林湘明,刘晓莉,时凯旋,张凌韬,张文津

• 1:北京师范大学体育与运动学院
• 2:北京市第三十五中学国际部

摘要(Abstract)：

目的:试图从内源性大麻素系统(e CBs)对纹状体突触Glu兴奋性毒性的调节作用入手,进一步阐释运动调控PD模型大鼠行为功能紊乱的神经生物学机制。方法:选用清洁级雄性SD大鼠,随机分为假手术组、假手术运动组、PD组、PD运动组,每组18只,共72只。6-OHDA于右内侧前脑束注射制备单侧PD大鼠模型,假手术组于相同位点注射等量生理盐水作为对照。术后恢复1周对大鼠进行强度11 m/min,时间30 min/d,每周5天,为期4周运动干预。在建模后7天于颈部皮下注射阿扑吗啡(APO)诱导旋转实验评价PD模型可靠性,并结合平衡木试验评价大鼠运动整合能力和平衡能力。采用微透析-高效液相色谱(HPLC)技术,检测纹状体神经细胞外Glu浓度;采用免疫组化和免疫印记技术检测纹状体CB1受体及RGS4蛋白表达。结果:运动干预第3、4周,与PD组相比,PD运动组大鼠穿越平衡木的潜伏期和总时间显著性减少(P<0.05),纹状体神经细胞外Glu含量显著降低(P<0.05),纹状体CB1受体、RGS4蛋白表达水平也显著降低(P<0.05)。结论:运动通过调节纹状体RGS4、CB1表达,降低纹状体胞外Glu增高的趋势,并改善了PD模型大鼠运动整合能力和平衡能力。e CBs参与运动对皮层-纹状体Glu突触兴奋性毒作用的调节过程,其机制可能与运动重塑皮层-纹状体Glu能突触e CBs介导的长时程抑制(e CB-LTD)有关。

关键词(KeyWords)： 帕金森病;大鼠;运动干预;谷氨酸;内源性大麻素系统

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金项目(项目编号:31571221)

