antioxidants and, thereby, production of reactive oxygen species (ROS). These properties are considerably based in alcohol dependence and several neurodegenerative disorders including Parkinson’s disease. Salsolinol is synthesized by the condensation of dopamine with acetaldehyde or pyruvate through enzymatic or non-enzymatic processes in the dopamine-rich neurons. Acute alcohol ingestion increase the level of acetaldehyde and salsolinol is structurally related to endogenous opioids. Therefore, it has been suggested that salsolinol may be the missing link between alcohol ingestion and the activation of reward pathway in the mesolimbic brain. The reinforcing effect of both alcohol and salsolinol in self-administration setting also strongly supports this hypothesis. N-methylsalsolinol, the major metabolite of salsolinol, is highly neurotoxic and responsible for the selective destruction of dopaminergic neurons in Parkinson’s disease. In contrast to this, several structural analogs of salsolinol act as endogenous anti-parkinsonism substances. Delicate structural differences may underlie this peculiar properties. It may become possible to introduce fine structural modifications, even stereo-specific manipulations, to develop entirely newer kinds of antiparkinsonism drugs. Although the implication of salsolinol in the pathophysiology of alcohol dependence had been suggested long ago, the progression of the related research was at most very limited up to now. Even now, this important chemical, deeply involved in a wide range of essential neurophysiological processes, still is relatively neglected by psychiatric researchers. However, it is expected that the accumulating knowledge of salsolinol’s neuromodulatory and neurotoxic effects will give new insights into the many dopamine related psychiatric disorders including substance dependence, parkinsonism and schizophrenia. We expect that many psychiatrists will give proper attention to this highly promising research subject. (J Korean Neuropsychiatr Assoc 2008;47(3):217-224)

Abstract

Salsolinol, a dopamine-derived tetrahydroisoquinoline, is one of the endogenous alkaloids structurally related to morphine. It has been implicated in the pathophysiology of alcohol dependence and Parkinson’s disease since it’s first discovery in 1970’s. Salsolinol is involved in many neurophysiological processes, including modulation of dopamine activity, facilitation of prolactin release and reinforcement of additive substance craving. In addition, salsolinol exerts highly neurotoxic effects on dopaminergic neurons ultimately leading to apoptosis, which is mediated by inhibition of endogenous antioxidants and, thereby, production of reactive oxygen species (ROS). These properties are considerably based in alcohol dependence and several neurodegenerative disorders including Parkinson’s disease. Salsolinol is synthesized by the condensation of dopamine with acetaldehyde or pyruvate through enzymatic or non-enzymatic processes in the dopamine-rich neurons. Acute alcohol ingestion increase the level of acetaldehyde and salsolinol is structurally related to endogenous opioids. Therefore, it has been suggested that salsolinol may be the missing link between alcohol ingestion and the activation of reward pathway in the mesolimbic brain. The reinforcing effect of both alcohol and salsolinol in self-administration setting also strongly supports this hypothesis. N-methylsalsolinol, the major metabolite of salsolinol, is highly neurotoxic and responsible for the selective destruction of dopaminergic neurons in Parkinson’s disease. In contrast to this, several structural analogs of salsolinol act as endogenous anti-parkinsonism substances. Delicate structural differences may underlie this peculiar properties. It may become possible to introduce fine structural modifications, even stereo-specific manipulations, to develop entirely newer kinds of antiparkinsonism drugs. Although the implication of salsolinol in the pathophysiology of alcohol dependence had been suggested long ago, the progression of the related research was at most very limited up to now. Even now, this important chemical, deeply involved in a wide range of essential neurophysiological processes, still is relatively neglected by psychiatric researchers. However, it is expected that the accumulating knowledge of salsolinol’s neuromodulatory and neurotoxic effects will give new insights into the many dopamine related psychiatric disorders including substance dependence, parkinsonism and schizophrenia. We expect that many psychiatrists will give proper attention to this highly promising research subject. (J Korean Neuropsychiatr Assoc 2008;47(3):217-224)

참고문헌 (52)

