パーキンソン病モデルマウスにおけるメマンチンの脳内インフュージョンと薬効評価

抄録

Parkinson's disease is a neurodegenerative disorder cased by loss of nigrostriatal dopaminergic neurons. For over 40 years, levodopa had been established as a gold standard for PD treatment. However, long-term treatment with levodopa is often complicated by the development of adverse effects such as abnormal involuntary movements (AIMs), referred to as levodopa-induced dyskinesia (LIDs). We here report the pharmacological effects of the intrastriatal infusion of memantine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, in a 6-OHDA-lesioned mouse model of hemiparkinsonism. Spontaneous and apomorphine-induced rotational activities with an abnormal hind limb stepping were assessed as Parkinsonian symptoms. Daily intraperitoneal injection of levodopa (15 mg/kg) was performed for 21 days, with assessing AIMs score as an index of LID development. Intrastriatal memantine infusion targeted into the right dorsal striatum, using an iPRECIO^TM programmable micro infusion pump with a brain infusion kit, was examined with 4 doses (3 days/dose). Infusion of memantine significantly alleviated Parkinsonian symptoms, and it also reduced AIMs score with a dose-dependent manner. These results support the idea that over-activation of the striatal NMDA receptor function might generate both Parkinsonian symptoms and LIDs.