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Study · Animal study (in vivo) · rat · 2015

1 result

Blocking a vicious cycle nNOS/peroxynitrite/AMPK by S-nitrosoglutathione: implication for stroke therapy.

Khan M, Dhammu TS, Matsuda F, Singh AK, Singh I

BMC neuroscience15 Jul 2015Cited by 32 (Europe PMC)

PMID26174015 (opens in a new tab)PMCIDPMC4502912 (opens in a new tab)DOI10.1186/s12868-015-0179-x (opens in a new tab)PepBankPUB-26174015
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Summary

BackgroundStroke immediately sets into motion sustained excitotoxicity and calcium dysregulation, causing aberrant activity in neuronal nitric oxide synthase (nNOS) and an imbalance in the levels of nitric oxide (NO). Drugs targeting nNOS-originated toxicity may therefore reduce stroke-induced damage. Recently, we observed that a redox-modulating agent of the NO metabolome, S-nitrosoglutathione (GSNO), confers neurovascular protection by reducing the levels of peroxynitrite, a product of aberrant NOS activity. We therefore investigated whether GSNO-mediated neuroprotection and improved neurological functions depend on blocking nNOS/peroxynitrite-associated injurious mechanisms using a rat model of cerebral ischemia reperfusion (IR).ResultsIR increased the activity of nNOS, the levels of neuronal peroxynitrite and phosphorylation at Ser(1412) of nNOS. GSNO treatment of IR animals decreased IR-activated nNOS activity and neuronal peroxynitrite levels by reducing nNOS phosphorylation at Ser(1412). The Ser(1412) phosphorylation is associated with increased nNOS activity. Supporting the notion that nNOS activity and peroxynitrite are deleterious following IR, inhibition of nNOS by its inhibitor 7-nitroindazole or reducing peroxynitrite by its scavenger FeTPPS decreased IR injury. GSNO also decreased the activation of AMP Kinase (AMPK) and its upstream kinase LKB1, both of which were activated in IR brain. AMPK has been implicated in nNOS activation via Ser(1412) phosphorylation. To determine whether AMPK activation is deleterious in the acute phase of IR, we treated animals after IR with AICAR (an AMPK activator) and compound c (an AMPK inhibitor). While AICAR potentiated, compound c reduced the IR injury.ConclusionsTaken together, these results indicate an injurious nNOS/peroxynitrite/AMPK cycle following stroke, and GSNO treatment of IR inhibits this vicious cycle, resulting in neuroprotection and improved neurological function. GSNO is a natural component of the human body, and its exogenous administration to humans is not associated with any known side effects. Currently, the FDA-approved thrombolytic therapy suffers from a lack of neuronal protective activity. Because GSNO provides neuroprotection by ameliorating stroke's initial and causative injuries, it is a candidate of translational value for stroke therapy.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study1

1 result from studies that gave the peptide. No result from this study comes from people.

  1. 01AnimalAnimal study (in vivo)Efficacy outcome

    In rats after cerebral ischemia reperfusion, AICAR potentiated the injury.

    In plain wordsIn rats after interrupted and restored brain blood flow, AICAR worsened the injury.

    Peptide
    AICAR (acadesine)
    Outcome
    IncreaseIschemia reperfusion injury
    Study

    ratn: not reported in source

    Cerebral ischemia reperfusion
    Outcome group
    Neuroprotection · Nervous system and cognition
    Studied dose
    Dose not stated

    Source sentences

    Summary
    While AICAR potentiated, compound c reduced the IR injury.
    2 context sentences
    Summary · context
    We therefore investigated whether GSNO-mediated neuroprotection and improved neurological functions depend on blocking nNOS/peroxynitrite-associated injurious mechanisms using a rat model of cerebral ischemia reperfusion (IR).
    Summary · context
    To determine whether AMPK activation is deleterious in the acute phase of IR, we treated animals after IR with AICAR (an AMPK activator) and compound c (an AMPK inhibitor).

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Version history

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  1. Version 2Current

    21 Oct 2026, 15:58 UTC

    Study results updated

  2. Version 1

    21 Oct 2026, 12:50 UTC

    First added · source update from Europe PMC

Subjects

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