  1. Naoi M, "Mitochondria determine the survival and death in apoptosis by an endogenous neurotoxin, N-methyl( R)salsolinol, and neuro-protection by propargylamines", J Neural Transm, 109, pp.607~621 (2002)
  2. Mravec B, "Salsolinol, a derivative of dopamine, is a posible modulator of catecholaminergic transmission: a review of recent developments", Physiol Res, 55, pp.353~364 (2006)
  3. Cohen G, "Alkaloids from catecholamines in adrenal tissue: possible role in alcoholism", Science, 167, pp.1749~1751 (1970)
  4. Naoi M, "Dopamine-derived salsolinol derivatives as endogenous monoamine oxidase inhibitors: occurrence, metabolism and function in human brains", Neurotoxicology, 25, pp.193~204 (2004)
  5. Yi H, "Type A monoamine oxidase is the target of an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, leading to apoptosis in SH-SY5Y cells", J Neurochem, 96, pp.541~549 (2006)
  6. Duncan C, "A critical evaluation of tetrahydroisoquinoline induced ethanol preference in rats", Pharmacol Biochem Behav, 13, pp.265~281 (1980)
  7. Musshoff F, "Systematic regional study of dopamine, norsalsolinol, and (R", S)-salsolinol levels in human brain areas of alcoholics, 2005, pp.29, 46~52
  8. Tóth BE, "Salsolinol is a putative endogenous neuro-intermediate lobe prolactin-releasing factor", J Neuroendocrinol, 13, pp.1042~1050 (2001)
  9. Homicskó KG, "Binding site of salsolinol: its properties in different regions of the brain and the pituitary gland of the rat", Neurochem Int, 42, pp.19~26 (2003)
  10. Chávez-Lara B, "Pharmacologic study of dopamine catabolites on the contractility of isolated guinea pig myocardium", Arch Inst Cardiol Mex, 59, pp.367~373 (1989)
  11. Lee HS, "Effect of tetrahydroisoquinoline alkaloids on the α-adrenoceptors in rat aorta and brain homogenates", J Korean Neurosurg Soc, 28, pp.5~12 (1999)
  12. Storch A, "1-Methyl-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline (salsolinol) is toxic to dopaminergic neuroblastoma SH-SY5Y cells via impairment of cellular energy metabolism", Brain Res, 855, pp.65~75 (2000)
  13. Naoi M, "A novel enzyme enantio-seletively synthesizes (R)salsolinol, a precursor of a dopaminergic neurotoxin, N-methyl (R)salsolinol", Neurosci Lett, 212, pp.183~186 (1996)
  14. Haber H, "Plasma and urine salsolinol in humans: effect of acute ethanol intake on the enantiomeric composition of salsolinol", Alcohol Clin Exp Res, 20, pp.87~92 (1996)
  15. Morikawa N, "Effects of various tetrahydroisoquinoline derivatives on mitochondrial respiration and the electron transfer complexes", J Neural Transm, 105, pp.677~688 (1998)
  16. Akao Y, "Mitochondrial permeability transition medicated apoptosis induced by N-methyl(R)salsolinol, and endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan", J Neurochem, 82, pp.913~923 (2002)
  17. Dringen R, "Glutathione pathways in the brain", Biol Chem, 384, pp.505~516 (2003)
  18. Wanpen S, "Salsolinol, a dopamine-derived tetrahydroisoquinoline, induces cell death by causing oxidative stress in dopaminergic SH-SY5Y cells, and the said effect is attenuated by metallothionein", Brain Res, 1005, pp.67~76 (2004)
  19. Kang JH, "Salsolinol, a tetrahydroisoquinoline catechol neurotoxin, induces human Cu,Zn-superoxidie dismutase modificaiton", J Biochem Mol Biol, 40, pp.684~689 (2007)
  20. Kim HJ, "Differential cell death induced by salsolinol with and without copper: possible role of reactive oxygen species", Mol Pharmacol, 60, pp.440~449 (2001)
  21. Rodd ZA, "Salsolinol produces reinforcing effects in the nucleus accumbens shell of alcohol-preferring (P) rats", Alcohol Clin Exp Res, 27, pp.440~449 (2003)
  22. Rodd ZA, "The reinforcing properties of salsolinol in the ventral tegmental area: evidence for regional heterogeneity and the involvement of serotonin and dopamine", Alcohol Clin Exp Res, 32, pp.230~239 (2008)
  23. Radnai B, "Pivotal role of an endogenous tetrahydroisoquinoline, salsolinol, in stress- and suckling-induced release of prolactin", Ann N Y Acad Sci, 1018, pp.183~191 (2004)
  24. Antkiewicz-Michaluk L, "Antidopaminergic effects of 1,2,3,4-tetrahydroisoquinoline and salsolinol", J Neural Transm, 107, pp.1009~1019 (2000)
  25. Tóth BE, "Physiological role of salsolinol: its hypophysiotrophic function in the regulation of pituitary prolactin secretion", Neurotoxicol Teratol, 24, pp.655~666 (2002)
  26. Székács D, "The role of catecholamines in the prolactin release induced by salsolinol", Neurochem Int, 51, pp.319~322 (2007)
  27. Bodnar I, "Immobilization stress-induced increase in plasma catecholamine levels is inhibited by a prolactoliberin (salsolinol) administration", Ann N Y Acad Sci, 1018, pp.124~130 (2004)
