Takinib inhibits microglial M1 polarization and oxidative damage after subarachnoid hemorrhage by targeting TAK1-dependent NLRP3 inflammasome signaling pathway

Abstract

Transforming growth factor-β-activated kinase 1 (TAK1) positively regulates oxidative stress and inflammation in different diseases. Takinib, a novel and specific TAK1 inhibitor, has beneficial effects in a variety of disorders. However, the effects of takinib on early brain injury (EBI) after subarachnoid hemorrhage (SAH) and the underlying molecular mechanisms remain unknown. Our study showed that takinib administration significantly inhibited phosphorylated TAK1 expression after SAH. In addition, takinib suppressed M1 microglial polarization and promoted M2 microglial polarization. Furthermore, blockade of TAK1 by takinib reduced neuroinflammation, oxidative damage, brain edema, and neuronal apoptosis, and improved neurological behavior after SAH. Mechanistically, we revealed that TAK1 inhibition by takinib mitigated reactive oxygen species (ROS) production and ROS-mediated nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation. In contrast, NLRP3 activation by nigericin abated the neuroprotective effects of takinib against EBI after SAH. In general, our study demonstrated that takinib could protect against EBI by targeting TAK1-ROS-NLRP3 inflammasome signaling. Inhibition of TAK1 might be a promising option in the management of SAH.

FGF21 attenuates neuroinflammation following subarachnoid hemorrhage through promoting mitophagy and inhibiting the cGAS-STING pathway

“…Neuroinflammation plays a pivotal role in the pathogenesis of EBI subsequent to SAH [ 38 ]. Shortly after the occurrence of SAH, neuroinflammation promptly ensues, characterized by glial cell activation and the release of pro-inflammatory cytokines, matrix metalloproteinases, cytotoxic factors, and more [ 39 ].…”

Ferroptosis in early brain injury after subarachnoid hemorrhage: review of literature

“…Protein tyrosine phosphatase 1B inhibitor (PTP1B-in-1) can regulate the IRS-2/AKT signaling pathway, improve neuroinflammation and neuronal apoptosis, and exert neuroprotective functions [ 73 ]. In animal experiments, it was found that takinib alleviates EBI by targeting the inhibition of the TAK1-ROS-NLRP3 inflammasome signaling pathway [ 74 ]. Inhibiting miR-26b can alleviate EBI by mediating the upregulation of KLF4/downregulation of STAT3/downregulation of HMGB1 signaling pathways [ 75 ].…”

TAK1 inhibition mitigates intracerebral hemorrhage-induced brain injury through reduction of oxidative stress and neuronal pyroptosis via the NRF2 signaling pathway

“…TAK1 mediates the production of ROS, exacerbating oxidative damage in different disease models ( 16 , 17 ). In the central nervous system (CNS), TAK1 is mainly expressed in neurons, where it modulates a variety of intracellular signaling pathways ( 18 ). It has demonstrated that TAK1 blockade restrains phosphorylated NF-κB p65 expression and NLRP3 inflammasome activation post-subarachnoid hemorrhage (SAH) ( 19 ).…”