S-nitrosylated pegylated hemoglobin reduces the size of cerebral infarction in rats.
ABSTRACT Cell-free hemoglobin-based oxygen carriers have well-documented safety and efficacy problems such as nitric oxide (NO) scavenging and extravasation that preclude clinical use. To counteract these effects, we developed S-nitrosylated pegylated hemoglobin (SNO-PEG-Hb, P(50) = 12 mm Hg) and tested it in a brain ischemia and reperfusion model. Neurological function and extent of cerebral infarction was determined 24 h after photochemically induced thrombosis of the middle cerebral artery in the rat. Infarction extent was determined from the integrated area in the cortex and basal ganglia detected by triphenyltetrazolium chloride staining in rats receiving various doses of SNO-PEG-Hb (2, 0.4, and 0.08 mL/kg) and compared with rats receiving pegylated hemoglobin without S-nitrosylation (PEG-Hb) or saline of the same dosage. Results indicated that successive dilution revealed SNO-PEG-Hb but not PEG-Hb to be effective in reducing the size of cortical infarction but not neurological function at a dose of 0.4 mL/kg. In conclusion, SNO-PEG-Hb in a dose of 0.4 mL/kg (Hb 24 mg/kg) showed to be most effective in reducing the size of cortical infarction, however, without functional improvement.
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ABSTRACT: Abstract Significance: Since their discovery in the early 1990's, S-nitrosylated proteins have been increasingly recognized as important determinants of many biochemical processes. Specifically, S-nitrosothiols in the cardiovascular system exert many actions, including promoting vasodilation, inhibiting platelet aggregation, and regulating Ca(2+) channel function that influences myocyte contractility and electrophysiologic stability. Recent Advances: Contemporary developments in liquid chromatography-mass spectrometry methods, the development of biotin- and His-tag switch assays, and the availability of cyanide dye-labeling for S-nitrosothiol detection in vitro have increased significantly the identification of a number of cardiovascular protein targets of S-nitrosylation in vivo. Critical Issues: Recent analyses using modern S-nitrosothiol detection techniques have revealed the mechanistic significance of S-nitrosylation to the pathophysiology of numerous cardiovascular diseases, including essential hypertension, pulmonary hypertension, ischemic heart disease, stroke, and congestive heart failure, among others. Future Directions: Despite enhanced insight into S-nitrosothiol biochemistry, translating these advances into beneficial pharmacotherapies for patients with cardiovascular diseases remains a primary as-yet unmet goal for investigators within the field. Antioxid. Redox Signal. 00, 000-000.Antioxidants & Redox Signaling 07/2012; · 8.20 Impact Factor
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ABSTRACT: Polynitroxylated pegylated hemoglobin (PNPH) as a multifunctional therapeutic takes advantage of the ability of hemoglobin (Hb) to transport oxygen, the antioxidative stress activities from the redox coupling of nitroxide and heme iron, and the hypercolloid properties of pegylation. The published preclinical data demonstrating that PNPH acts as a neurovascular protective multifunctional therapeutic in an animal model simulating prehospital resuscitation of traumatic brain injury (TBI) with hemorrhagic shock (HS) are reviewed. Preliminary results on the potential utility of PNPH for neurovascular protection in thrombolytic stroke therapy and for correction of vascular dysfunction through transfusion in sickle-cell disease (SCD) are also discussed. We hypothesize that with PNPH, Hb has more than been tamed--it has become a therapeutic and not just a nontoxic extracellular oxygen carrier--and that successful PNPH development as a multifunctional therapeutic that protects the neurovasculature and reduces oxidative stress may represent a paradigm shift in transfusion and critical care medicine, which may meet a number of unmet medical needs resulting from oxidative stress and inadequate blood flow, such as HS, TBI, SCD, and stroke.Artificial Organs 09/2011; 36(2):215-20. · 1.96 Impact Factor
- Artificial Organs 02/2012; 36(2):123-6. · 1.96 Impact Factor