No abstract

Inflammatory mechanisms mediated by prostaglandins may contribute to the progression of intracerebral hemorrhage (ICH)-induced brain injury, but they are not fully understood. In this study, we examined the effect of prostaglandin E2 receptor EP1 (EP1R) activation and inhibition on brain injury in mouse models of ICH and investigated the underlying mechanism of action. ICH was induced by injecting collagenase, autologous blood, or thrombin into the striatum of middle-aged male and female mice and aged male mice. Effects of selective EP1R agonist ONO-DI-004, antagonist SC51089, and nonspecific Src family kinase inhibitor PP2 were evaluated by a combination of histologic, magnetic resonance imaging (MRI), immunofluorescence, molecular, cellular, and behavioral assessments. EP1R was expressed primarily in neurons and axons but not in astrocytes or microglia after ICH induced by collagenase. In middle-aged male mice subjected to collagenase-induced ICH, EP1R inhibition mitigated brain injury, brain edema, cell death, neuronal degeneration, neuroinflammation, and neurobehavioral deficits, whereas its activation exacerbated these outcomes. EP1R inhibition also was protective in middle-aged female mice and aged male mice after collagenase-induced ICH and in middle-aged male mice after blood- or thrombin-induced ICH. EP1R inhibition also reduced oxidative stress, white matter injury, and brain atrophy and improved functional outcomes. Histologic results were confirmed by MRI. Src kinase phosphorylation and matrix metalloproteinase-9 activity were increased by EP1R activation and decreased by EP1R inhibition. EP1R regulated matrix metalloproteinase-9 activity through Src kinase signaling, which mediated EP1R toxicity after collagenase-induced ICH. We conclude that prostaglandin E2 EP1R activation plays a toxic role after ICH through mechanisms that involve the Src kinases and the matrix metalloproteinase-9 signaling pathway. EP1R inhibition could be a novel therapeutic strategy to improve outcomes after ICH.

Extensional basins with an element of strike-slip deformation can form because of a perturbation in a strike-slip fault zone (pull-apart and fault wedge basins), or where extension is oblique to the margins of the deforming zone (transtensional basins). Transtensional basins are characterized by en echelon arrays of normal faults which are individually oblique to the basin margins. The Bohai Basin, northern China, has previously been modelled as either (1) a giant pull-apart between NNE-SSW trending dextral strike-slip faults, or (2) a rift basin caused by WNW-ESE extension, without significant strike-slip deformation. We present a model for the Bohai Basin’s rift history in which the basin formed as a result of dextral transtension. The Bohai Basin is one of a family of early Tertiary extensional basins present within eastern Asia from northeastern Russia to southeast China. The structural grain in this basin was inherited from a phase of late Mesozoic sinistral transpression. Tertiary extension began in the Paleocene. Most half-grabens in the eastern and western regions of the Bohai Basin have master faults with a NE-SW or NNE-SSW orientation. Secondary normal faults strike oblique to the main structures, in en echelon arrays which indicate a component of dextral transtension. The central part of the basin, the Bozhong Depression, became a significant depocentre for the first time in the middle Eocene. It formed when activity on transtensional zones to its east and west created an extensional overlap between them. Thus the basin as a whole resembles a giant pull-apart basin, with the Bozhong Depression as its central depocentre, but dextral transtension rather than simple strike-slip controlled the deformation. The component of dextral deformation in the Bohai Basin is shared by other early Tertiary east Asian extensional basins, and is consistent with the sense of shear implied by the oblique convergence of the Pacific and Asian plates: an east-west convergence vector applied to a NE-SW trending plate boundary. The consistency of this dextral shear along the Asian margin, and the fact that several of these basins pre-date the India-Asia collision, supports an origin by subduction roll-back of the oceanic Pacific plate from Asia. The extrusion model for east Asian basin formation, whereby extension was caused by lateral transport of lithospheric blocks out of India’s northward path following the India-Asia collision, is not applicable to major basins east and northeast of the Red River Fault.

In this study, we examined injury progression after intracerebral haemorrhage (ICH) induced by collagenase in mice using a preclinical 11.7 Tesla MRI system. On T2-weighted MRI, lesion and striatal volumes were increased on day 3 and then decreased from days 7 to 28. On day 3, with an increase in striatal water content, vasogenic oedema in the perihaematomal region presented as increased T2 and increased apparent diffusion coefficient (ADC) signal. With a synchronous change in T2 and ADC signals, microglial activation peaked on day 3 in the same region and decreased over time. Iron deposition appeared on day 3 around the haematoma border but did not change synchronously with ADC signals. Vascular permeability measured by Evans blue extravasation on days 1, 3, and 7 correlated with the T1-gadolinium results, both of which peaked on day 3. On diffusion tensor imaging, white matter injury was prominent in the corpus callosum and internal capsule on day 3 and then partially recovered over time. Our results indicate that the evolution of grey/white matter injury and blood-brain barrier disruption after ICH can be assessed with multimodal MRI, and that perihaematomal vasogenic oedema might be attributable to microglial activation, iron deposition, and blood-brain barrier breakdown.