Abstract
More and more evidence suggests oxidative stress and inflammation contribute importantly to subarachnoid hemorrhage (SAH)-induced cerebral vasospasm and secondary brain injury. Recent evidence indicates Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) increases the expression of antioxidant genes and decreases the expression of pro-inflammatory genes. This study examines the effects of an activator of Nfr2, RTA 408, on SAH-induced cerebral vasospasm and possible mechanism underlying its effect in a two-hemorrhage rodent model of SAH. We randomly assigned 60 Sprague-Dawley male rats (350 to 420g) to five groups twelve rats each: one control group (no SAH), one untreated SAH only group and three RTA-408 treatment groups (SAH+ RTA 408 0.5 mg/kg/day, SAH+RTA 408 1 mg/kg/day and a SAH+RTA 408 1.5 mg/kg/day). The treatment groups were administered RTA 408 by intraperitoneal injection thirty min following first induction of SAH for seven days starting with first hemorrhage. Cerebral vasospasm was determined by averaging the cross-sectional areas of basilar artery 7 days after first SAH. Expressions of Nrf2, NF-κB and iNOS in basilar artery and expressions of Nrf2, HO-1, NQO1 and Cleaved caspase-3 were evaluated. Tissue TNF-alpha was assessed by ELISA using the protein sampled from the dentate gyrus, cerebral cortex, and hippocampus. Prior to perfusion fixation, there were no significant physiological differences among the control and treated groups. RTA 408 treatment attenuated the morphological changes caused by cerebral vasospasm. It mitigated SAH-induced suppression of Nrf2 and increased expression of NF-κB and iNOS in the basilar artery. In dentate gyrus, it reversed SAH-decreases in Nrf2, HO-1, NQO-1 and cleaved caspase-3 and RTA 408 1.5 mg/kg/day reversed SAH increases in TNF-alpha. It was concluded that RTA 408 reversal vasospasm was achieved via increases in Nrf2 and decreases in NF-κB and iNOS. It exerted a neuron-protection effect by decreasing the apoptosis-related protein cleaved caspase-3 and decreasing the information cytokine TNF-alpha expression, which it achieved by increasing HO-1 and NQO-1 protein found downstream from Nrf2 and Nrf2. We believe that RTA 408 can potentially be used to manage of cerebral vasospasm and secondary brain injury following SAH.
Highlights
Cerebral vasospasm (CV)-induced delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH) has been recognized for more than 50 years, its pathophysiology remains unknown, limiting the range of effective treatment strategies [1] Despite advances in the diagnosis and treatment of aneurysmal SAH, cerebral vasospasm (CV)-induced delayed cerebral ischemia continues to be the leading but potentially treatable cause of death and disability in patients with ruptured cerebral aneurysms [2]
It was concluded that RTA 408 reversal vasospasm was achieved via increases in Nuclear factor erythroid 2-related factor 2 (Nrf2) and decreases in Nuclear factor kappa B (NF-κB) and Inducible nitric oxide synthase (iNOS)
SAH rats were found to have significantly reduced areas in cross-sections taken from basilar arteries in SAH rats compared to controls (24585.34±4361.925 μm2 vs. (53478.24 ±5563.646 μm2) (54% reduction; p
Summary
Cerebral vasospasm (CV)-induced delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH) has been recognized for more than 50 years, its pathophysiology remains unknown, limiting the range of effective treatment strategies [1] Despite advances in the diagnosis and treatment of aneurysmal SAH, CV-induced delayed cerebral ischemia continues to be the leading but potentially treatable cause of death and disability in patients with ruptured cerebral aneurysms [2]. There is increasing evidence that oxidative stress and inflammation may be the leading causes of subarachnoid hemorrhage (SAH)–induced cerebral vasospasm and secondary brain injury [7]. When under inflammatory and oxidative stress, activated Nrf detaches from Keap and moves into the nucleus, there binding to the antioxidant response element [13], a 51-bp DNA element often observed in the promoter region of various genes encoding detoxification enzymes and cytoprotective proteins [14]. Once the Nrf2–ARE signaling pathway is activated, it regulates the expression of antioxidant and anti-inflammatory genes, which translates to RTA 408 in subarachnoid hemorrhage–induced delayed cerebral vasospasm and secondary brain injury cytokines that play a role in antioxidant and anti-inflammatory defense in cells. Several Nrf pathway-stimulating drugs are being investigated as potentially useful in the management of different diseases, including cancer, mitochondrial myopathies, metabolic and neurodegenerative disorders, as well as disorders involving inflammation and oxidative stress [17,18,19]
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