Rifampicin attenuates the MPTP-induced neurotoxicity in mouse brain.
Rifampicin, an antibacterial drug, is highly effective in the treatment of tuberculosis and leprosy. Recently, it has been reported to have neuroprotective effects in in vitro and in vivo models. This study was designed to elucidate its neuroprotective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity (known as an in vivo mouse model of Parkinson's disease). Mice were injected intraperitoneally (i.p.) with MPTP (10 mg/kg) four times at 1-h intervals, and brains were analyzed 3 or 7 days later. Rifampicin at 20 mg/kg (i.p., twice) had protective effects against MPTP-induced neuronal damage (immunohistochemical changes in tyrosine hydroxylase) in both the substantia nigra and striatum. Rifampicin also protected against the MPTP-induced depletions of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the striatum. The maximal concentrations of rifampicin between 30 and 240 min after a single rifampicin injection (20 mg/kg, i.p.) were 2.6 microM (at 30 min) in plasma and 0.77 microM (at 60 min) in striatum. Next, the effects of rifampicin on oxidative stress [lipid peroxidation in mouse brain homogenates and free radical-scavenging activity against diphenyl-p-picrylhydrazyl (DPPH)] were evaluated to clarify the underlying mechanism. At 1 microM or more, rifampicin significantly inhibited both lipid peroxidation in the striatum and free radical production. These findings suggest that in mice, rifampicin can reach brain tissues at concentrations sufficient to attenuate MPTP-induced neurodegeneration in the nigrostriatal dopaminergic neuronal pathway, and that an inhibitory effect against oxidative stress may be partly responsible for its observed neuroprotective effects.
Oida
Y
Y
Department of Biofunctional Molecules, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan.
Kitaichi
K
K
Nakayama
H
H
Ito
Y
Y
Fujimoto
Y
Y
Shimazawa
M
M
Nagai
H
H
Hara
H
H
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology*; D001923:Brain Chemistry / Q000187:drug effects; D002452:Cell Count / Q000379:methods; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005609:Free Radicals / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D012293:Rifampin / Q000097:blood / Q000627:therapeutic use*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D004791:Enzyme Inhibitors; D005609:Free Radicals; D015102:3,4-Dihydroxyphenylacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D012293:Rifampin; D004298:Dopamine; D006719:Homovanillic Acid