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.