RESUMO
Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Although the causes of PD are not understood, evidence suggests that its pathogenesis is associated with oxidative stress and inflammation. Recent studies have suggested a protective role of the cannabinoid signalling system in PD. ß-caryophyllene (BCP) is a natural bicyclic sesquiterpene that is an agonist of the cannabinoid type 2 receptor (CB2R). Previous studies have suggested that BCP exerts prophylactic and/or curative effects against inflammatory bowel disease through its antioxidative and/or anti-inflammatory action. The present study describes the neuroprotective effects of BCP in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced murine model of PD, and we report the results of our investigation of its neuroprotective mechanism in neurons and glial cells. In the murine model, BCP pretreatment ameliorated motor dysfunction, protected against dopaminergic neuronal losses in the SN and striatum, and alleviated MPTP-induced glia activation. Additionally, BCP inhibited the levels of inflammatory cytokines in the nigrostriatal system. The observed neuroprotection and inhibited glia activation were reversed upon treatment with the CB2R selective antagonist AM630, confirming the involvement of the CB2R. These results indicate that BCP acts via multiple neuroprotective mechanisms in our murine model and suggest that BCP may be viewed as a potential treatment and/or preventative agent for PD.
RESUMO
The neuroprotective effects of melatonin in an experimental model of aging-induced apoptosis have been examined. Cerebellar granule neurons show characteristics of apoptosis after 17 days in culture (DV). The addition of melatonin to neuronal cell cultures (100-500 mum) resulted in neuroprotective and antiapoptotic effects, which were revealed by nuclear condensed cell counting. In a thorough analysis by Western-blot of the potential pathways responsible for melatonin's neuroprotective effects, we found an increase in the activation of prosurvival Akt. Subsequently GSK3beta inhibition and an increase in p-FOXO1 phosphorylation occurred. In this model of aging, apoptosis was associated with an elevated DNA damage, as demonstrated by an increase in the activation of ataxia telangiectasia muted (ATM). Subsequently, downstream targets such as p53 were activated. Furthermore, the process of DNA damage was coupled to an increase in the expression of certain proteins involved in cell cycle regulation; these were cyclin D and the proapoptotic transcription factor E2F-1. We conclude that the antiapoptotic effects of melatonin were mediated by two potential mechanisms: by increasing the activity of prosurvival pathways via Akt and by the prevention of DNA damage (via ATM inhibition) followed by the reduction of cell cycle re-entry.
