Calpain upregulation in spinal cords of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a heroin analogue, is a neurotoxin that undergoes in vivo oxidation by monoamine oxidase-B (MAO-B) to 1-methyl-4-phenylpyridinium ion (MPP+) which preferentially exerts its toxic effects on the dopaminergic neurons of the substantia nigra in brain. Spinal interneuronal pathways are also likely to be affected in the course of MPP+ neurotoxicity. The primary effect of MPP+ is mediated by irreversible inhibition of mitochondrial complex I, releasing free radicals. MPP+ may also activate N-methyl-D-aspartate (NMDA) receptors, increasing the cytosolic concentration of free Ca2+. Intracellular free radicals indirectly and free Ca2+ directly can activate Ca2+-dependent proteases such as calpain. We investigated involvement of calpain in spinal cord degeneration due to neurotoxin by subjecting male C57BL/6N mice (17 months old) to MPTP administration (12.5 mg/kg for 0.5 h; 25 mg/kg for 0.25 h; and 50 mg/kg for 0.25, 0.5, 1, 2, and 24 h). RT-PCR and Western blot analysis were performed using the thoracic segment of spinal cords from control and MPTP-administered mice. The administration of MPTP caused calpain upregulation at the mRNA and protein levels to various extents, compared to control mice. Calpain activity was measured by 68 kDa neurofilament protein (NFP) degradation, which was increased in MPTP-induced PD mice. These results suggest that calpain may play a role in spinal cord degeneration in mice with MPTP-induced PD.
Ray
S K
SK
Department of Neurology, Medical University of South Carolina, Charleston 29425, USA.
Wilford
G G
GG
Ali
S F
SF
Banik
N L
NL
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage*; D000286:Administration, Sublingual; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D020267:MPTP Poisoning / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D012333:RNA, Messenger; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D002154:Calpain