KMID : 1237720110440020135
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Anatomy & Cell Biology 2011 Volume.44 No. 2 p.135 ~ p.142
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Cannabinoid receptor agonist protects cultured dopaminergic neurons from the death by the proteasomal dysfunction
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Jeon Po-Sung
Yang Sung-Jun Jeong Ho-Joong Kim Hyun
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Abstract
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Cannabinoids have been proposed to possess neuroprotective properties; though their mechanism of action remains contentious, they are posited to prevent neurodegenerative disorders, including Parkinson¡¯s disease, the pathogenesis of which has not been established. Recent studies have demonstrated that induction of proteasomal dysfunction in animal models results in a phenotype similar to Parkinson¡¯s disease. Here, we investigated the neuroprotective function of a synthetic cannabinoid-receptor agonist (WIN55.212.2) in dopaminergic neuronal death induced by a proteasomal synthase inhibitor (PSI), additionally testing the hypothesis that WIN55.212.2 modulates cytoplasmic accumulation of parkin and ¥á-synuclein, a key feature of proteasomal dysfunction in Parkinson¡¯s. WIN55.212.2 protects PC12 cells from PSI-induced cytotoxicity, concomitantly inhibiting PSI-induced polyADP ribose polymerase expression and activation of caspase-3. While PSI induces cytoplasmic accumulation of ¥á-synuclein and parkin, WIN55.212.2 counters these effects. Interestingly, however, while PSI induces the activation and nuclear translocalization of nuclear factor ¥êB, WIN55.212.2 potentiates this effect. These data are suggestive that WIN55.212.2 might confer a neuroprotective benefit in PSI-induced proteasomal dysfunction, and could further protect against neuronal degeneration stemming from cytoplasmic accumulation of ¥á-synuclein and parkin. These results indicate that WIN55.212.2 may be a candidate for treatment of neurodegenerative diseases, including Parkinson¡¯s disease.
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KEYWORD
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Cannabinoid-receptor agonist, PC12 cells, Proteasomal inhibitor, Alpha-synuclein, NF-kappa B
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