Abstract
Objective: The present study explored whether levetiracetam (LEV) could protect against experimental brain ischemia and enhance angiogenesis in rats, and investigated the potential mechanisms in vivo and in vitro. Methods: The middle cerebral artery was occluded for 60 min to induce middle cerebral artery occlusion (MCAO). The Morris water maze was used to measure cognitive ability. The rotation test was used to assess locomotor function. T2-weighted MRI was used to assess infarct volume. The neuronal cells in the cortex area were stained with cresyl purple. The anti-inflammatory effects of LEV on microglia were observed by immunohistochemistry. Enzyme-linked immunosorbent assays (ELISA) were used to measure the production of pro-inflammatory cytokines. Western blotting was used to detect the levels of heat shock protein 70 (HSP70), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1α (HIF-1α) in extracts from the ischemic cortex. Flow cytometry was used to observe the effect of LEV on neuronal cell apoptosis. Results: LEV treatment significantly increased the density of the surviving neurons in the cerebral cortex and reduced the infarct size (17.8 ± 3.3% vs. 12.9 ± 1.4%, p < 0.01) after MCAO. Concurrently, the time required to reach the platform for LEV-treated rats was shorter than that in the saline group on day 11 after MCAO (p < 0.01). LEV treatment prolonged the rotarod retention time on day 14 after MCAO (84.5 ± 6.7 s vs. 59.1 ± 6.2 s on day 14 compared with the saline-treated groups, p < 0.01). It also suppressed the activation of microglia and inhibited TNF-α and Il-1β in the ischemic brain (135.6 ± 5.2 pg/ml vs. 255.3 ± 12.5 pg/ml, 18.5 ± 1.3 pg/ml vs. 38.9 ± 2.3 pg/ml on day 14 compared with the saline-treated groups, p < 0.01). LEV treatment resulted in a significant increase in HIF-1α, VEGF, and HSP70 levels in extracts from the ischemic cerebral cortex. At the same time, LEV reduced neuronal cell cytotoxicity and apoptosis induced by an ischemic stroke (p < 0.01). Conclusion: LEV treatment promoted angiogenesis and functional recovery after cerebral ischemia in rats. These effects seem to be mediated through anti-inflammatory and antiapoptotic activities, as well as inducing the expression of HSP70, VEGF, and HIF-1α.
Highlights
Ischemic stroke is the second most common cause of death worldwide and the main cause of disability (Grysiewicz et al, 2008; Warner et al, 2019)
Vascular endothelial growth factor (VEGF) is one of the key pro-angiogenic factors that increase after ischemia in both rodent and human brains
VEGF is regulated by the transcriptional hypoxia-inducible factor-1 (HIF-1), which regulates gene transcription to facilitate adaptation and survival after hypoxia–ischemia (Hong et al, 2019)
Summary
Ischemic stroke is the second most common cause of death worldwide and the main cause of disability (Grysiewicz et al, 2008; Warner et al, 2019). There has been great progress in understanding the mechanism of brain injury after ischemia, the development of new drugs for the treatment of ischemic stroke has not progressed as rapidly. The mechanisms of cell death caused by cerebral ischemic injury are complicated and include excitotoxicity, ion imbalance, oxidative stress, and inflammation (Anrather and Iadecola, 2016; Jayaraj et al, 2019; Yang et al, 2019). Due to the increasing prevalence of ischemic stroke in the general population and the lack of adequate treatment methods, it is imperative to research and develop more effective drugs for this neurodegenerative disease. Vascular endothelial growth factor (VEGF) is one of the key pro-angiogenic factors that increase after ischemia in both rodent and human brains. Heat shock protein 70 (HSP70) in mice has been shown to provide protection from cerebral ischemia in an animal model of stroke, suggesting that there is a correlation between induction of HSP and resistance to damage (Doeppner et al, 2017; Shao et al, 2019)
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