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Dynorphin A (1-17) ...
Dynorphin A (1-17) induces apoptosis in striatal neurons in vitro through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor-mediated cytochrome c release and caspase-3 activation.
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Singh, I N (författare)
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Goody, R J (författare)
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Goebel, S M (författare)
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Martin, K M (författare)
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Knapp, P E (författare)
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Marinova, Z (författare)
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Hirschberg, Daniel (författare)
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Yakovleva, T (författare)
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- Bergman, T (författare)
- Karolinska Institutet
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Bakalkin, G (författare)
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Hauser, K F (författare)
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(creator_code:org_t)
- Elsevier BV, 2003
- 2003
- Engelska.
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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522 .- 1873-7544. ; 122:4
- Relaterad länk:
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https://europepmc.or...
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https://urn.kb.se/re...
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http://kipublication...
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https://doi.org/10.1...
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Abstract
Ämnesord
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- 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 alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate antagonist; or (-)-naloxone, a general opioid antagonist. The results show that dynorphin A (1-17) (>or=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.
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- Av författaren/redakt...
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Singh, I N
-
Goody, R J
-
Goebel, S M
-
Martin, K M
-
Knapp, P E
-
Marinova, Z
-
visa fler...
-
Hirschberg, Dani ...
-
Yakovleva, T
-
Bergman, T
-
Bakalkin, G
-
Hauser, K F
-
visa färre...
- Artiklar i publikationen
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Neuroscience
- Av lärosätet
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Umeå universitet
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Karolinska Institutet