Abstract
A growing body of evidence suggests that oxidative stress-mediated cell death signaling mechanisms may exert neurotoxic effects of methamphetamine (MA)-induced dopaminergic neuronal loss. However, the means by which oxidative stress induced by MA causes neurodegeneration remains unclear. In recent years, resveratrol has garnered considerable attention owing to its antioxidant, anti-inflammatory, anti-aging, and neuroprotective properties. In the present study, we sought to investigate the neuroprotective effects of resveratrol against apoptotic cell death in a mesencephalic dopaminergic neuronal cell culture model of MA neurotoxicity. MA treatment in the N27 dopaminergic neuronal cell model produced a time-dependent activation of the apoptotic cascade involving caspase-3 and DNA fragmentation. We found that the caspase-3 activation preceded DNA fragmentation. Notably, treatment with resveratrol almost completely attenuated MA-induced caspase-3 activity, but only partially reduced apoptotic cell death. We conclude that the neuroprotective effect of resveratrol is at least in part mediated by suppression of caspase-3 dependent cell death pathways. Collectively, our results demonstrate that resveratrol can attenuate MA-induced apoptotic cell death and suggest that resveratrol or its analogs may have therapeutic benefits in mitigating MA-induced dopaminergic neurodegeneration.
Highlights
Methamphetamine (MA) is a psychostimulant that is widely abused in the US and worldwide [1]
We previously demonstrated that caspase-3 activation is one of the key events in dopaminergic neurotoxicity caused by several neurotoxicants, including MA and MPP+ [32,33,34]
In the present study we examined the neuroprotective effects of a polyphenolic natural product, resveratrol, on MA-induced neurotoxicity
Summary
Methamphetamine (MA) is a psychostimulant that is widely abused in the US and worldwide [1]. Repeated use has been shown to be associated with euphoria, decreased appetite, increased alertness, and hyperthermia [2]. Several of these effects are believed to play a central role in the high abuse potential of MA, which causes severe health problems and poor socioeconomic conditions for the abusers. Several studies have repeatedly demonstrated that in rodents MA causes long term neurodegenerative changes in dopaminergic and serotonergic nerve terminals in several brain regions, including the cortex, striatum, and hippocampus [7,8,9]. The changes include long term reductions in striatal dopamine (DA) and serotonin (5-HT) levels, decreased tryptophan hydroxylase and tyrosine hydroxylase, loss of DA and 5-HT transporters, and associated neurodegenerative changes in the monoaminergic terminals [10].
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