Inhibition of Cdk5/p25 by TFP5 protects dopaminergic neurons in MPTP-induced mouse model of Parkinson's disease

Abstract

Objective To study the neuroprotective role of TFP5 in a MPTP-induced mouse model of Parkinson's disease (PD). Methods C57BL/6 mice were used as experimental animals. Briefly, 5 consecutive days of intraperitoneal injection of 25 mg/Kg 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) was applied to induce mouse PD model. The mice were randomized into 5 groups including control group, model group, scrambled TFP5 peptide (Scb) group, TFP5 group and roscovitine group. On the 7th day after the first injection of MPTP, behavior tests were performed, and then western blot method was employed to detect the expression of p25 and phosphorylated MEF2D in substantia nigra.Tyrosine hydroxylase (TH) immunohistochemical staining was performed to observe the apoptosis of dopaminergic neurons in substantia nigra pars compacta (SNpc) 28 days after the first injection of MPTP. Results MPTP increased the expression of p25 (0.48±0.10 vs 0.26±0.02, P<0.05) and phosphorylated MEF2D (0.81±0.10 vs 0.22±0.02, P<0.05) in substantia nigra, but decreased the number of dopaminergic neurons in SNpc (348.67±24.40 vs 463.29±19.61, P<0.05), resulting in motor impairment in the model mice (P<0.05). Intraperitoneal injection of 30mg/Kg of TFP5 for 3 days effectively reduced the excessive phosphorylation of MEF2D (0.25±0.12 vs 0.81±0.10, P<0.05) in substantia nigra, rescued dopaminergic neuron reduction of SNpc (422.92±8.41 vs 348.67±24.40, P<0.05), and improved the motor ability of the model mice (P<0.05). Roscovitine exerted almost same neuroprotective role as TFP5, while Scb had no protective effect. Conclusion TFP5 can rescue MPTP-induced damage of dopaminergic neurons in substantia nigra, and thus improve motor impairment of model mice, which may be mediated by the inhibition of Cdk5/p25 activity. Key words: Parkinson's disease; Cyclin-dependent kinase 5; TFP5; Dopaminergic neurons