Drug Des Devel Ther. 2015 Apr 17;9:2233-47.

Promoting endothelial function by S-nitrosoglutathione through the HIF-1α/VEGF pathway stimulates neurorepair and functional recovery following experimental stroke in rats.

 

Khan M1, Dhammu TS1, Matsuda F2, Baarine M3, Dhindsa TS1, Singh I1, Singh AK4.
  • 1Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
  • 2Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA ; School of Health Sciences, Kagoshima University, Kagoshima, Japan.
  • 3Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA.
  • 4Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA ; Ralph H Johnson VA Medical Center, Charleston, SC, USA.

 

Abstract

BACKGROUND:

For stroke patients, stimulating neurorepair mechanisms is necessary to reduce morbidity and disability. Our previous studies on brain and spinal cord trauma show that exogenous treatment with the S-nitrosylating agent S-nitrosoglutathione (GSNO) – a nitric oxide and glutathione metabolite of the human body – stimulates neurorepair and aids functional recovery. Using a rat model of cerebral ischemia and reperfusion (IR) in this study, we tested the hypothesis that GSNO invokes the neurorepair process and improves neurobehavioral functions through the angiogenic HIF-1α/VEGF pathway.

METHODS:

Stroke was induced by middle cerebral artery occlusion for 60 minutes followed by reperfusion in adult male rats. The injured animals were treated with saline (IR group, n=7), GSNO (0.25 mg/kg, GSNO group, n=7), and GSNO plus the HIF-1α inhibitor 2-methoxyestra-diol (2-ME) (0.25 mg/kg GSNO + 5.0 mg/kg 2-ME, GSNO + 2-ME group, n=7). The groups were studied for either 7 or 14 days to determine neurorepair mediators and functional recovery. Brain capillary endothelial cells were used to show that GSNO promotes angiogenesis and that GSNO-mediated induction of VEGF and the stimulation of angiogenesis are dependent on HIF-1α activity.

RESULTS:

IR injury increased the expression of neurorepair mediators HIF-1α, VEGF, and PECAM-1 and vessel markers to a limited degree that correlate well with significantly compromised neurobehavioral functions compared with sham animals. GSNO treatment of IR not only remarkably enhanced further the expression of HIF-1α, VEGF, and PECAM-1 but also improved functioning compared with IR. The GSNO group also had a higher degree of vessel density than the IR group. Increased expression of VEGF and the degree of tube formation (angiogenesis) by GSNO were reduced after the inhibition of HIF-1α by 2-ME in an endothelial cell culture model. 2-ME treatment of the GSNO group also blocked not only GSNO’s effect of reduced infarct volume, decreased neuronal loss, and enhanced expression of PECAM-1 (P<0.001), but also its improvement of motor and neurological functions (P<0.001).

CONCLUSION:

GSNO stimulates the process of neurorepair, promotes angiogenesis, and aids functional recovery through the HIF-1α-dependent pathway, showing therapeutic and translational promise for stroke.

KEYWORDS: GSNO; HIF-1α; IR; S-nitrosylation; VEGF; angiogenesis; motor function; neuroprotection; neurorepair; stroke; subtle behavior

PMID: 25945035

 

 

 

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