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

BMC Neuroscience

Inderjit Singh²  Avtar K Singh¹  Fumiyo Matsuda³  Tajinder S Dhammu²  Mushfiquddin Khan² 

[1] Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA;Department of Pediatrics, Medical University of South Carolina, Charleston 29425, SC, USA;School of Health Science, Kagoshima University, Kagoshima, Japan

关键词: Cerebral ischemia reperfusion;    Stroke;    S-nitrosoglutathione;    Peroxynitrite;    Neuroprotection;    Neuronal nitric oxide synthase;    AMP-activated protein kinase;   

Others  :  1220308
DOI  :  10.1186/s12868-015-0179-x

 received in 2015-01-28, accepted in 2015-07-06,  发布年份 2015

【 摘 要 】

Background

Stroke 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).

Results

IR increased the activity of nNOS, the levels of neuronal peroxynitrite and phosphorylation at Ser ¹⁴¹²of nNOS. GSNO treatment of IR animals decreased IR-activated nNOS activity and neuronal peroxynitrite levels by reducing nNOS phosphorylation at Ser ¹⁴¹² . The Ser ¹⁴¹²phosphorylation 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 ¹⁴¹²phosphorylation. 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.

Conclusions

Taken 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.

【 授权许可】

   
2015 Khan et al.

【 图 表 】

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