Neuroprotective effects of andrographolide derivative CX-10 in transient focal ischemia in rat: Involvement of Nrf2/AE and TLR/NF-κB signaling.

Ischemic stroke is a major cause of mortality and disability worldwide. To date there is no ideal effective treatment. 3, 14, 19-triacetyl andrographolide (CX-10) is a new molecule entity derived from andrographolide. The aim of the present study was to evaluate the neuroprotection of CX-10 against experimental cerebral ischemia. The anti-inflammation of CX-10 was screened using LPS-induced inflammation in vitro and in vivo. Rats were subjected to 1.5 h of middle cerebral occlusion (MCAO) and then reperfusion for 72 h. The infarct size was evaluated by TTC staining, and the behavioral disturbance was evaluated, and inflammatory cytokines and anti-oxidant enzymes in brain tissues were examined. Western blot was used to analyze the expression of proteins. The results showed that CX-10 exerted potent anti-inflammatory and anti-oxidation activities, which significantly inhibited LPS-induced TNF-α and NO release, lowered TNF-α and IL-1β levels in the brain, meanwhile increased activities of SOD, CAT and GSH-P × . The effect of CX-10 was equivalent to that of dexamethasone, and was obviously superior to that of andrographolide. CX-10 exhibited a neuroprotective effects, manifested as reducing infarct size, improving neurological function and reducing motor impairments. Furthermore, western blot analysis revealed that treatment with CX-10 down-regulated the expression of TLR4, NF-κB, TNF-α and iNOS, induced Nrf2 and HO-1 expression. Overall, CX-10 has a favorable neuroprotection in ischemic brain injury. The mechanism may involve inhibition of TLR4/NF-κB signaling pathway and upregulation of Nrf2/ARE signaling pathway. All these indicated that CX-10 is likely to be a promising agent for ischemic stroke.