Amentoflavone attenuates oxidative stress and neuroinflammation induced by cerebral ischemia/reperfusion in rats by targeting HMGB1-mediated TLR4/NF-KB signaling pathway

Surveys indicated that stroke classified among the leading cause of death as well as combined death and disability worldwide resulting in a great loss for the global economy. The present study aims to evaluate the neuroprotective potential of the biflavonoid amentoflavone (AMNT) in alleviating cerebral ischemia/ reperfusion (IR) injury in rats, and to elucidate the possible underlying mechanism of an experimental condition with similar circumstances to stroke. Cerebral ischemia was achieved through left common carotid artery occlusion for 60 min, followed by blood flow restoration. Sham-operated control rats subjected to the same surgical process except for brain IR. Rats were orally administered AMNT/ or vehicle for three days' prior surgical operation, and for another three days after left brain IR. Rats of all groups were assessed for neurological deficits 24 h following brain IR. Each group was divided into two subgroups one for the rotarod testing and biochemical assessment while the other subgroup to perform the activity cage testing, histopathological study, immunohistochemistry, and gene expression analysis. AMNT enhanced brain levels of GSH and CAT activities, suppressed neuroinflammation via reducing the inflammatory cytokines in the serum, and enhanced brain contents of TBK1 and IFNb. AMNT downregulated TLR4-/NF-KB signaling pathway as a result of the HMGB1 suppression. Moreover, AMNT blocked apoptotic cell death by suppressing the NF-KB signaling pathway and reducing the activation of caspase-3. These findings revealed that AMNT attenuates I/R-induced cerebral injury possibly by regulating the HMGB1-mediated TLR4/NF-kB pathway. Thus, AMNT could provide potential preventive and therapeutic option for cerebral stroke.(c) 2023 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).