Nitric Oxide Donors as Neuroprotective Agents after an Ischemic Stroke-Related Inflammatory Reaction

Table 1

Nitric oxide donors in experimental cerebral ischemia.

Species	Model	Time of ischemia/reperfusion	Nitric oxide donor	Doses and administration	Effect	Reference
Rat	MCAO	20′/24 h	GSNO	1 mg/kg at the onset of reperfusion	Reduction in infarct size; Increase in CBF; Decrease in cortical expression of TNF-α and IL-1 in penumbral region; Attenuation of iNOs expression in microglia, astrocytes and vessels of penumbral region; Inhibition of monocyte/macrophage infiltration; Downregulates adhesion molecules (ICAM-1, LFA-1); Reduction in TUNEL-positive cells and caspase-3 activity; Blocks NF-𝜅B (p65/p50 complex) and is able to bind to DNA in astrocytes and microglial cells in vitro	[53]
Rat	MCAO	20′/24 h	SNP; GSNO; SNAP; MAHMA/NONO-ate; PAPA/NONOate; SIN-1	2 and 3 𝜇mol/kg per 10 min IV at onset of reperfusion	Increase in CBF (except MAHMA and PAPA); Reduction in infarct size (GSNO, SNP, and SNAP); Improvement in neurological score (GSNO, SNP, and SNAP); Reduction in lipid peroxidation in plasma (all of them); Decrease in plasma levels of nitrotyrosine (GSNO, SNP and SNAP); Increase in NO plasma level (except SNAP); Reduction in mRNA expression of ICAM-1 (GSNO, SNAP, SNP) and E-selectin (except SIN-1)	[38]
Rat	MCAO	90′/24 h	ZJM-289	0.1 and 0.2 mmol/kg IV 1 h prior to ischemia	Improvement in neurological deficit (motor function); Reduction in infarct size; Reduction in brain water content; Decrease of neuronal degeneration; Inhibition of nNOS expression; Increase of NO level ipsilateral to ischemia; Increase in cGMP level	[85]
Rat	MCAO	90′/1.5, 3, 4.5, 6 and 12 h	Sodium nitrite	480 nmol per 1 min at 1.5, 3, 4.5, and 6 h postischemia, IV	Reduction in infarct size (1.5, 3, 4.5 and 6 h); Improvement in motor function (4.5 h); Decrease of microhypoxic areas (12 h); Reduction in free reactive oxygen and nitrogen species (12 h)	[86]
Rat	MCAO	2 h/7 days	SNP; Sperm-ine/NONO-ate	SNP: 0.11 mg/kg per 120 min, trans-ischemia, IV; Spermine: 0.36 mg/kg per 120 min, trans-ischemia, IV	Reduction in infarct size; Increase in cerebral perfusion	[87]
Rat	MCAO	2 h/3 days	SIN-1	0.1 and 1 mg/kg 30 min before ischemia, IV	Reduction in infarct size in normo- and hyperglycemic rats	[88]
Rat	Permanent MCAO	24 h/no reperfusion	SNP; SIN-1	SNP: 3 mg/kg/h trans-ischemia, IA; SIN-1: 1.5, 3, and 6 mg/kg/h trans-ischemia, IA	Both produced an increase in CBF and a reduction in infarct size; SNP decreased platelet aggregation in vitro but not in vivo at the same doses	[80]
Rat	Permanent MCAO	24 h/no reperfusion	SIN-1	3 mg/kg/h per 60 min at 3, 15, 30, 60, and 120 min after ischemia, IA	Reduction in infarct size; Increase in CBF	[89]
Rat	4-VO	15′/30′, 6 h, 12 h, 3 and 5 days	SNP	5 mg/kg, 3 doses: 30 min prior to ischemia, 1 h postischemia, and 2.5 h postischemia, IP	Suppression of JNK3 downstream pathway (30′, 3 h); Increase in Akt and Bad phosphorylation (12h); Inhibition of Cytochrome c release from mitochondria (6 h); Reduction in TUNEL-positive cells and caspase-3 activity (3 h); Augmentation of neuronal survival in CA1 pyramidal layer (3–5 d)	[61]
Rat	4-VO	15′/6 h, 3 and 5 days	SNP	5 mg/kg, 3 doses: 30′ prior to ischemia, 1 h postischemia and 2.5 h postischemia, IP	Decreased hippocampal activation of nNOS by nitrosylation and phosphorylation (6 h); Suppression of JNK3 downstream pathway (6 h); Inhibition of release of Cytochrome C into cytoplasm (6 h); Attenuation of caspase-3 activity (6 h); Reduction in neuronal degeneration (5 d) and TUNEL-positive cells (3 d) in CA1 pyramidal layer	[65]
Rabbit and rat	MCAO	60′/2, 4 h respectively	ProliNO/; NONO-ate	Rabbit: 10^−6 mol/L; Rat: 10^−5 mol/L; At the onset of reperfusion per 60 min, IA	Reduction in free reactive oxygen species; Reduction in infarct size	[90]
Goat	MCAO	20′/7 days	SNP; DEA/NONOate; DETA/NONOate	SNP: 10^−9–3 × 10^−4 mol/L, IV; DEA: 10^−9–3 × 10^−4 mol/L, IV; DETA: 10^−7–3 × 10^−4 mol/L, IV	MCA relaxation	[91]

Lines of evidence are ordered first by animal model and then by surgical procedure and severity of the ischemia. In cases in which the effects were different at different reperfusion times, this is indicated after each effect by the corresponding time as a superscript between parentheses. MAP: Mean arterial pressure; CA1: Cornu Ammonis; CBF: Cerebral blood flow; GSNO: S-nitrosoGlutathione; IA: IntraArterial; ICAM-1: Intercellular adhesion molecule-1; IL1: Interleukin 1; iNOS: inducible Nitric oxide synthase; IP: Intraperitoneal; IV: Intravenous; JNK3: c-Jun N-terminal kinase-3; LFA: Lymphocyte function-associated antigen-1; MAHMA: Methylamine hexamethylene methylamine NONOate; MCA: Middle cerebral artery; MCAO: Middle cerebral artery occlusion; nNOS: neuronal Nitric oxide synthase; NO: Nitric oxide; PAPA: Propylamine propylamine NONOate; SAP: Systolic arterial pressure; SIN-1: 3-morpholinoSydnonimine; SNAP: S-nitroso-N-acetyl-penicillamine; SNP: Sodium nitroprusside; TNF: Tumor necrosis factor; TUNEL: Terminal dUTP nick end labeling; 4-VO: four Vessel occlusion model.