Chrysophanol Inhibits NALP3 Inflammasome Activation and Ameliorates Cerebral Ischemia/Reperfusion in Mice

Abstract

The most effective way to contain cerebral ischemic injury is reperfusion; however, reperfusion itself may result in tissue injury, for which inflammatory damage is one of the main causative factors. NALP3 inflammasome is a multiprotein complex. It consists of NALP3, ASC, and caspase-1, whose function is to switch on the inflammatory process. Chrysophanol is an extract from plants of Rheum genus and it possesses many pharmacological effects including its anti-inflammation activity. In this study, the effects of chrysophanol in cerebral ischemia/reperfusion and the potential mechanisms were investigated. Male CD1 mice were subject to transient middle cerebral artery occlusion (tMCAO). The NALP3 inflammasome activation status and its dynamic expression during the natural inflammatory response induced by tMCAO were first profiled. The neuroprotective effects of chrysophanol were then assessed and the potential mechanisms mediating the observed neuroprotection were then explored. Physical parameters including neurological deficit, infarct size, brain edema, and BBB permeability were measured at 24 h after tMCAO. Confocal microscopy, Western blotting, immunohistochemistry, and qRT-PCR techniques were utilized to analyze the expression of NALP3 inflammasome and IL-1β. Our results indicated that the brain tissue damage during cerebral ischemia/reperfusion is accompanied by NALP3 inflammasome activation. Chrysophanol could inhibit the activation of NALP3 inflammasome and protect cerebral ischemic stroke.

Poststroke Inflammasome Expression and Regulation in the Peri-Infarct Area by Gonadal Steroids after Transient Focal Ischemia in the Rat Brain

“…The knowledge about inflammasome activation during ischemic stroke is sketchy, and only in the past years were distinct inflammasome complexes discovered as mediators of inflammatory mechanism leading to cell death in ischemic stroke [10,43,44]. A recently published review article by Trendelenburg [45] focuses on the importance of inflammatory processes during severe ischemic stroke conditions and gives a state-of-the-art overview about the current knowledge.…”

“…This would explain steroid effects. And finally, since NLRP1 and NLRP3 signaling converges to Casp1 activation [10,44,45] and they show a different cellular allocation, our Western blot analysis might mix up different reactions and only give a summation of effects rather than individual responses.…”

Inflammasomes are neuroprotective targets for sex steroids

“…Table 1 gives a brief overview about the most recent findings on the regulation of inflammasome components in the brain by E2 and P. In brain hypoxia, NLRP1 and NLRP3 inflammasome formation occurs in neurons and local glia [26,72]. The neutralization of NLRP1 activity [71], the application of plant extracts such as chrysophanol [96], and treatment with cell-protective omega-3 polyunsaturated fatty acids (PUFA) [26] which both antagonize NLRP3 activation strongly reduce post-ischemic inflammation and damage. We have investigated in more detail the time course of activation of different inflammasome complexes in the penumbra after transient focal middle cerebral occlusion (tMCAO) in male rats and their cellular allocation (manuscript submitted).…”

Neuroprotective effect of a novel Chinese herbal decoction on cultured neurons and cerebral ischemic rats

“…(Chishao)A component of BYHWD [22] and Nao-Shuan-Tong [30]; showed proliferative effects on injured rat peripheral neurons and Schwann cells [31, 32] ; an isolate, paeoniflorin, was neuroprotective in cerebral ischemic rats [86]4. Cassia obtusifolia L. (Juemingzi)Used for hyperlipidemia treatment [44]; showed neuroprotective effects in hippocampal neurons and in cell and animal models of Parkinson’s disease in mice [33, 34] ; an isolate, chrysophanol, showed neuroprotective effect in ischemic mice [87]5. Ligusticum chuanxiong Hort.…”