纹状体内注射甲基丙二酸会诱发惊厥并产生硫代巴比妥酸反应物（TBARS），并改变大鼠纹状体和大脑皮层中的钠钾ATP酶活性。
Intrastriatal methylmalonic acid administration induces convulsions and TBARS production, and alters Na+,K+-ATPase activity in the rat striatum and cerebral cortex.
作者信息
Malfatti Carlos Ricardo Maneck, Royes Luiz Fernando Freire, Francescato Leandro, Sanabria Emílio Rafael Garrido, Rubin Maribel Antonello, Cavalheiro Esper Abrão, Mello Carlos Fernando
机构信息
Departamento de Química, Universidade Federal de Santa Maria, Brazil.
出版信息
Epilepsia. 2003 Jun;44(6):761-7. doi: 10.1046/j.1528-1157.2003.42902.x.
PURPOSE
Methylmalonic acid (MMA) inhibits succinate dehydrogenase (SDH) and beta-hydroxybutyrate dehydrogenase activity in vitro. Acute intrastriatal administration of MMA induces convulsions through glutamatergic mechanisms probably involving primary adenosine triphosphate (ATP) depletion and free radical generation. In this study we investigated whether the intrastriatal administration of MMA causes lipoperoxidation and alteration in Na+, K+-ATPase activity ex vivo and characterized the electrographic changes elicited by the intrastriatal administration of this organic acid.
METHODS
MMA-induced lipoperoxidation, alterations in Na+, K+-ATPase activity and electrographic changes were measured by measuring total thiobarbituric acid-reacting substances and inorganic phosphate release by spectrophotometry, and by depth electrode recording, respectively.
RESULTS
We demonstrated that intrastriatal MMA (6 mmol) injection causes convulsive behavior and electrographically recorded convulsions that last approximately 2 h. Concomitant with the increase of thiobarbituric acid-reacting substances (TBARS) content, we observed a significant inhibition of Na+,K+-ATPase activity in the striatum, and activation of Na+,K+-ATPase activity in the ipsilateral cerebral cortex. Intrastriatal MMA injection increased the content of TBARS in the striatum measured 30 min (32.4 +/- 12.0%, compared with the noninjected contralateral striatum) and 3 h (39.7 +/- 5.1%, compared with the noninjected contralateral striatum) after MMA injection. TBARS content of the ipsilateral cerebral cortex increased after MMA injection at 30 min (42.1 +/- 6.0%) and 3 h (40.4 +/- 20.2%), and Na+,K+-ATPase activity in the ipsilateral cerebral cortex increased during ictal activity (113.8 +/- 18%) and returned to basal levels as electrographic convulsions vanished in the cortex. Interestingly, intrastriatal MMA administration induced a persistent decrease in Na+,K+-ATPase activity only in the injected striatum (44.9 +/- 8.1% at 30 min and 68.7 +/- 9.4 at 3 h).
CONCLUSIONS
These data suggest that MMA induces lipoperoxidation associated with Na+,K+-ATPase inhibition or activation, depending on the cerebral structure analyzed. It is suggested that Na+,K+-ATPase inhibition may play a primary role in generating MMA-induced convulsions.
目的
甲基丙二酸（MMA）在体外可抑制琥珀酸脱氢酶（SDH）和β-羟基丁酸脱氢酶的活性。急性纹状体内注射MMA可通过谷氨酸能机制诱发惊厥，这可能涉及原发性三磷酸腺苷（ATP）耗竭和自由基生成。在本研究中，我们调查了纹状体内注射MMA是否会在离体状态下引起脂质过氧化和Na⁺，K⁺-ATP酶活性改变，并对纹状体内注射这种有机酸所引发的脑电图变化进行了特征描述。
方法
分别通过分光光度法测量总硫代巴比妥酸反应物质和无机磷释放，以及通过深度电极记录来测量MMA诱导的脂质过氧化、Na⁺，K⁺-ATP酶活性改变和脑电图变化。
结果
我们证明纹状体内注射MMA（6 mmol）会导致惊厥行为和脑电图记录的惊厥发作，持续约2小时。伴随着硫代巴比妥酸反应物质（TBARS）含量的增加，我们观察到纹状体内Na⁺，K⁺-ATP酶活性受到显著抑制，而同侧大脑皮质中的Na⁺，K⁺-ATP酶活性则被激活。纹状体内注射MMA后30分钟（与未注射的对侧纹状体相比，增加32.4±12.0%）和3小时（与未注射的对侧纹状体相比，增加39.7±5.1%）时，纹状体内TBARS含量增加。MMA注射后30分钟（增加42.1±6.0%）和3小时（增加40.4±20.2%）时，同侧大脑皮质的TBARS含量增加，并且在发作期活动期间同侧大脑皮质中的Na⁺，K⁺-ATP酶活性增加（113.8±18%），随着皮质脑电图惊厥消失，其恢复到基础水平。有趣的是，纹状体内注射MMA仅在注射的纹状体内导致Na⁺，K⁺-ATP酶活性持续下降（30分钟时为44.9±8.1%，3小时时为68.7±9.4%）。
结论
这些数据表明，根据所分析的脑结构不同，MMA会诱导与Na⁺，K⁺-ATP酶抑制或激活相关的脂质过氧化。提示Na⁺，K⁺-ATP酶抑制可能在MMA诱导的惊厥发作中起主要作用。
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