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.