항정신병약물 클로자핀이 흰쥐 뇌실로 주입한 인슐린의 반응에 미치는 영향
The Effect of Clozapine on Central Insulin Response in Rats
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Objectives : Although antipsychotic drug clozapine has superior efficacy, this is hampered by metabolic side effects such as weight gain and diabetes. Recent studies demonstrate that clozapine induces insulin resistance. However, the identity and location of insulin resistance induced by clozapine has not been clarified. In this study, the effect of clozapine on central insulin response was investigated in rats. Methods : Male Sprague-Dawley rats received intraperitoneal injection of clozapine or vehicle, which was followed by intracerebroventricular injection of insulin or its vehicle. The effects of clozapine on insulin-induced changes in blood glucose level and Akt phosphorylation in hypothalamus were investigated. Results : Intraperitoneal injection of clozapine (20 mg/kg) increased blood glucose in rats. Intracerebroventricular injection of insulin reduced blood glucose in rats, which was blunted by pretreatment of clozapine. Accompanied with the antagonistic effect of clozapine to central insulin action in terms of blood glucose, clozapine inhibited the insulin-induced phosphorylation of Akt at Ser473 in rat hypothalamus. Conclusion : Administration of clozapine inhibited the central insulin-induced changes in blood glucose and Akt phosphorylation in rat hypothalamus. These findings suggest that hypothalamus could be the site of action for the clozapine-induced insulin resistance.
Abstract
Objectives : Although antipsychotic drug clozapine has superior efficacy, this is hampered by metabolic side effects such as weight gain and diabetes. Recent studies demonstrate that clozapine induces insulin resistance. However, the identity and location of insulin resistance induced by clozapine has not been clarified. In this study, the effect of clozapine on central insulin response was investigated in rats. Methods : Male Sprague-Dawley rats received intraperitoneal injection of clozapine or vehicle, which was followed by intracerebroventricular injection of insulin or its vehicle. The effects of clozapine on insulin-induced changes in blood glucose level and Akt phosphorylation in hypothalamus were investigated. Results : Intraperitoneal injection of clozapine (20 mg/kg) increased blood glucose in rats. Intracerebroventricular injection of insulin reduced blood glucose in rats, which was blunted by pretreatment of clozapine. Accompanied with the antagonistic effect of clozapine to central insulin action in terms of blood glucose, clozapine inhibited the insulin-induced phosphorylation of Akt at Ser473 in rat hypothalamus. Conclusion : Administration of clozapine inhibited the central insulin-induced changes in blood glucose and Akt phosphorylation in rat hypothalamus. These findings suggest that hypothalamus could be the site of action for the clozapine-induced insulin resistance.
참고문헌 (42)
- Newcomer JW, "Metabolic considerations in the use of antipsychotic medications: a review of recent evidence", J Clin Psychiatry, 68(Suppl 1), pp.20~27 (2007)
- Henderson DC, "Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study", Am J Psychiatry, 157, pp.975~981 (2000)
- Henderson DC, "Glucose metabolism in patients with schizophrenia treated with olanzapine or quetiapine: a frequently sampled intravenous glucose tolerance test and minimal model analysis", J Clin Psychiatry, 67, pp.789~797 (2006)
- Henderson DC, "Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study", J Clin Psychiatry, 66, pp.1116~1121 (2005)
- Sernyak MJ, "Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia", Am J Psychiatry, 159, pp.561~566 (2002)
- Houseknecht KL, "Acute effects of atypical antipsychotics on wholebody insulin resistance in rats: implications for adverse metabolic effects", Neuropsychopharmacology, 32, pp.289~297 (2007)
- Nasrallah HA, "Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles", Mol Psychiatry, 13, pp.27~35 (2008)
- American Diabetes Association, "Consensus development conference on antipsychotic drugs and obesity and diabetes", Diabetes Care, 27, pp.596~601 (2004)
- Kim SH, "Relationship between body mass index and insulin resistance in patients treated with second generation antipsychotic agents", J Psychiatr Res, 44, pp.493~498 (2010)
- Hou JC, "Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking", Curr Opin Cell Biol, 19, pp.466~473 (2007)
- Ardizzone TD, "Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine", Brain Res, 923, pp.82~90 (2001)
