Inhibition of the cdk5/p25 fragment formation may explain the antiapoptotic effects of melatonin in an experimental model of Parkinson's disease.
In this study, the effects of melatonin on MPP+ -treated cerebellar granule neurons (CGNs) in culture were investigated. Results showed that MPP+ treatment significantly decreased cell viability and increased the apoptotic cell population at 24 and 48 hr. Calpain and caspase-3 activation was also determined, with results showing a strong increase in calpain (74%) and caspase 3 activity (70%), as measured by alpha-spectrin cleavage and fluorometric and colorimetric analysis, respectively. There are several studies suggesting that the activation of the cdk5/p35 pathway at its cleavage to cdk5/p25 may play a role in neuronal cell death in neurodegenerative diseases. Moreover, these studies indicate that this cleavage is mediated by calpains, and that MPP+ prompted an increase in cdk5 expression, as well as the cleavage of p35-p25, in a time-dependent manner. 1 mm Melatonin not only reduced the neurotoxic effects of MPP+ on cell viability, but also prevented apoptosis mediated by this Parkinsonian toxin in CGNs. 1 mm Melatonin reduced cdk5 expression, as well as the cleavage of p35-p25. These data indicate that melatonin possesses some neuro-protective properties against MPP+ -induced apoptosis. Moreover, these data suggest that the calpain/cdk5 signaling cascade has a potential role in the MPP+ -mediated apoptotic process in CGNs.
Alvira
Daniel
D
Unitat de Farmacologia i Farmacognòsia, Facultat de Farmacia, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.
Tajes
Marta
M
Verdaguer
Ester
E
Acuña-Castroviejo
Dario
D
Folch
Jaume
J
Camins
Antoni
A
Pallas
Mercè
M
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004789:Enzyme Activation; D008550:Melatonin / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000187:drug effects; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley
D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5; D002154:Calpain; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D008550:Melatonin; D015655:1-Methyl-4-phenylpyridinium