Pretreatment with low-dose fimasartan ameliorates NLRP3 inflammasome-mediated neuroinflammation and brain injury after intracerebral hemorrhage

Abstract

Nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which is composed of an NLRP3 domain, the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC) domain, and procaspase-1, plays an important role in the immune pathophysiology of the secondary damage induced by intracerebral hemorrhage (ICH). This study aims to investigate whether pre-stroke treatment with fimasartan, an angiotensin II receptor blocker, has anti-inflammatory effects on ICH by inhibiting the activation of the NLRP3 inflammasome. Sprague-Dawley rats were divided into five groups: sham, vehicle, low-dose (0.5 mg/kg) and regular-doses (1.0 and 3.0 mg/kg) fimasartan. These rats were treated for 30 days before the induction of collagenase-induced ICH and continuously 3 days after surgery. The mean blood pressure (BP) in the low-dose fimasartan group was not significantly different from that of control, and BP in the regular-dose groups was decreased in a dose-dependent manner. Pretreatment with low-dose fimasartan attenuated ICH-induced edema and improved neurological functions. Activation of the NLRP3/ASC/caspase-1 and the NF-κB pathways after ICH was markedly reduced by low-dose fimasartan. The double immunofluorescence staining of brain cells showed a significant decrease in the co-localization of NLRP3 with Iba1 (microglia marker) positive cells by fimasartan treatment. Cultured microglia cells stimulated by hemolysate demonstrated significant activation of the inflammasome, which was reduced by fimasartan. Pretreatment with a low-dose fimasartan alleviated brain damage after acute ICH by inhibiting the NLRP3 inflammasome without lowering MBP. Our study suggests pre-stroke administration of fimasartan could potentially attenuate ICH-induced secondary brain injury by targeting the inflammasome.

Meisoindigo Protects Against Focal Cerebral Ischemia-Reperfusion Injury by Inhibiting NLRP3 Inflammasome Activation and Regulating Microglia/Macrophage Polarization via TLR4/NF-κB Signaling Pathway

“…a P < 0.05 vs. sham; b P < 0.05 vs. vehicle; c P < 0.05 vs. Mei. Yang X. et al, 2018;Tan et al, 2019). NLRP3 inflammasome have been demonstrated to significantly increase brain injury and neuroinflammation after stroke (Ma et al, 2018;Jing et al, 2019).…”

Neuroprotection of Glibenclamide against Brain Injury after Cardiac Arrest via Modulation of NLRP3 Inflammasome

“…The nucleotide-binding oligomerization domain, leucine rich, repeat and, pyrin domaincontaining 3 (NLRP3) inflammasome, is a subcellular multiprotein complex that is abundantly expressed in the central nervous system (CNS) [12]. Cryopyrin/NALP3/NLRP3 can sense and respond to a wide range of exogenous and endogenous stimuli, which results in the activation of caspase-1.…”

“…Activated caspase-1 and other pro-inflammatory cytokines drive inflammatory responses through diverse downstream signaling pathways, leading to neuronal damage and possibly cell death [13]. We have previously shown that by inhibiting the NLRP3 inflammasome, fimasartan can protect against secondary brain damage in an intracerebral hemorrhage model [12].…”

Tanshinone IIA attenuates demyelination and promotes remyelination in A. cantonensis-infected BALB/c mice

“…The neuroinflammatory response modulates both the pathological changes of demyelination and axonal injury and remyelination and repair 33. It is becoming apparent that inflammatory response activation is essential component of tissue regeneration and remyelination 34, 35. When an eosinophilic mechanism for TSIIA effects on demyelination and remyelination was excluded, we speculated that inflammation may be the key reason for TSIIA efficacy following A. cantonensis infection.…”