IMM-H004, a coumarin derivative, attenuated brain ischemia/reperfusion injuries and subsequent inflammation in spontaneously hypertensive rats through inhibition of VCAM-1

Abstract

Strokes are the leading cause of death and disability all over the world, however, there are few satisfactory therapies. IMM-H004 citrate (004), 7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-coumarin, is a coumarin derivative which has potential therapeutic effects in brain ischemia with ambiguous mechanisms. We aim to study the anti-brain ischemia effect and mechanism of 004 in spontaneously hypertensive (SHR) rats. Adult male Wistar-Kyoto (WKY) rats and SHR rats were subjected to 24 h reperfusion after transient middle cerebral artery occlusion (tMCAO) for 1 h and were intravenously injected with 004 or Edaravone at the time of reperfusion. Behavioral scores, magnetic resonance imaging (MRI) and TTC staining were used to test the therapeutic effect of 004. To study the mechanism, the infiltration of leukocytes, the activation of microglia, blood viscosity, the expression of VCAM-1, MMPs and proteins involved in the MAPK/NF-κB pathway were researched. The results indicated that tMCAO/R induced serious injury, while 004 significantly alleviated the infarct volume and improved neurological deficits. 004 improved inflammatory processes, such as the enhancement of blood viscosity, expression of VCAM-1 and MMP2, release of TNF-α, IL-1β, IL-6 and IL-23, phosphorylation of JNK and p38 and translocation of NF-κB, which play crucial roles in brain I/R in SHR rats. An in vitro study also proved that 004 regulated JNK and NF-κB pathways and decreased the expression of VCAM-1, which eventually led to the suppression of neuroinflammation.