Salvianolic acid B (SalB), a natural polyphenolic compound extracted from the herb of Salvia miltiorrhiza, possesses antioxidant and neuroprotective properties and has been shown to be beneficial for diseases that affect vasculature and cognitive function. Here we investigated the protective effects of SalB against subarachnoid hemorrhage (SAH)-induced oxidative damage, and the involvement of underlying molecular mechanisms. In a rat model of SAH, SalB inhibited SAH-induced oxidative damage. The reduction in oxidative damage was associated with suppressed reactive oxygen species generation; decreased lipid peroxidation; and increased glutathione peroxidase, glutathione, and superoxide dismutase activities. Concomitant with the suppressed oxidative stress, SalB significantly reduced neurologic impairment, brain edema, and neural cell apoptosis after SAH. Moreover, SalB dramatically induced nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and increased expression of heme oxygenase-1 and NADPH: quinine oxidoreductase-1. In a mouse model of SAH, Nrf2 knockout significantly reversed the antioxidant effects of SalB against SAH. Additionally, SalB activated sirtuin 1 (SIRT1) expression, whereas SIRT1-specific inhibitor sirtinol pretreatment significantly suppressed SalB-induced SIRT1 activation and Nrf2 expression. Sirtinol pretreatment also reversed the antioxidant and neuroprotective effects of SalB. In primary cultured cortical neurons, SalB suppressed oxidative damage, alleviated neuronal degeneration, and improved cell viability. These beneficial effects were associated with activation of the SIRT1 and Nrf2 signaling pathway and were reversed by sirtinol treatment. Taken together, these in vivo and in vitro findings suggest that SalB provides protection against SAH-triggered oxidative damage by upregulating the Nrf2 antioxidant signaling pathway, which may be modulated by SIRT1 activation.
Inflammation plays a key role in the progression of subarachnoid hemorrhage (SAH). Here, we examined the effects of astaxanthin (ATX) on the inflammatory response and secondary damage after SAH and the underlying mechanisms of action. In vivo, a prechiasmatic cistern injection model was established in rats and mice. In addition, neuron-microglia cocultures were exposed to oxyhemoglobin to mimic SAH in vitro. Western blotting revealed that protein expression of TLR4 was markedly increased in microglia at 24 h after SAH, with consequent increases in the downstream molecules myeloid differentiation factor 88 and NF-кB. Treatment with ATX significantly inhibited the TLR4 activation, increased sirtuin 1 expression, and inhibited the subsequent inflammatory response both in vivo and in vitro. ATX also significantly decreased high-mobility group box 1 nuclear translocation and secretion in neurons, an effect that was reversed by the sirtuin 1-specific inhibitor sirtinol. ATX administered 4 h after SAH ameliorated cerebral inflammation, brain edema, and neuronal death and improved neurologic function. ATX reduced neuronal death but did not improve neurologic function in TLR4 knockout mice. These results suggest that ATX reduces the proinflammatory response and secondary brain injury after SAH, primarily by increasing sirtuin 1 levels and inhibiting the TLR4 signaling pathway.-Zhang, X., Lu, Y., Wu, Q., Dai, H., Li, W., Lv, S., Zhou, X., Zhang, X., Hang, C., Wang, J. Astaxanthin mitigates subarachnoid hemorrhage injury primarily by increasing sirtuin 1 and inhibiting the Toll-like receptor 4 signaling pathway.
Background and Purpose Post-stroke hyperglycemia and diabetes mellitus are associated with lower thrombolytic efficacy and an increased risk of post-ischemic cerebral hemorrhage. We aimed to develop a rodent model of thrombolysis in diabetic stroke that mimics the clinical situation. Method Male 6 weeks type I diabetic rats (14 weeks old) rats were subjected to embolic focal stroke and treated with tPA at 1.5 hours. Reperfusion and 24-hour neurological outcomes were measured and compared to non-diabetic control rats. Results Diabetic rats exhibited resistance to thrombolytic reperfusion, larger infarction volumes, and increased intracerebral hemorrhage. Conclusion This animal model would be relevant to future studies investigating pathophysiological mechanisms and in developing new therapeutic approaches to enhance the efficacy of tPA thombolysis in stroke patients with diabetes or post-stroke hyperglycemia.
The blood-brain barrier (BBB) is a layer between the blood circulation and neural tissue. It plays a pivotal role in maintaining the vulnerable extracellular microenvironment in the neuronal parenchyma. Neuroinflammatory events can result in BBB dysregulation by disturbing adherens junctions (AJs) and tight junctions (TJs). VE-cadherin, as one of the most important components of the vascular system, is specifically responsible for the assembly of AJs and BBB architecture. Here, we present a review, which highlights recently available insights into the relationship between the neuroinflammation and BBB dysregulation. We then explore the specific interaction between VE-cadherin and BBB. Finally, we discuss the changes of VE-cadherin with different neurological diseases from both experimental and clinical studies. An understanding of VE-cadherin in BBB regulation may indicate that VE-cadherin can partially be a biomarker of neuroinflammation disease and lead to novel approaches for abating BBB dysregulation under pathological conditions and the opening of the BBB following central nervous system (CNS) drug delivery.
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