Ceftriaxone increases glutamate uptake and reduces striatal tyrosine hydroxylase loss in 6-OHDA Parkinson's model.
Ceftriaxone increases glutamate uptake and reduces striatal tyrosine hydroxylase loss in 6-OHDA Parkinson's model.
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DOI：
10.1007/s12035-013-8598-0
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发表时间：
2014-06
影响因子：
5.1
通讯作者：
Salvatore MF
中科院分区：
文献类型：
--
作者：
Chotibut T;Davis RW;Arnold JC;Frenchek Z;Gurwara S;Bondada V;Geddes JW;Salvatore MF
过量的谷氨酸能神经传递可能导致帕金森病（PD）中黑质纹状体神经元的兴奋性毒性损失。在这里，我们确定增加谷氨酸摄取是否可以减少PD进展中酪氨酸羟化酶（TH）损失的程度。β -内酰胺类抗生素头孢曲松增加谷氨酸转运蛋白1 （GLT-1）的表达，GLT-1是一种谷氨酸转运蛋白，在中枢神经系统的谷氨酸清除中起主要作用，并可能减轻其他神经退行性疾病模型中的不良行为或神经生物学功能。在建立的6-羟多巴胺（6-OHDA） PD模型中，我们观察到与bbb80 % TH损失相关的谷氨酸摄取显著减少。头孢曲松（200mg /kg, i.p）使未损伤大鼠纹状体谷氨酸摄取增加，连续注射≥5天，注射后持续14天，超过6-羟色胺产生bb0 - 70% TH损失所需的时间（~9天）。当在6-OHDA时给予头孢曲松时，TH损失为~ 57%，而暂时匹配的车辆注射对照组为~ 85%，安非他明诱导的旋转减少了约2倍。这种TH损失的衰减与谷氨酸摄取增加、GLT-1表达增加和丝氨酸19 TH磷酸化减少有关，丝氨酸19 TH磷酸化是黑质纹状体神经元特异性的钙依赖性靶点。这些结果表明，谷氨酸摄取可以在PD模型中靶向，以钙依赖的方式降低TH损失率，并减弱与6-OHDA病变相关的运动行为。考虑到检测可靠的PD标记物最终将用于易感人群，我们的研究结果证明增加谷氨酸摄取可能会延长运动障碍发生前的时间。
Excess glutamatergic neurotransmission may contribute to excitotoxic loss of nigrostriatal neurons in Parkinson’s disease (PD). Here, we determined if increasing glutamate uptake could reduce the extent of tyrosine hydroxylase (TH) loss in PD progression. The beta-lactam antibiotic, ceftriaxone, increases the expression of glutamate transporter 1 (GLT-1), a glutamate transporter that plays a major role in glutamate clearance in central nervous system and may attenuate adverse behavioral or neurobiological function in other neurodegenerative disease models. In association with >80 % TH loss, we observed a significant decrease in glutamate uptake in the established 6-hydroxydopamine (6-OHDA) PD model. Ceftriaxone (200 mg/kg, i.p.) increased striatal glutamate uptake with ≥ 5 consecutive days of injection in nonlesioned rats and lasted out to 14 days postinjection, a time beyond that required for 6-OHDA to produce >70 % TH loss (~9 days). When ceftriaxone was given at the time of 6-OHDA, TH loss was ~57 % compared to ~85 % in temporally matched vehicle-injected controls and amphetamine-induced rotation was reduced about 2-fold. This attenuation of TH loss was associated with increased glutamate uptake, increased GLT-1 expression, and reduced Serine 19 TH phosphorylation, a calcium-dependent target specific for nigrostriatal neurons. These results reveal that glutamate uptake can be targeted in a PD model, decrease the rate of TH loss in a calcium-dependent manner, and attenuate locomotor behavior associated with 6-OHDA lesion. Given that detection of reliable PD markers will eventually be employed in susceptible populations, our results give credence to the possibility that increasing glutamate uptake may prolong the time period before locomotor impairment occurs.