The Expression of CYP2D22, An Ortholog of Human CYP2D6, in Mouse Striatum and Its Modulation in 1-Methyl 4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinson's Disease Phenotype and Nicotine-Mediated Neuroprotection

Abstract

The main contributory factors of Parkinson's disease (PD) are aging, genetic factors, and environmental exposure to pesticides and heavy metals. CYP2D22, a mouse ortholog of human CYP2D6, is expected to participate in a chemically induced PD phenotype due to its structural resemblance with CYP2D6. Despite its expected participation in PD, its expression in the nigrostriatal tissues and modulation by the chemicals that induce PD or offer neuroprotection have not yet been investigated. The present study was undertaken to investigate CYP2D22 expression in mouse striatum and to assess its involvement in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD phenotype and nicotine-mediated neuroprotection. The animals were treated intraperitoneally daily with nicotine (1 mg/kg) for 8 weeks, followed by MPTP (20 mg/kg) + nicotine (1 mg/kg) for 2-4 weeks and vice versa, along with respective controls. In some sets of experiments, the animals were treated with ketoconazole (300 mg/kg), a CYP3AH/CYP2D22 inhibitor, along with nicotine and/or MPTP. Tyrosine hydroxylase (TH)-immunoreactivity in the substantia nigra, the expression of nicotinic acetylcholine receptors (nAChRs) alpha6 and alpha4, dopamine content, and 1-methyl-4-phenylpyridinium ion (MPP(+)) level in the striatum were measured to confirm the MPTP-induced PD phenotype and nicotine-mediated neuroprotection. CYP2D22 and nAChRs expressions were measured in the striatum by RT-PCR/western blotting and dopamine level; CYP2D22 catalytic activity and MPP(+) content were determined by high-performance liquid chromatography (HPLC). MPTP increased dopaminergic neuronal degeneration and the striatal MPP(+) level and reduced striatal dopamine content; it attenuated expression/activity of CYP2D22 and nAChRs that were significantly restored in nicotine-treated animals. Ketoconazole reduced the nicotine-mediated increase in CYP2D22 expression and activity, dopamine content, and TH-immunoreactivity. The results indicate the expression of CYP2D22 in mouse striatum and its possible role in the MPTP-induced PD phenotype and nicotine-mediated neuroprotection.