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Attenuation of oxidative neuronal necrosis by a dopamine D1 agonist in mouse cortical cell cultures
1Department of Psychiatry and Behavioral Sciences, Ajou University School of Medicine Suwon, Kyungkido, Korea.
Abstract:
Events which lead to an increase in intracellular free radicals induce necrotic cell death of cultured cortical neurons. In the present study, we report that treatment with 1 microM (+/-)-SKF-38393 hydrochloride, a selective D1 agonist, as well as 100 microM trolox, a lipophilic vitamin E analogue, significantly prevented oxidative-related necrotic cell death following exposure to 10 microM Fe2+ or 1 mM buthionine sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase. The neuroprotective effect of (+/-)-SKF-38393 hydrochloride was partially reversed by addition of (+/-)-SKF-83566 hydrochloride, a selective D1 antagonist. Quinelorane dihydrochloride, a selective D2 agonist, did not influence free radical neurotoxicity. Interestingly, inclusion of (+/-)-SKF-38393 hydrochloride or quinelorane dihydrochloride did not attenuate apoptotic cell death of cortical neurons deprived of serum. The present study provides evidence that (+/-)-SKF-38393 hydrochloride attenuates oxidative neuronal necrosis, which has unique therapeutic potential for the treatment of various neurodegenerative diseases linked to oxidative stress.
Insights
Selective D1 agonist (+/-)-SKF-38393 hydrochloride protects cultured neurons from oxidative stress and necrotic cell death. This neuroprotective effect suggests potential therapeutic applications for neurodegenerative diseases associated with oxidative damage.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Increased intracellular free radicals cause necrotic neuronal cell death.
- Oxidative stress is implicated in neurodegenerative diseases.
Purpose of the Study:
- To investigate the neuroprotective effects of a selective D1 agonist, (+/-)-SKF-38393 hydrochloride, against oxidative stress-induced neuronal death.
- To determine if D1 receptor activation influences oxidative-related necrotic cell death in cultured cortical neurons.
Main Methods:
- Cultured cortical neurons were exposed to oxidative stressors (Fe2+ or buthionine sulfoximine).
- Neuroprotection was assessed by treating neurons with (+/-)-SKF-38393 hydrochloride, trolox, or D1/D2 receptor antagonists/agonists.
- Apoptotic cell death was induced by serum deprivation to differentiate mechanisms.
Main Results:
- (+/-)-SKF-38393 hydrochloride and trolox significantly reduced oxidative-related necrotic cell death.
- The neuroprotective effect of (+/-)-SKF-38393 hydrochloride was partially reversed by a D1 antagonist, (+/-)-SKF-83566 hydrochloride.
- A selective D2 agonist, quinelorane dihydrochloride, did not affect free radical neurotoxicity.
- (+/-)-SKF-38393 hydrochloride did not prevent apoptotic cell death.
Conclusions:
- (+/-)-SKF-38393 hydrochloride attenuates oxidative neuronal necrosis via D1 receptor pathways.
- This D1 agonist demonstrates therapeutic potential for neurodegenerative conditions characterized by oxidative stress.