Neuroprotection and Neurometabolic Diseases Laboratory (Wyse´S Lab), Department of Biochemistry, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Graduate Program in Biological Sciences: Biochemistry, Department of Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Neurotox Res. 2024 Aug 27;42(5):39. doi: 10.1007/s12640-024-00718-y.
There is a public health concern about the use of methylphenidate (MPH) since the higher prescription for young individuals and non-clinical purposes is addressed to the limited understanding of its neurochemical and psychiatric consequences. This study aimed to evaluate the impact of early and chronic MPH treatment on the striatum focusing on amino acid profile, glutamatergic excitotoxicity, redox status, neuroinflammation and glial cell responses. Male Wistar rats were treated with MPH (2.0 mg/kg) or saline solution from the 15th to the 44th postnatal day. Biochemical and histological analyses were conducted after the last administration. MPH altered the amino acid profile in the striatum, increasing glutamate and ornithine levels, while decreasing the levels of serine, phenylalanine, and branched-chain amino acids (leucine, valine, and isoleucine). Glutamate uptake and Na,K-ATPase activity were decreased in the striatum of MPH-treated rats as well as increased ATP levels, as indicator of glutamatergic excitotoxicity. Moreover, MPH caused lipid peroxidation and nitrative stress, increased TNF alpha expression, and induced high levels of astrocytes, and led to a decrease in BDNF levels. In summary, our results suggest that chronic early-age treatment with MPH induces parallel activation of damage-associated pathways in the striatum and increases its vulnerability during the juvenile period. In addition, data presented here contribute to shedding light on the mechanisms underlying MPH-induced striatal damage and its potential implications for neurodevelopmental disorders.
人们对哌醋甲酯（MPH）的使用存在公共卫生方面的担忧，因为针对年轻人和非临床用途的较高处方剂量，表明人们对其神经化学和精神科后果的认识有限。本研究旨在评估早期和慢性 MPH 治疗对纹状体的影响，重点关注氨基酸谱、谷氨酰胺能兴奋性毒性、氧化还原状态、神经炎症和神经胶质细胞反应。雄性 Wistar 大鼠从第 15 天到第 44 天接受 MPH（2.0mg/kg）或生理盐水治疗。最后一次给药后进行生化和组织学分析。MPH 改变了纹状体中的氨基酸谱，增加了谷氨酸和鸟氨酸水平，同时降低了丝氨酸、苯丙氨酸和支链氨基酸（亮氨酸、缬氨酸和异亮氨酸）水平。MPH 处理大鼠纹状体中的谷氨酸摄取和 Na，K-ATP 酶活性降低，同时增加了作为谷氨酸能兴奋性毒性指标的 ATP 水平。此外，MPH 导致脂质过氧化和硝化应激，增加 TNF alpha 表达，并诱导高水平的星形胶质细胞，导致 BDNF 水平降低。总之，我们的结果表明，慢性早期 MPH 治疗会在纹状体中平行激活与损伤相关的途径，并在青少年时期增加其易损性。此外，这里呈现的数据有助于阐明 MPH 诱导的纹状体损伤的机制及其对神经发育障碍的潜在影响。
