Back to Search
Start Over
Dynorphin A (1–17) induces apoptosis in striatal neurons in vitro through α-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor-mediated cytochrome C release and caspase-3 activation
- Source :
-
Neuroscience . Dec2003, Vol. 122 Issue 4, p1013. 11p. - Publication Year :
- 2003
-
Abstract
- Dynorphin A (1–17), an endogenous opioid neuropeptide, can have pathophysiological consequences at high concentrations through actions involving glutamate receptors. Despite evidence of excitotoxicity, the basic mechanisms underlying dynorphin-induced cell death have not been explored. To address this question, we examined the role of caspase-dependent apoptotic events in mediating dynorphin A (1–17) toxicity in embryonic mouse striatal neuron cultures. In addition, the role of opioid and/or glutamate receptors were assessed pharmacologically using dizocilpine maleate (MK(+)801), a non-equilibrium N-methyl-d-aspartate (NMDA) antagonist; 6-cyano-7-nitroquinoxaline-2,3-dione, a competitive α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate antagonist; or (−)-naloxone, a general opioid antagonist. The results show that dynorphin A (1–17) (≥10 nM) caused concentration-dependent increases in caspase-3 activity that were accompanied by mitochondrial release of cytochrome c and the subsequent death of cultured mouse striatal neurons. Moreover, dynorphin A-induced neurotoxicity and caspase-3 activation were significantly attenuated by the cell permeable caspase inhibitor, caspase-3 inhibitor-II (z-DEVD-FMK), further suggesting an apoptotic cascade involving caspase-3. AMPA/kainate receptor blockade significantly attenuated dynorphin A-induced cytochrome c release and/or caspase-3 activity, while NMDA or opioid receptor blockade typically failed to prevent the apoptotic response. Last, dynorphin-induced caspase-3 activation was mimicked by the ampakine CX546 [1-(1,4-benzodioxan-6-ylcarbonyl)piperidine], which suggests that the activation of AMPA receptor subunits may be sufficient to mediate toxicity in striatal neurons. These findings provide novel evidence that dynorphin-induced striatal neurotoxicity is mediated by a caspase-dependent apoptotic mechanism that largely involves AMPA/kainate receptors. [Copyright &y& Elsevier]
- Subjects :
- *DYNORPHINS
*OPIOID peptides
*EXCITON theory
*CELL death
Subjects
Details
- Language :
- English
- ISSN :
- 03064522
- Volume :
- 122
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 11830453
- Full Text :
- https://doi.org/10.1016/j.neuroscience.2003.08.033