The parthenolide derivative ACT001 synergizes with low doses of L-DOPA to improve MPTP-induced Parkinson's disease in mice

Abstract L-3,4-dihydroxyphenylalanine (L-DOPA) is currently the main drug used to treat Parkinson's disease (PD). However, long-term use of l -DOPA causes substantial side effects, and we hope to find a biological active ingredient that synergizes with a low-dose of l -DOPA to achieve the same therapeutic effect as that of a high-dose of l -DOPA. The natural product parthenolide (PTL) is the active ingredient in the medicinal plant feverfew (Tanacetum parthenium) and has antioxidant and anti-inflammatory properties. ACT001, a fumarate salt form of dimethylaminomicheliolide (DMAMCL), is a derivative of parthenolide and has comparable effects to those of PTL but exhibits higher stability in the plasma and is available at a lower cost. In our study, we used ACT001 in combination with l -DOPA to treat 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice. Specifically, ACT001 significantly reduced motor dysfunction and dopaminergic neurodegeneration in MPTP-treated mice. Furthermore, ACT001 abolished MPTP-induced α-synuclein overexpression, astrocyte activation and interleukin-1β (IL-1β) production in the substantia nigra and striatum of the mouse brain. In addition, ACT001 increased the levels of the anti-apoptotic signalling molecule Bcl-2 and the pAkt/Akt ratio and reduced the levels of the pro-apoptotic signalling molecule Bax and the activation of Caspase3 in the substantia nigra and striatum. We found that the effects of the co-administration of ACT001 and l -DOPA (5 mg/kg) were equivalent to those of the administration of 8 mg/kg l -DOPA in MPTP-induced Parkinson's disease in mice. Then, this evidence suggests that l -DOPA + ACT001 may be used for the treatment of PD.