A cell-permeable peptide inhibitor TAT-JBD reduces the MPP+-induced caspase-9 activation but does not prevent the dopaminergic degeneration in substantia nigra of rats.
Many studies showed that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which was widely used to produce Parkinson's disease (PD)-like models in animals can elicit apoptosis with increase of caspase activity via its neurotoxic metabolite 1-methyl-4-phenylpyridinium ion (MPP(+)). Another pathway shown in MPTP-mediated nigrostriatal dopaminergic cell death involved the c-Jun-N-terminal kinases (JNKs) which are stress-activated protein kinases (SAPKs). Activation of the JNKs leads to the activation of transcription factors such as c-Jun that regulates its own expression. However, it is not known whether the activation of c-Jun is crucial in the stimulation of caspases leading to apoptosis observed in PD-like models. The aim of this study was to investigate the cellular expression and phosphorylation of c-Jun and the caspase-9 activity in rat injured with an intranigral injection of MPP(+). Furthermore, we determined the effects of a cell-permeable peptide TAT-JBD, inhibiting selectively JNKs, on apoptosis markers and on the expression of tyrosine hydroxylase (TH). Our results showed that MPP(+) induced not only an activation of c-Jun but also an early and robust stimulation of caspase-9 in midbrain of rats. Furthermore, a preliminary intravenous injection of TAT-JBD reduced the caspase-9 activation specifically induced by MPP(+) suggesting a control of the JNKs pathway on the intrinsic way of apoptosis in MPP(+)-toxicity. However, the inhibition of the JNK pathway did not prevent TH inhibition, DNA fragmentation and Bad expression in MPP(+)-lesioned substantia nigra of rats. Therefore, the possibility of intervention on the JNK pathway as a therapeutic strategy in Parkinson's disease is questionable.
Research Group on Brain Aging, GReViC, EA 3808, 6 rue de la Milétrie, BP 199, 86034 Poitiers Cedex, France. stephanie.pain@univ-poitiers.fr
Stéphanie
S
Pain
Laurence
L
Barrier
Julie
J
Deguil
Serge
S
Milin
Alain
A
Piriou
Bernard
B
Fauconneau
Guylène
G
Page
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053453:Caspase 9 / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; C520542:tat peptide (48-57), Human immunodeficiency virus 1; D014446:Tyrosine 3-Monooxygenase; D048031:JNK Mitogen-Activated Protein Kinases; C506435:Casp9 protein, rat; D053453:Caspase 9; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine