Toki-to protects dopaminergic neurons in the substantia nigra from neurotoxicity of MPTP in mice

Parkinson's disease (PD) is a neurodegenerative disease of the brain characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). No clinically proven drugs that may halt or retard the progression of PD have been reported. This study examined the anti-PD effect of a traditional Japanese/Chinese herbal remedy Toki-to (TKT) using mice treated with a neurotoxin 1-methy 1-4-pheny 1-1,2,3,6-tetrahydroxypyridine (MPTP). TKT showed improvement of MPTP-induced PD-like symptoms (bradykinesia) in a behavioral test (pole test). Histological studies of SNs from these mice demonstrated that TKT had a protective effect on dopaminergic neurons against MPTP neurotoxicity. Real-time RT-PCR analyses of mRNA from SNs demonstrated that expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT) genes were decreased by MPTP treatment and that these decreases were reversed by TKT administration prior to MPTP treatment. DNA microarray analyses indicated that TKT per se suppressed gene expression of serum-and glucocorticoid regulated kinase (SGK) that is believed to be a molecule that drives the pathogenesis of PD. Hence, it is suggested that TKT may inhibit the activation of SGK at the transcriptional level and thusmay participate in halting the progression of MPTP-induced neurotoxicity.