Neuroprotective effects of alpha-ketoglutarate and ethyl pyruvate against motor dysfunction and oxidative changes caused by repeated 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine exposure in mice

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin associated with drug abuse and causes permanent symptoms of Parkinson's disease (PD) by destroying dopaminergic neurons in the substantia nigra of the brain. In the present study, the neuroprotective effects of two carboxylic acid compounds, viz. alpha-ketoglutarate (A-KG), a Kreb's cycle intermediate and ethyl pyruvate (EP), a lipid-soluble analogue of pyruvate, were evaluated against MPTP intoxication in mice and compared with madopar (MD; combination of levodopa plus benserazide), a standard drug. Animals received oral treatment of A-KG (500mg/kg), EP (100mg/kg) or MD (5mg/kg) daily for 5days followed by intraperitoneal administration of MPTP (20mg/kg) and posttreatment (+10min) of A-KG, EP or MD daily for the remaining 5days. MPTP caused the inhibition of complex I of electron transport chain accompanied by oxidative stress in the brain. It also caused cytotoxicity in the midbrain region as characterized by histology and immunohistochemistry. Treatments of A-KG and EP were found to resolve the loss of motor coordination, oxidative stress, diminished complex I activity and tyrosine hydroxylase-positive neurons in midbrain. A-KG and EP also regressed the histological damage in the brain and minimized the accumulation of alpha-synuclein in the midbrain region. The data suggest that A-KG and EP which are nontoxic carboxylic acid compounds could be of potential therapeutic value in the treatment of PD.