作者(Author): 林湘明,刘晓莉,时凯旋,张凌韬,张文津

DOI: 10.13297/j.cnki.issn1005-0000.2017.03.014

参考文献(References)：

• [1]时凯旋,刘晓莉,乔德才,等.跑台运动对PD模型大鼠运动皮层异常β振荡的调节作用[J].西安体育学院学报,2017,34(5):590-298.
• [2]BOULT S,MOUNAYAR S,POUPARD A,et al.Behavioral recovery in MPTP-treated monkeys:neurochemical mechanisms studied by intrastriatalmicrodialysis[J].J Neurosci,2008,28(38):9575-9584.
• [3]MENG T,YUAN S,ZHENG Z,et al.Effects of endogenous melatonin on glutamate and GABA rhythms in the striatum of unilateral 6-hydroxydopamine-lesioned rats[J].Neuroscience,2015,286:308-315.
• [4]VILLALBA R M,MATHAI A,SMITH Y.Morphological changes of glutamatergic synapses in animal models of Parkinson's disease[J].Front Neuroanat,2014,9:117-117.
• [5]VAN LAAR V S,ROY N,LIU A,et al.Glutamate excitotoxicity in neurons triggers mitochondrial and endoplasmic reticulum accumulation of Parkin,and,in the presence of N-acetyl cysteine,mitophagy[J].Neurobiol Dis,2015,74:180-193.
• [6]SUN Z,JIA J,GONG X,et al.Inhibition of glutamate and acetylcholine release in behavioral improvement induced by electroacupuncture in parkinsonian rats[J].Neurosci Lett,2012,520(1):32-37.
• [7]FERNANDEZ‐RUIZ J.The endocannabinoid system as a target for the treatment of motor dysfunction[J].Br J Pharmacol,2009,156(7):1029-1040.
• [8]FAGAN S G,CAMPBELL V A.The influence of cannabinoids on generic traits of neurodegeneration[J].Br J Pharmacol,2014,171(6):1347-1360.
• [9]陈巍,魏翔,刘晓莉,等.运动对PD模型大鼠皮层-纹状体Glu能神经传递的影响[J].北京体育大学学报,2015(2):61-66.
• [10]PAXIONS G,WASTON C.The rat brain in stereotaxic coordinates[M].Elsevier Academic Press,2007,17-18.
• [11]DEUMENS R,BLOKLAND A,PRICKAERTS J.Modeling Parkinson's disease in rats:an evaluation of 6-OHDA lesions of the nigrostriatalpathway[J].Exp Neurol,2002,175(2):303-317.
• [12]TAJIRI N,YASUHARA T,SHINGO T,et al.Exercise exerts neuroprotective effects on Parkinson's disease model of rats[J].Brain Res,2010,1310:200-207.
• [13]ALLBUTT H N,HENDERSON J M.Use of the narrow beam test in the rat,6-hydroxydopamine model of Parkinson's disease[J].J Neurosci Methods,2007,159(2):195-202.
• [14]侯莉娟,林然,刘晓莉,等.一次性力竭运动对大鼠苍白球外侧部神经元自发放电活动的影响[J].西安体育学院学报,2015,32(2):196-200.
• [15]LANG A E,OBESO J A.Challenges in Parkinson's disease:restoration of the nigrostriatal dopamine system is not enough[J].Lancet Neurol,2004,3(5):309-316.
• [16]FLORIO T,DILORETO S,CERRITO F,et al.Influence of prelimbic and sensorimotor cortices on striatal neurons in the rat:electrophysiological evidence for converging inputs and the effects of 6-OHDA-induced degeneration of the substantia nigra[J].Brain Res,1993,619(1):180-188.
• [17]BEZARD E,DOVERO S,PRUNIER C,et al.Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease[J].J Neurosci,2001,21(17):6853-6861.
• [18]RAJU D V,AHERN T H,SHAH D J,et al.Differential synaptic plasticity of the corticostriatal and thalamostriatal systems in an MPTPtreated monkey model of parkinsonism[J].Eur J Neurosci,2008,27(7):1647-1658.
• [19]LEWERENZ J,MAHER P.Chronic glutamate toxicity in neurodegenerative diseases-what is the evidence?[J].Front Neurosci,2015,9.
• [20]CASTILLO P E,YOUNTS T J,CHAVEZ A E,et al.Endocannabinoid signaling and synaptic function[J].Neuron,2012,76(1):70-81.
• [21]MORES V,CHOI D K.Promising cannabinoid-based therapies for Parkinson’s disease:motor symptoms to neuroprotection[J].Mol Neurodegener,2015,10(1):17.
• [22]HASHIMOTODANI Y,OHNO-SHOSAKU T,KANO M.Endocannabinoids and synaptic function in the CNS[J].Neuroscientist,2007,13(2):127-137.
• [23]MATHUR B N,LOVINGER D M.Endocannabinoid–dopamine interactions in striatal synaptic plasticity[J].Front Pharmacol,2012,3:66.
• [24]GERDEMAN G L,RONESI J,LOVINGER D M.Postsynaptic endocannabinoid release is critical to long-term depression in the striatum[J].Nat Neurosci,2002,5(5):446-451.
• [25]CEROVIC M,D’ISA R,TONINI R,et al.Molecular and cellular mechanisms of dopamine-mediated behavioral plasticity in the striatum[J].Neurobiol Learn Mem,2013,105:63-80.
• [26]KREITZER A C,MALENKA R C.Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models[J].Nature,2007,445(7128):643-647.
• [27]LERNER T N,KREITZER A C.RGS4 is required for dopaminergic control of striatal LTD and susceptibility to parkinsonian motor deficits[J].Neuron,2012,73(2):347-359.
• [28]TILLERSON J L,COHEN A D,PHILHOWER J,et al.Forced limbuse effects on the behavioral and neurochemical effects of 6-hydroxydopamine[J].J Neurosci,2001,21(12):4427-4435.
• [29]POTHAKOS K,KURZ M J,LAU Y S.Restorative effect of endurance exercise on behavioral deficits in the chronic mouse model of Parkinson's disease with severe neurodegeneration[J].BMC Neurosci,2009,10(1):6.
• [30]PETZINGER G M,FISHER B E,MCEWEN S,et al.Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson’s disease[J].Lancet Neurol,2013,12(7):716-726.
• [31]TOY W A,PETZINGER G M,LEYSHON B J,et al.Treadmill exercise reverses dendritic spine loss in direct and indirect striatal medium spiny neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)mouse model of Parkinson's disease[J].Neurobiol Dis,2014,63:201-209.
• [30]ROMERO J,BERRENd ERO F,Perez-Rosado A,et al.Unilateral 6-hydroxydopamine lesions of nigrostriatal dopaminergic neurons increased CB1 receptor m RNA levels in the caudate-putamen[J].Life Sci,2000,66(6):485-494.