- Panariello F, "Clozapine impairs insulin action by up-regulating Akt phosphorylation and Ped", Pea-15 protein abundance, 2012, pp.227, 1485~1492
- Dwyer DS, "Antipsychotic drugs affect glucose uptake and the expression of glucose transporters in PC12 cells", Prog Neuropsychopharmacol Biol Psychiatry, 23, pp.69~80 (1999)
- Hill JW, "Hypothalamic pathways linking energy balance and reproduction", Am J Physiol Endocrinol Metab, 294, pp.E827~E832 (2008)
- Levin BE, "Metabolic sensing and the brain: who, what, where, and how?", Endocrinology, 152, pp.2552~2557 (2011)
- Routh VH, "Glucose sensing neurons in the ventromedial hypothalamus", Sensors (Basel), 10, pp.9002~9025 (2010)
- Tulipano G, "Clozapine-induced alteration of glucose homeostasis in the rat: the contribution of hypothalamic-pituitary-adrenal axis activation", Neuroendocrinology, 85, pp.61~70 (2007)
- Martins PJ, "Central nervous system delivery of the antipsychotic olanzapine induces hepatic insulin resistance", Diabetes, 59, pp.2418~2425 (2010)
- García-San Frutos M, "Impaired central insulin response in aged Wistar rats: role of adiposity", Endocrinology, 148, pp.5238~5247 (2007)
- Kim SH, "Dosedependent effect of intracerebroventricular injection of ouabain on the phosphorylation of the MEK1", 2-ERK1, Prog Neuropsychopharmacol Biol Psychiatry, pp.2008, 32[DOI]
- Yu HS, "Intracerebroventricular administration of ouabain, a Na", K-ATPase inhibitor, activates tyrosine hydroxylase through extracellular signal-regulated kinase in rat striatum, 2011, pp.59(6), 779~786[DOI]
- Niswender KD, "Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia", Diabetes, 52, pp.227~231 (2003)
- Gerozissis K, "Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies", Eur J Pharmacol, 585, pp.38~49 (2008)
- Kalra SP, "Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention?", Gene Ther, 18, pp.319~325 (2011)
- Prodi E, "Minireview: the brain as a molecular target for diabetic therapy", Endocrinology, 147, pp.2664~2669 (2006)
- Sánchez-Lasheras C, "Integrative neurobiology of energy homeostasis-neurocircuits, signals and mediators", Front Neuroendocrinol, 31, pp.14~15 (2010)
- Cone RD, "The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis", Int J Obes Relat Metab Disord, 25(Suppl 5), pp.S63~S67 (2001)
- Lin JY, "Effects of various neuroactive substances on single-unit activities of hypothalamic arcuate neurons in brain slices", Brain Res Bull, 31, pp.587~594 (1993)
- Boura-Halfon S, "Phosphorylation of IRS proteins, insulin action, and insulin resistance", Am J Physiol Endocrinol Metab, 296, pp.E581~E591 (2009)
- Aubry JM, "Early effects of mood stabilizers on the Akt", GSK-3beta signaling pathway and on cell survival and proliferation, 2009, pp.205, 419~429
- Kang UG, "The effects of clozapine on the GSK-3-mediated signaling pathway", FEBS LETTERS, 560, pp.115~119 (2004), ELSEVIER SCIENCE BV
- Lu XH, "Second-generation antipsychotic drugs, olanzapine, quetiapine, and clozapine enhance neurite outgrowth in PC12 cells via PI3K", AKT, ERK, and pertussis toxin-sensitive pathways, 2005, pp.27, 43~64
- Olianas MC, "Regulation of PI3K", Akt signaling by N-desmethylclozapine through activation of δ-opioid receptor, 2011, pp.660, 341~350
- Myoung-Sun Roh, "Haloperidol and clozapine differentially regulate signalsupstream of glycogen synthase kinase 3 in the rat frontal cortex", Experimental and Molecular Medicine, 39(3), pp.353~360 (2007), 생화학분자생물학회
- Kim SF, "From the Cover: Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase", Proc Natl Acad Sci U S A, 104, pp.3456~3459 (2007)
- Boyda HN, "Preclinical models of antipsychotic drug-induced metabolic side effects", Trends Pharmacol Sci, 31, pp.484~497 (2010)
- Boyda HN, "A parametric study of the acute effects of antipsychotic drugs on glucose sensitivity in an animal model", Prog Neuropsychopharmacol Biol Psychiatry, 34, pp.945~954 (2010)
- Murashita M, "Acute administration of clozapine concurrently increases blood glucose and circulating plasma ghrelin levels in rats", Psychoneuroendocrinology, 32, pp.777~784 (2007)
- Girgis RR, "Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway", Mol Psychiatry, 13, pp.918~929 (2008)
- Citrome L, "Consensus development conference on antipsychotic drugs and obesity and diabetes: response to consensus statement", Diabetes Care, 27, pp.2087~2090 (2004)
- Jin H, "Atypical antipsychotics and glucose dysregulation: a systematic review", Schizophr Res, 71, pp.195~212 (2004)
- Mukherjee S, "Family history of type 2 diabetes in schizophrenic patients", Lancet, 1, pp.495~ (1989)
