Abstract
Purpose: To investigate the neuroprotective potential of apocynin nitrone (AN-1), a nitrone analogue of apocynin, in rat brain tissue as a novel candidate for ischemic stroke treatment. Methods: In vitro neuroprotection of AN-1 was studied in SH-SY5Y cells treated with oxygen glucose deprivation (OGD). Cell viability was measured using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2Htetrazolium bromide (MTT) assay, and intracellular reactive oxygen species (ROS) level was investigated using flow cytometry. The protection of AN-1 in cerebral ischemia-reperfusion (I/R) rats was evaluated by cerebral infarct area and neurological deficit score. Oxidative stress of the ischemic hemisphere was assessed by malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) levels. Results: In OGD-treated SH-SY5Y cells, AN-1 reduced cell death and ROS level. In I/R rats, AN-1 exerted potential protection against neurological deficit by reducing infarction area, decreasing neurological deficit score and relieving oxidative stress. AN-1 exhibited stronger action than its parent compound apocynin in vitro , but the two had similar effects in vivo. In addition, AN-1 demonstrated efficacy close to or higher than the positive reference Edaravone® both in vitro and in vivo . Furthermore, AN-1 showed lower toxicity than apocynin in vitro. Conclusion: The results suggest that AN-1 may be a potential neuroprotective agent for the treatment of ischemic stroke in human. Keywords: Apocynin nitrone, Cerebral ischemia-reperfusion injury, Neuroprotection, Reactive oxygen species, Oxidative stress
Highlights
Ischemic stroke is a disturbance caused by occlusion of the cerebral vasculature, which lead to decreased delivery of glucose and oxygen to the brain, disruption of the ionic equilibrium and calcium homeostasis, excitotoxicity and eventual cell death [1,2]
NADPH oxidase (NOX) can effectively generate superoxide anion, which further interacts with nitric oxide to form peroxynitrite, another key reactive species accounting for neuronal death [6]
To evaluate the efficacy of AN-1, human neuroblastoma cell line (SH-SY5Y) treated by oxygen glucose deprivation (OGD) followed by reoxygenation was used for test in vitro, and rats with cerebral I/R caused by middle cerebral artery occlusion (MCAO) were studied in vivo
Summary
Ischemic stroke is a disturbance caused by occlusion of the cerebral vasculature, which lead to decreased delivery of glucose and oxygen to the brain, disruption of the ionic equilibrium and calcium homeostasis, excitotoxicity and eventual cell death [1,2]. Apo was reported to improve ischemic infarction and show neuroprotection against middle cerebral artery occlusion (MCAO)-induced impairments in wildtype rodent models but not in NOX2-deficient mice [7,8]. To evaluate the efficacy of AN-1, human neuroblastoma cell line (SH-SY5Y) treated by oxygen glucose deprivation (OGD) followed by reoxygenation was used for test in vitro, and rats with cerebral I/R caused by middle cerebral artery occlusion (MCAO) were studied in vivo. The animals were euthanized, and the brains were collected for measurement of the cerebral infarct area and anti-oxidative activity. A value of p < 0.05 was considered statistically significant
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