Secondary White Matter Injury Mediated by Neuroinflammation after Intracerebral Hemorrhage and Promising Therapeutic Strategies of Targeting the NLRP3 Inflammasome

Abstract

Intracerebral hemorrhage (ICH) is a neurological disease with high mortality and disability. Recent studies showed that white matter injury (WMI) plays an important role in motor dysfunction after ICH. WMI includes WMI proximal to the lesion and WMI distal to the lesion, such as corticospinal tract injury located at the cervical enlargement of the spinal cord after ICH. Previous studies have tended to focus only on gray matter (GM) injury after ICH, and fewer studies have paid attention to WMI, which may be one of the reasons for the poor outcome of previous drug treatments. Microglia and astrocyte-mediated neuroinflammation are significant mechanisms responsible for secondary WMI following ICH. The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation, has been shown to exacerbate neuroinflammation and brain injury after ICH. Moreover, NLRP3 inflammasome is activated in microglia and astrocytes and exerts a vital role in microglia and astrocytes-mediated neuroinflammation. We speculate that NLRP3 inflammasome activation is closely related to the polarization of microglia and astrocytes and that NLRP3 inflammasome activation may exacerbate WMI by polarizing microglia and astrocytes to the pro-inflammatory phenotype after ICH, while NLRP3 inflammasome inhibition may attenuate WMI by polarizing microglia and astrocytes to the anti-inflammatory phenotype following ICH. Therefore, NLRP3 inflammasome may act as leveraged regulatory fulcrums for microglia and astrocytes polarization to modulate WMI and WM repair after ICH. This review summarized the possible mechanisms by which neuroinflammation mediated by NLRP3 inflammasome exacerbates secondary WMI after ICH and discussed the potential therapeutic targets.

Diselenide-Bridged Mesoporous Silica-Based Nanoplatform with a Triple ROS-Scavenging Effect for Intracerebral Hemorrhage Treatment

“…Clearance Assay. ICH mice were intravenously injected with PDA-DSeMSN@Eda, and the biological matrices including feces and urine were digested at various time points (12,24,48, and 72 h postadministration). The Si concentration was quantified by using ICP-OES analysis.…”

“…Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with a monthly mortality rate of approximately 30–50%. , Also, only one-third of ICH survivors achieve functional independence at 12 months after ICH onset . In addition to primary brain injury, which is mainly attributed to the mechanical compression of hematoma, secondary brain injury (SBI), involving a complex array of pathophysiological processes, has been proven as a vital factor leading to neurological deterioration after ICH and a significant determinant of the adverse neurological outcome of patients. − Currently, surgical clot evacuation targeting the primary injury has not yielded conclusive benefits, suggesting that SBI after ICH may represent a complementary and essential pathophysiological target. − Excessive generation and accumulation of reactive oxygen species (ROS) leading to oxidative stress has been increasingly recognized as a main contributing factor of SBI. − Thus, antioxidant therapy may be a promising therapeutic strategy to alleviate SBI after ICH. Edaravone (Eda), a strong free radical scavenger, has been widely used for ischemic stroke treatment. − In recent years, clinical and animal experiments have demonstrated that edaravone exerts promising neuroprotective effects against ICH-induced injury. − However, the therapeutic efficacy of edaravone is far from satisfaction owing to its poor water solubility, metabolic unstability, and off-target side effects .…”

Sphk1/S1P pathway promotes blood-brain barrier breakdown after intracerebral hemorrhage through inducing Nlrp3-mediated endothelial cell pyroptosis

“…Pyroptosis, an in ammatory cell death pathway, is mediated by Nlrp3 (NOD-like receptor family pyrin domain containing 3), which forms the in ammasome complex and activates Caspase-1, leading to the release of IL-1β and IL-18 [27][28][29][30][31][32] . While Nlrp3's role in neuroin ammation and injury post-ICH is established, its direct effects on BBB disruption are less explored [33][34][35][36][37][38][39][40] .…”