  28. Mravec B, "Salsolinol, an antagonist of prolactoliberine, induces an increase in plasma catecholamine levels in the rat", Auton Neurosci, 115, pp.35~40 (2004)
  29. Antkiewicz-Michaluk L, "Endogenous risk factors in Parkinson’s disease: dopamine and tetrahydroisoquinolines", Pol J Pharmacol, 54, pp.567~572 (2002)
  30. Maruyama W, "A dopaminergic neurotoxin, (R)-N-methylsalsolinol, increases in Parkinsonian cerebrospinal fluid", Ann Neurol, 40, pp.119~122 (1996)
  31. Moser A, "Salsolinol, catecholamine metabolites, and visual hallucinations in L-dopa treated patients with Parkinson’s disease", J Neural Transm, 103, pp.421~432 (1996)
  32. Naoi M, "-methyl(R)salsolinol, a dopamine neurotoxin, in Parkinson’s disease", Adv Neurol, 80, pp.259~264 (1999)
  33. Maruyama W, "A dopaminergic neurotoxin, 1(R), 2(N)-dimethyl-6,7-dihydroxy- 1,2,3,4-tetrahydro isoquinoline, N-methyl(R)salsolinol, and its oxidation product, 1,2(N)-dimethyl-6,7-dihydroxyisoquinolinium ion, accumulate in the nigro-striatal system of the human brain", Neurosci Lett, 223, pp.61~64 (1997)
  34. Micieli G, "Autonomic dysfunction in Parkinson’s disease", Neurol Sci, 24(1), pp.32~34 (2003)
  35. Li ST, "Progressive loss of cardiac sympathetic innervation in Parkinson’s disease", Ann Neurol, 52, pp.220~223 (2002)
  36. Makino Y, "Confirmation of the enantiomers of 1-methyl-1,2,3,4-tetrahydroisoquinoline in the mouse brain and foods applying gas chromatography", mass spectrometry with negative ion chemical ionization, 1990, pp.19, 415~419
  37. Okuda K, "Parkinsonism-preventing activity of 1- methyl-1,2,3,4-tetrahydroisoquinoline derivatives in C57BL mouse in vivo", Biol Pharm Bull, 29, pp.1401~1403 (2006)
  38. Kream RM, "De novo biosynthesis of morphine in animal cells: an evidence-based model", Med Sci Monit, 12, pp.207~219 (2006)
  39. Marshall A, "Potentiation of ethanol narcosis by dopamineand l-DOPA-based isoquinolines", Experientia, 32, pp.201~203 (1976)
  40. Lucchi L, "Action of ethanol and salsolinol on opiate receptor function", Brain Res, 232, pp.506~510 (1982)
  41. Hamilton MG, "Opiate-like activity of salsolinol on the electrically stimulated guinea pig ileum", Life Sci, 25, pp.2205~2210 (1979)
  42. Matsuzawa S, "Involvement of mu-opioid receptor in the salsolinol-associated place preference in rats exposed to conditioned fear stress", Alcohol Clin Exp Res, 24, pp.366~372 (2000)
  43. Myers RD, "Isoquinolines, beta-carbolines and alcohol drinking: involvement of opioid and dopaminergic mechanisms", Experientia, 45, pp.436~443 (1989)
  44. Putscher I, "Effect of S(-)- and R(+)-salsolinol on the POMC gene expression and ACTH release of an anterior pituitary cell line", Alcohol, 12, pp.447~452 (1995)
  45. Costall B, "Hyperactivity induced by tetrahydroisoquinoline derivatives injected into the nucleus accumbens", Eur J Pharmacol, 39, pp.153~160 (1976)
  46. Rodd ZA, "Comparison of intracranial self-administration of ethanol within the posterior ventral tegmental area between alcohol-preferring and Wistar rats", Alcohol Clin Exp Res, 28, pp.1212~1219 (2004)
  47. Rodd-Henricks ZA, "Effects of serotonin-3 receptor antagonists on the intracranial self-administration of ethanol within the ventral tegmental area of Wistar rats", Psychopharmacology (Berl), 165, pp.252~259 (2003)
  48. Rodd ZA, "The reinforcing actions of a serotonin-3 receptor agonist within the ventral tegmental area: evidence for subregional and genetic differences and involvement of dopamine neurons", J Pharmacol Exp Ther, 321, pp.1003~1012 (2007)
  49. Faraj BA, "Elevation of plasma salsolinol sulfate in chronic alcoholics as compared to nonalcoholics", Alcohol Clin Exp Res, 13, pp.155~163 (1989)
  50. Rommelspacher H, "Determination of (R)- and (S)-salsolinol sulfate and dopamine sulfate levels in plasma of nonalcoholics and alcoholics", Alcohol, 12, pp.309~315 (1995)
  51. Strolin Benedetti M, "Influence of food intake on the enantiomeric composition of urinary salsolinol in man", J Neural Transm Gen Sect, 78, pp.43~51 (1989)
  52. Haber H, "Assay of salsolinol in peripheral blood mononuclear cells of alcoholics and healthy subjects by gas chromatography-mass spectrometry", Addict Biol, 7, pp.403~407 (2002)

이 간행물의 다른 논문 (10건)

사회공포증의 아형 분류와 가해형 사회공포증의 임상적 의의오강섭, 임세원pp. 225-229아스퍼거 증후군의 진단과 관련된 혼돈들신석호pp. 230-238정신분열병 환자에서 가상현실을 이용한 추론과제 수행 중 활성화된 뇌영역과 현존감과의 관계：기능자기공명영상 연구김소영, 이형래, 김인영, 박일호, 윤강준, 구정훈, 최수희, 김선일, 김재진pp. 239-246한국인 만성 긴장형두통 환자에서 바이오피드백을 활용한 자율적 이완훈련의 효과구문선, 박주언, 유범희, 강은호, 안주연pp. 247-253경도인지손상 환자에서 야간수면과 전두엽기능의 연관성김성재, 정재석, 주진형, 이정희pp. 254-262
원문 보기