Metformin Inhibits the Development of l-DOPA-Induced Dyskinesia in a Murine Model of Parkinson’s Disease

Autor: Young-Kyoung Ryu, Hye-Yeon Park, Tae Geol Lee, Jung Hwan Hwang, Yong-Hoon Kim, Kyoung-Shim Kim, Chul-Ho Lee, Jung-Ran Noh, Dong-Hee Choi, Jun Go
Rok vydání: 2017
Předmět:
Zdroj: Molecular Neurobiology. 55:5715-5726
ISSN: 1559-1182
0893-7648
Popis: Metformin is a medication that is widely prescribed for the management of type 2 diabetes. In addition to its anti-diabetic uses, metformin has been proposed as a therapeutically effective drug candidate in various central nervous system disorders, including Parkinson's disease (PD). PD is characterized by severe movement defects and is commonly treated with the dopamine (DA) precursor 3,4-dihydroxyphenyl-l-alanine (L-DOPA). However, prolonged use of L-DOPA can lead to the development of L-DOPA-induced dyskinesia (LID). Here, we hypothesized that metformin co-treatment would improve LID in the 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Metformin did not interfere the pharmacotherapeutic effects of L-DOPA in the cylinder test. Furthermore, metformin co-treatment with L-DOPA attenuated the development of LID in unilaterally 6-OHDA-lesioned mice. Metformin showed a long-lasting effect on axial, limb, and orofacial abnormal involuntary movement scores for up to 20 days after treatment initiation. Interestingly, persistent enhancement of the mammalian target of rapamycin, dopamine D1 receptor, and extracellular signaling-regulated kinase 1/2 signaling was maintained in the DA-denervated striatum during metformin treatment. Metformin globally normalized the increased glycogen synthase kinase 3β activity induced by chronic treatment of L-DOPA in a manner associated with Akt activation in unilaterally 6-OHDA-lesioned mice. These findings suggest that metformin may have therapeutic potential for the suppression or management of L-DOPA-induced motor complications in patients with PD.
Databáze: OpenAIRE
Externí odkaz: