Xanthotoxol Exerts Neuroprotective Effects Via Suppression of the Inflammatory Response in a Rat Model of Focal Cerebral Ischemia
- 400 Downloads
We previously found that xanthotoxol, one of the major active ingredients in Cnidium monnieri (L.) Cusson, exerts protective effects in a rat model of focal cerebral ischemia/reperfusion injury by alleviating brain edema, inhibiting the neutrophil infiltration, and decreasing the expression of intercellular adhesion molecule-1 (ICAM-1) and E-selectin. The present study was designed to further determine the possible mechanisms of action of neuroprotective properties of xanthotoxol after cerebral ischemia. Transient focal cerebral ischemia/reperfusion model in male Sprague–Dawley rats was induced by 2-h middle cerebral artery occlusion followed by 24-h reperfusion. Xanthotoxol (5 and 10 mg/kg) or vehicle were administered intraperitoneally at 1 and 12 h after the onset of ischemia. At 24 h after reperfusion, we assessed the effect of xanthotoxol on the blood–brain barrier (BBB) permeability, the production of pro-inflammatory mediators such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-8, nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and the p65 subunit of the transcription factor, nuclear factor-κB (NF-κB) in the cortex after ischemic insult. The results showed that xanthotoxol treatment significantly attenuated BBB disruption, reduced the IL-1β, TNF-α, IL-8 and NO level, and attenuated the iNOS activity compared with vehicle-treated animals. Further, xanthotoxol treatment also significantly prevented the ischemia/reperfusion-induced increase in the protein expression of iNOS, COX-2, and the nuclear NF-κB p65. These results, taken together with those of our previous study, suggest that the neuroprotection may be attributed to the ability of xanthotoxol to attenuate the expression of pro-inflammatory mediators and thereby inhibit the inflammatory response after cerebral ischemia.
KeywordsXanthotoxol Cerebral ischemia/reperfusion Inflammatory response
This study was supported by Grants (to Wei He) from the National Natural Science Foundation of China (NSFC, 81060269) and from the Science and Technology Foundation of Educational Department of Jiangxi Province of China (GJJ08391).
- Candelario-Jalil E, González-Falcón A, García-Cabrera M, León OS, Fiebich BL (2007) Post-ischaemic treatment with the cyclooxygenase-2 inhibitor nimesulide reduces blood-brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats. J Neurochem 100(4):1108–1120PubMedCrossRefGoogle Scholar
- Collino M, Aragno M, Mastrocola R, Gallicchio M, Rosa AC, Dianzani C, Danni O, Thiemermann C, Fantozzi R (2006) Modulation of the oxidative stress and inflammatory response by PPAR-gamma agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion. Eur J Pharmacol 530(1–2):70–80PubMedCrossRefGoogle Scholar
- He W, Chen WW, Ye HY, Zhou YM, Huang XH (2009) Inhibitory effects of xanthotoxol on neutrophil infiltration and brain edema induced by focal cerebral ischemia-reperfusion injury in rats. Chin Pharmacol Bull 25(5):668–672Google Scholar
- Lian QS, Zhang ZZ, Shangguan Z, Zhou L, Pi RB, Xiang RD, Han Y, Zhang XY (1996) Studies on the anti-arrhythmic effect of xanthotoxol in experimental animals. Chin Tradit Herb Drugs 27(6):347–349Google Scholar
- Lian QS, Zhang ZZ, Hu X, Zhou L, Ye HY, He W, Zhu ZP (1998) Studies on the anti-inflammatory effect of xanthotoxol in experimental animals. Chin Tradit Herb Drugs 29(2):102–104Google Scholar
- Shangguan Z, Lian QS, Zeng J, Zhou Q, Pi RB, Liu JX, Yang JG (1997) Studies on the analgesic effect of xanthotoxol in experimental animals. Tradit Chin Drug Res Clin Pharmacol 8(1):45–46Google Scholar
- Villa P, Triulzi S, Cavalieri B, Di Bitondo R, Bertini R, Barbera S, Bigini P, Mennini T, Gelosa P, Tremoli E, Sironi L, Ghezzi P (2007) The interleukin-8 (IL-8/CXCL8) receptor inhibitor reparixin improves neurological deficits and reduces long-term inflammation in permanent and transient cerebral ischemia in rats. Mol Med 13(3–4):125–133PubMedGoogle Scholar
- Xiang RD, Fu XH (1984) Studies on the chemical constituents of common cnidium(cnidium monnieri)(I). Chin Tradit Herb Drugs 15(9):14–15Google Scholar