Selective Toll-Like Receptor 4 Antagonists Prevent Acute Blood-Brain Barrier Disruption After Subarachnoid Hemorrhage in Mice

Abstract

There are no direct evidences showing the linkage between Toll-like receptor 4 (TLR4) and blood-brain barrier (BBB) disruption after subarachnoid hemorrhage (SAH). The purpose of this study was to examine if selective blockage of TLR4 prevents BBB disruption after SAH in mice and if the TLR4 signaling involves mitogen-activated protein kinases (MAPKs). One hundred and fifty-one C57BL/6 male mice underwent sham or endovascular perforation SAH operation, randomly followed by an intracerebroventricular infusion of vehicle or two dosages (117 or 585 ng) of a selective TLR4 antagonist IAXO-102 at 30 min post-operation. The effects were evaluated by survival rates, neurological scores, and brain water content at 24-72 h and immunoglobulin G immunostaining and Western blotting at 24 h post-SAH. IAXO-102 significantly prevented post-SAH neurological impairments, brain edema, and BBB disruption, resulting in improved survival rates. IAXO-102 also significantly suppressed post-SAH activation of a major isoform of MAPK p46 c-Jun N-terminal kinase (JNK) and matrix metalloproteinase-9 as well as periostin induction and preserved tight junction protein zona occludens-1. Another selective TLR4 antagonist TAK-242, which has a different binding site from IAXO-102, also showed similar effects to IAXO-102. This study first provided the evidence that TLR4 signaling is involved in post-SAH acute BBB disruption and that the signaling is mediated at least partly by JNK activation. TLR4-targeted therapy may be promising to reduce post-SAH morbidities and mortalities.

Plasma Periostin and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

“…ROC curve analyses suggested that plasma POSTN levels at days 1-3 and 4-6 could be used as a biomarker for predicting DCI in patients without CSF drainage. The underlying mechanism of DCI development has not been clarified exactly, and nonvasospastic causes of DCI have been attracted attention to recently [4,27,28]. However, inflammation is considered to be an important cause of DCI irrespective of vasospasm [4,[27][28][29][30].…”

“…The underlying mechanism of DCI development has not been clarified exactly, and nonvasospastic causes of DCI have been attracted attention to recently [4,27,28]. However, inflammation is considered to be an important cause of DCI irrespective of vasospasm [4,[27][28][29][30]. As tissue injury and inflammation induce the expression of POSTN, post-SAH neuroinflammation may cause POSTN upregulation [11,19].…”

“…MAPKs and MMP-9 are well known to cause the degradation of cerebral microvessel basal lamina and tight junction protein zona occludens-1, resulting in BBB disruption and brain edema formation after SAH [31,32]. A more recent study also showed the possible involvement of POSTN in the development of EBI or BBB disruption after experimental SAH [28]. Thus, post-SAH increases in POSTN may cause EBI, which in turn may lead to DCI with no vasospasm [13].…”

The role of Toll-like receptor signaling pathways in cerebrovascular disorders: the impact of spreading depolarization

“…Microglial cells play a crucial role in SAH-induced vasospasm in both the early and late phases of SAH [83]. The effects of two selective TLR4 inhibitors on SAH-induced disruption of the blood rain barrier (BBB) were assessed in a SAH experimental model [138,139]. Intracerebroventricular application of these selective TLR4 antagonists, IAXO-102, and TAK-242, in male mice with SAH significantly reduced post-SAH neurological deficits, the BBB disruption, and brain edema, leading to a better survival rate [139].…”

The Role of Periostin in Brain Injury Caused by Subarachnoid Hemorrhage

“…TLR-4 is expressed in most of the cells in the brain and the cerebral arterial wall, as well as in the inflammatory cells and platelets, and has been reported to induce maximal inflammatory response among all the TLR family members (Figure 3) [2,7,57]. TLR-4 activates both NF-κΒ and mitogen-activated protein kinase (p38, ERK, and JNK) pathways, and induces various pro-inflammatory factors such as ILs, MMP-9, reactive oxygen species, and matricellular proteins including tenascin-C and periostin [2,7,58]. Among the matricellular proteins, periostin and tenascin-C positively affect each other's function and expression levels [59], and tenascin-C and galectin-3 are known to be the ligands of TLR-4 [7,60].…”