Glutaric acidemia type 1 (GA1) is caused by glutaryl-CoA dehydrogenase deficiency that leads to a blockage in the metabolic route of the amino acids lysine and tryptophan and subsequent accumulation of glutaric acid (GA), 3-hydroxyglutaric acids and glutarylcarnitine (C5DC). Patients predominantly manifest neurological symptoms, associated with acute striatal degeneration, as well as progressive cortical and striatum injury whose pathogenesis is not yet fully established. Current treatment includes protein/lysine restriction and -carnitine supplementation of (L-car). The aim of this work was to evaluate behavior parameters and pro-inflammatory factors (cytokines IL-1β, TNF-α and cathepsin-D levels), as well as the anti-inflammatory cytokine IL10 in striatum of ) and wild type (WT) mice submitted to a normal or a high Lys diet. The potential protective effects of L-car treatment on these parameters were also evaluated. Gcdh mice showed behavioral changes, including lower motor activity (decreased number of crossings) and exploratory activity (reduced number of rearings). Also, Gcdh mice had significantly higher concentrations of glutarylcarnitine (C5DC) in blood and cathepsin-D (CATD), interleukin IL-1β and tumor factor necrosis alpha (TNF-α) in striatum than WT mice. Noteworthy, L-car treatment prevented most behavioral alterations, normalized CATD levels and attenuated IL-1β levels in striatum of Gcdh mice. Finally, IL-1β was positively correlated with CATD and C5DC levels and L-car was negatively correlated with CATD Our results demonstrate behavioral changes and a pro-inflammatory status in striatum of the animal model of GA1 and, most importantly, L-car showed important protective effects on these alterations.

中文翻译：

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左旋肉碱对戊二酰辅酶A脱氢酶缺陷小鼠纹状体行为改变和神经炎症的保护作用


1 型戊二酸血症 (GA1) 是由戊二酰辅酶 A 脱氢酶缺乏引起的，导致氨基酸赖氨酸和色氨酸的代谢途径受阻，随后戊二酸 (GA)、3-羟基戊二酸和戊二酰肉碱 (C5DC) 积累。患者主要表现为神经系统症状，与急性纹状体变性以及进行性皮质和纹状体损伤有关，其发病机制尚未完全确定。目前的治疗包括蛋白质/赖氨酸限制和补充肉碱(L-car)。这项工作的目的是评估纹状体中的行为参数和促炎因子（细胞因子 IL-1β、TNF-α 和组织蛋白酶-D 水平）以及抗炎细胞因子 IL10 和野生型 (WT)小鼠接受正常或高赖氨酸饮食。还评估了 L-car 治疗对这些参数的潜在保护作用。 Gcdh 小鼠表现出行为变化，包括运动活动降低（交叉次数减少）和探索活动（饲养次数减少）。此外，Gcdh 小鼠血液中的戊二酰肉碱 (C5DC) 浓度以及纹状体中的组织蛋白酶-D (CATD)、白细胞介素 IL-1β 和肿瘤因子坏死 α (TNF-α) 浓度显着高于 WT 小鼠。值得注意的是，L-car 治疗阻止了 Gcdh 小鼠纹状体中的大多数行为改变、CATD 水平正常化和 IL-1β 水平减弱。最后，IL-1β 与 CATD 和 C5DC 水平呈正相关，而 L-car 与 CATD 呈负相关。我们的结果表明 GA1 动物模型纹状体中的行为变化和促炎状态，最重要的是，L-car 显示对这些改变具有重要的保护作用。