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Nitric oxide donors protect cultured rat astrocytes from 1-methyl-4-phenylpyridinium-induced toxicity
1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, The Republic of China.
Abstract:
MPP+ is thought to mediate MPTP's toxicity on dopamine neurons by inhibiting mitochondrial respiration. However, astrocytic injuries are also observed in MPTP/MPP+-treated rats. Because nitric oxide (NO.) is suggested to be cytoprotective, we examined the effects of nitroprusside (SNP), S-nitroso-N-acetylpenicillamine (SNAP), and 3-morpholinosydnonimine (SIN-1) on MPP+-induced toxicity in astrocytes. Incubation of astrocytes with MPP+ for 2 days produced a dose-dependent toxicity, including increase in lactate level and lipid peroxidation, decrease of metabolic activity and cell damage. SNP, SNAP, and SIN-1 all attenuated MPP+-induced toxicity. The same protection was not achieved with N-acetylpenicillamine or ferrocyanide, structural analogues of SNAP or SNP but devoid of NO.. Further, the effect was not attributed to the increased cGMP levels or blockade of MPP+ accumulation in astrocytes. Notably, catalase, dimethyl sulfoxide and ferricyanide, an extracellular electron acceptor, were also effective in inhibiting MPP+ damage. NO. donors and analogues were also tested against damage produced by rotenone, an irreversible complex I inhibitor. Only ferricyanide and SNP effectively protected rotenone's toxicity. These results concluded that (1) NO. may protect astrocytes from MPP+-induced free radical formation, and (2) prevention of energy depletion/free radicals production alleviate MPP+-induced toxicity.
Insights
Nitric oxide (NO.) donors protect astrocytes from MPP+-induced toxicity by reducing free radical formation and energy depletion. This finding offers new insights into neuroprotection strategies against MPTP-related damage.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- MPTP/MPP+ toxicity affects dopamine neurons by inhibiting mitochondrial respiration.
- Astrocytic injuries are also observed in MPTP/MPP+-treated subjects.
- Nitric oxide (NO.) is suggested to have cytoprotective properties.
Purpose of the Study:
- To investigate the protective effects of NO. donors against MPP+-induced toxicity in astrocytes.
- To elucidate the mechanisms underlying NO.-mediated protection.
Main Methods:
- Astrocytes were incubated with MPP+ and various NO. donors (SNP, SNAP, SIN-1) or control compounds.
- Assessed MPP+-induced toxicity through lactate levels, lipid peroxidation, metabolic activity, and cell damage.
- Evaluated the role of cGMP and MPP+ accumulation.
- Tested protection against rotenone-induced toxicity.
Main Results:
- MPP+ induced dose-dependent toxicity in astrocytes.
- SNP, SNAP, and SIN-1 significantly attenuated MPP+-induced toxicity.
- Protection was linked to NO. and not cGMP or MPP+ uptake.
- Catalase, DMSO, and ferricyanide also inhibited MPP+ damage.
- Ferricyanide and SNP protected against rotenone toxicity.
Conclusions:
- NO. may protect astrocytes from MPP+-induced free radical formation.
- Preventing energy depletion and free radical production alleviates MPP+-induced toxicity.
- These findings suggest potential therapeutic strategies involving NO. for neurodegenerative conditions.