Luteolin Confers Cerebroprotection after Subarachnoid Hemorrhage by Suppression of NLPR3 Inflammasome Activation through Nrf2‐Dependent Pathway

Abstract

Luteolin (LUT) possesses multiple biologic functions and has beneficial effects for cardiovascular and cerebral vascular diseases. Here, we investigated the protective effects of LUT against subarachnoid hemorrhage (SAH) and the involvement of underlying molecular mechanisms. In a rat model of SAH, LUT significantly inhibited SAH-induced neuroinflammation as evidenced by reduced microglia activation, decreased neutrophil infiltration, and suppressed proinflammatory cytokine release. In addition, LUT markedly ameliorated SAH-induced oxidative damage and restored the endogenous antioxidant systems. Concomitant with the suppressed oxidative stress and neuroinflammation, LUT significantly improved neurologic function and reduced neuronal cell death after SAH. Mechanistically, LUT treatment significantly enhanced the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), while it downregulated nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation. Inhibition of Nrf2 by ML385 dramatically abrogated LUT-induced Nrf2 activation and NLRP3 suppression and reversed the beneficial effects of LUT against SAH. In neurons and microglia coculture system, LUT also mitigated oxidative stress, inflammatory response, and neuronal degeneration. These beneficial effects were associated with activation of the Nrf2 and inhibitory effects on NLRP3 inflammasome and were reversed by ML385 treatment. Taken together, this present study reveals that LUT confers protection against SAH by inhibiting NLRP3 inflammasome signaling pathway, which may be modulated by Nrf2 activation.

Cycloastragenol Confers Cerebral Protection after Subarachnoid Hemorrhage by Suppressing Oxidative Insults and Neuroinflammation via the SIRT1 Signaling Pathway

“…Haemoglobin- (Hb-) induced in vitro SAH model was performed according to a previous study [ 5 ]. For cell culture, the cortex was dissociated from rat pups (postnatal days 0-1).…”

Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders

“…Celastrol, a pentacyclic triterpene from Tripterygium wilfordi root extract, exhibited neuroprotective properties in a MPTP-induced PD mouse model and AAV-mediated human α-synuclein overexpression in a PD model by inhibiting NLRP3 through the Nrf2 signaling pathway ( 135 ). Luteolin, a flavone, exerted cerebroprotection after subarachnoid hemorrhage ( 136 ) and neuroprotection after spinal cord ischemia-reperfusion injury ( 137 ) by preventing activation of NLRP3 inflammasome via the Nrf2 pathway. Astragaloside IV, a saponin found in Astragalus membranaceus , was found beneficial against cerebral ischemia-reperfusion injury ( 138 ), motor deficits, and dopaminergic neuron degeneration in a MPTP PD mouse model ( 139 ) via NLRP3/Nrf2 pathway regulation.…”

NLRP3 Inflammasome Overactivation in Patients with Aneurysmal Subarachnoid Hemorrhage

“…For instance, MCC-950 attenuated early brain injury and cerebral vasospasm after experimental SAH in animal models [49,50]. Besides, a plethora of other molecules of uneven origin rather than NLRP3i, such as melatonin [10,11], resolvin D1 [12], the HSP90 inhibitor 17-AAG [13], the saponin dioscin [14], also plant-derived antioxidants such as resveratrol, pterostilbene, and luteolin [15][16][17], caspase inhibitors [30,51,52], and commercialized drugs from ansiolitics [18][19][20] to antibiotics [21], have demonstrated to alleviate neurological deficits and improve neurobehavioral outcomes in SAH animal models by targeting, from diverse pathways, NLRP3 inflammasome axis.…”

“…mechanism underlying aSAH complications [8,9]. Recently, increasing evidence has indicated the role of the NLRP3 (nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome as a key component of post-SAH inflammatory response in animal models [10][11][12][13][14][15][16][17][18][19][20][21]. In fact, activation of NLRP3 inflammasome in pathology of intracerebral hemorrhage has been recently reviewed [22].…”