Abstract
Ischemic stroke is a severe neurological disorder with a high prevalence rate in developed countries. It is characterized by permanent or transient cerebral ischemia and it activates syndrome of pathological events such as membrane depolarization, glutamate excitotoxicity, and intracellular calcium buildup. Carveol is widely employed as anti-inflammatory and antioxidant in traditional Chinese medicine. In the present study, the neuroprotective effects of post-treated carveol were demonstrated against transient middle cerebral artery occlusion (MCAO) induced focal ischemic cerebral injury. Male Sprague Dawley (SD) rats were subjected to two different experimental protocols to determine the dose and effects of carveol, and to demonstrate the underlying role of the nuclear factor E2-related factor (Nrf2) pathway. Our results showed that MCAO induced marked neuronal injury in the ipsilateral cortex and striatum associated with higher inflammatory cytokines expression, along with apoptotic markers such as caspase-3 and the phosphorylated c-Jun N-terminal kinase (JNK). Furthermore, MCAO induced a marked increase in oxidative stress as evidenced by high lipid peroxidase (LPO) content accompanied by the depressed antioxidant system. Carveol significantly reversed the oxidative stress and downregulated inflammatory cascades by enhancing endogenous antioxidant mechanisms including the Nrf2 gene, which critically regulates the expression of several downstream antioxidants. Further, to determine the possible involvement of Nrf2 in carveol mediated neuroprotection, we antagonized Nrf2 by all-trans retinoic acid (ATRA), and such treatment abrogated the protective effects of carveol accompanied with exaggerated neuronal toxicity as demonstrated by higher infarction area. The target effects of carveol were further supported by molecular docking analysis of drug–protein interactions. Together, our findings suggest that carveol could activate endogenous master anti-oxidant Nrf2, which further regulates the expression of downstream antioxidants, eventually ameliorating MCAO-induced neuroinflammation and neurodegeneration.
Highlights
Ischemic stroke is a neurological disorder with a high prevalence in developed countries
middle cerebral artery occlusion (MCAO) produced a significantly larger infarction area as compared to sham-operated group (p < 0.001, Figure 2B), while carveol treatment significantly attenuated the infarction in a dose-dependent manner (p < 0.05, p < 0.01, Figure 2B), with the corrected infarct area of 33.14 ± 0.59%
We performed the thiobarbituric acid reactive substances (TBARS) test and the results showed a drastic increase of peroxides in the MCAO group, an effect that could be rescued by carveol treatment (Table 1)
Summary
Ischemic stroke is a neurological disorder with a high prevalence in developed countries. Ischemic injury can cause a varying degree of cellular damage marked by complex events of signaling cascades (Dirnagl et al, 1999). This, mingled with the vascular and tissue damage incurred by early mitochondrial dysfunction and oxidative phosphorylation, trigger the release of reactive oxygen species (ROS) and pro-inflammatory mediators such as interleukin-1 (IL-1β), tumor necrosis factor-alpha (TNFα), and interleukin-6 (IL-6), eventually leading to cellular damage as well as peroxidation of membranous protein and cytoplasmic organelles (Vila et al, 2000). Nrf activation and its associated signalings are neuroprotective in ischemic and other brain injuries in various pre-clinical animal models (Hong et al, 2010; Jiang et al, 2017; Zhang et al, 2018; Duan et al, 2019; Shah et al, 2019a). Nrf dependent signaling pathway presents an appropriate therapeutic target to cope against a variety of insults including cerebral ischemia
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