Abstract
c-Jun N-terminal kinase (JNK) is activated by various brain insults and is implicated in neuronal injury triggered by reperfusion-induced oxidative stress. Some JNK inhibitors demonstrated neuroprotective potential in various models, including cerebral ischemia/reperfusion injury. The objective of the present work was to study the neuroprotective activity of a new specific JNK inhibitor, IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt), in the model of global cerebral ischemia (GCI) in rats compared with citicoline (cytidine-5′-diphosphocholine), a drug approved for the treatment of acute ischemic stroke and to search for pleiotropic mechanisms of neuroprotective effects of IQ-1S. The experiments were performed in a rat model of ischemic stroke with three-vessel occlusion (model of 3VO) affecting the brachiocephalic artery, the left subclavian artery, and the left common carotid artery. After 7-min episode of GCI in rats, 25% of animals died, whereas survived animals had severe neurological deficit at days 1, 3, and 5 after GCI. At day 5 after GCI, we observing massive loss of pyramidal neurons in the hippocampal CA1 area, increase in lipid peroxidation products in the brain tissue, and decrease in local cerebral blood flow (LCBF) in the parietal cortex. Moreover, blood hyperviscosity syndrome and endothelial dysfunction were found after GCI. Administration of IQ-1S (intragastrically at a dose 50 mg/kg daily for 5 days) was associated with neuroprotective effect comparable with the effect of citicoline (intraperitoneal at a dose of 500 mg/kg, daily for 5 days).The neuroprotective effect was accompanied by a decrease in the number of animals with severe neurological deficit, an increase in the number of animals with moderate degree of neurological deficit compared with control GCI group, and an increase in the number of unaltered neurons in the hippocampal CA1 area along with a significant decrease in the number of neurons with irreversible morphological damage. In rats with IQ-1S administration, the LCBF was significantly higher (by 60%) compared with that in the GCI control. Treatment with IQ-1S also decreases blood viscosity and endothelial dysfunction. A concentration-dependent decrease (IC50 = 0.8 ± 0.3 μM) of tone in isolated carotid arterial rings constricted with phenylephrine was observed after IQ-1S application in vitro. We also found that IQ-1S decreased the intensity of the lipid peroxidation in the brain tissue in rats with GCI. 2.2-Diphenyl-1-picrylhydrazyl scavenging for IQ-1S in acetonitrile and acetone exceeded the corresponding values for ionol, a known antioxidant. Overall, these results suggest that the neuroprotective properties of IQ-1S may be mediated by improvement of cerebral microcirculation due to the enhanced vasorelaxation, beneficial effects on blood viscosity, attenuation of the endothelial dysfunction, and antioxidant/antiradical IQ-1S activity.
Highlights
Introduction cJun N-terminal kinase (JNK) is a critical mitogen activated protein kinase (MAPK) modulated by various brain stimuli and implicated in neuronal injury triggered by reperfusion-induced oxidative stress [1]
We evaluated the content of lipid peroxidation products in the brain tissue, local cerebral blood flow (LCBF), blood viscosity, hematocrit, parameters of erythrocyte aggregation, erythrocyte elongation index, indices of plasma hemostasis, and vasodilator activity of endothelium in IQ-1S-treated and nontreated rats at day 5 after global cerebral ischemia (GCI)
The models of cerebral ischemia are divided into two groups based on the extent of brain involved in ischemia: focal cerebral ischemia (FCI) and GCI [28]
Summary
Introduction cJun N-terminal kinase (JNK) is a critical mitogen activated protein kinase (MAPK) modulated by various brain stimuli and implicated in neuronal injury triggered by reperfusion-induced oxidative stress [1]. Increased JNK phosphorylation and JNK activity in the hippocampus have been reported after cerebral ischemia and reperfusion injury [5,6]. Sustained JNK activation has been shown to be associated with neuronal death and apoptosis following ischemic stroke. The specific JNK inhibitors selectively attenuate the activity of brain-expressed JNK3 and/or JNK signaling pathway that form in pathological conditions of ischemia/reperfusion [13,18]. These data suggest that searching for the efficacious neuroprotectors among JNK inhibitors is a promising area for the development of approaches to treatment of acute ischemic and reperfusion brain injury [13,18]
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