Region-specific attenuation of a trypsin-like protease in substantia nigra following dopaminergic neurotoxicity by 1-methyl-4-phenyl-1,2, 3,6-tetrahydropyridine.
We analysed apoptosis, caspase-1 and -3, and trypsin-like protease activity in the nigrostriatal pathway during 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP injected (30 mg/kg, i.p., twice, 16 h apart) mice were sacrificed on 1, 2 and 7 days. DNA extracted from nucleus caudatus putamen (NCP) and substantia nigra (SN) was subjected to agarose gel electrophoresis. Typical apoptotic-like DNA cleavage was absent in SN or NCP after this dose of MPTP. A trypsin-like protease activity was significantly decreased in SN and not in NCP. While caspase-3 activity in the whole brain was increased significantly, caspase-1 activity was unaffected. Striatal dopamine content was decreased to 75% by 7 days. The absence of typical DNA 'ladder' when there was severe striatal dopamine depletion suggests that in vivo MPTP-mediated dopaminergic neurotoxicity may not involve apoptotic cell death, and explains why in mice MPTP-induced dopamine depletion is transient. The region-specific decrease in trypsin-like protease activity and absence of caspase-3 activation in SN signify the importance of trypsin-like protease in the regulation of apoptosis in MPTP-neurotoxicity in mice.
Usha
R
R
Protein Design and Engineering Division, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, 700 032, Calcutta, India.
Muralikrishnan
D
D
Thomas
B
B
Ghosh
S
S
Mandal
C
C
Mohanakumar
K P
KP
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002421:Caudate Nucleus / Q000293:injuries / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents; D051379:Mice; D008807:Mice, Inbred BALB C; D011699:Putamen / Q000293:injuries / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism*; D014357:Trypsin / Q000378:metabolism*
D015259:Dopamine Agents; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014357:Trypsin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D004298:Dopamine