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Subarachnoid hemorrhage (SAH) can be associated with neurological deficits and has profound consequences for mortality and morbidity. Cerebral vasospasm (CVS) and delayed cerebral ischemia affect neurological outcomes in SAH patients, but their mechanisms are not fully understood, and effective treatments are limited. Here, we report that urotensin II receptor UT plays a pivotal role in both early events and delayed mechanisms following SAH in male mice. Few days post-SAH, UT expression is triggered by blood or hemoglobin in the leptomeningeal compartment. UT contributes to perimeningeal glia limitans astrocyte reactivity, microvascular alterations and neuroinflammation independent of CNS-associated macrophages (CAMs). Later, CAM-dependent vascular inflammation and subsequent CVS develop, leading to cognitive dysfunction. In an SAH model using humanized UTh+/h+ male mice, we show that post-SAH CVS and behavioral deficits, mediated by UT through Gq/PLC/Ca2+ signaling, are prevented by UT antagonists. These results highlight the potential of targeting UT pathways to reduce early meningeal response and delayed cerebral ischemia in SAH patients. "In subarachnoid hemorrhage (SAH), therapies are limited and clinical outcomes remain disappointing. The authors show a contribution of the urotensin II system in microvascular changes, vasospasm, neuroinflammation and cognitive deficits post-SAH, primarily through meningeal cells and border-associated macrophages [ABSTRACT FROM AUTHOR]

Background: Subarachnoid hemorrhage (SAH) can lead to acute hydrocephalus (AH). AH pathophysiology is classically attributed to an obstruction of the arachnoid granulations by blood. Recent findings in rodents suggest that after intraventricular hemorrhage, AH is related to cerebrospinal fluid (CSF) hypersecretion by the choroid plexus (CP), as it can be reduced by intracerebroventricular (ICV) injection of bumetanide. Objective: Here, we investigated if and how CSF hypersecretion and/or CSF outflow disorders contribute to post-SAH hydrocephalus. Methods: Ninety-four Wistar rats were used. SAH was induced by the endovascular perforation technique. The presence of AH was confirmed by magnetic resonance imaging (MRI), and rats with AH were randomly assigned to 4 groups: control group, superior sagittal sinus (SSS) thrombosis to block CSF reabsorption, ICV injection of saline, and ICV injection of bumetanide to decrease CSF secretion. Clinical outcome was evaluated with a neuroscore. A second MRI was performed 24 h later to evaluate the ventricular volume. Results: Fifty percent of rats that survived SAH induction had AH. Their ventricular volume correlated well to the functional outcome after 24 h (r = 0.803). In rats with AH, 24 h later, ventricular volume remained equally increased in the absence of any further procedure. Similarly, ICV injection of saline or SSS thrombosis had no impact on the ventricular volume. However, ICV injection of bumetanide reduced AH by 35.9% (p = 0.002). Conclusion: In rodents, post-SAH hydrocephalus is may be due to hypersecretion of CSF by the CP, as it is limited by ICV injection of bumetanide. However, we cannot exclude other mechanisms involved in post-SAH acute hydrocephalus. [ABSTRACT FROM AUTHOR]

Rodent animal models of stroke are widely used with brain ischemia inducible by various occlusion methods. Permanent or transient occlusion of the distal portion of the middle cerebral artery (MCAO) offers a reproducible model with low mortality rates, and it is the most likely model of choice for mid- and long-term studies to assess neurorepair or long-term effects of neuroprotective drugs. Therefore, a measurable and stable neurological assessment would be required to evaluate sensorimotor and cognitive deficits at short and long terms as suggested by the Stroke Therapy Academic Industry Roundtable preclinical recommendations. We review the usefulness of different tests used to measure functional outcome after distal MCAO in mice and further sustain these data with our own multilaboratories' experience. Results show that several tests were suitable to detect neurological deterioration at short term. Grip strength and latency to move have shown some usefulness at long term, with important differences between strains, while less clear are the data for the corner test. Important strain differences in terms of infarct volume are also reported in this study. Statistical power analysis and sample size calculation of our data confirmed the value of grip strength and latency to move tests but suggest that larger sample size would be required. In conclusion, there are no robust data supporting the use of a specific behavior test to assess long-term functional outcome after distal MCAO in mice. This is an important limitation since translational basic research should provide data to help further clinical trial evaluation. New multicenter studies with larger sample size and specific mouse strains are needed to confirm the validity of tests, such as the corner, latency to move or grip strength. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that pre- or perinatal events that influence the immune system contribute to the development of behavioral or neuropsychiatric disorders. For instance, exposure of pregnant rats to the bacterial endotoxin lipopolysaccharide (LPS) disrupts sensorimotor information processing, as assessed by the prepulse inhibition test (PPI), and also the immune function in adult offspring, which might be of particular relevance as regards schizophrenia. However, the consequences of maternal LPS exposure during pregnancy on synaptic functioning in adult offspring and, more importantly, the therapeutic opportunity to re-establish PPI and immune function have still to be demonstrated. In this work, we analyzed the consequences of prenatal LPS exposure on dopaminergic neurotransmission and presynaptic markers in adult brain areas related to PPI circuitry. In addition, we tested whether oral treatment with the typical antipsychotic drug haloperidol (HAL) could reinstate PPI performances and cytokine serum levels in six-month-old male rats with prenatal LPS exposure. Both sensory information processing deficits and immune anomalies induced by prenatal exposure to LPS were accompanied by changes in dopaminergic neurotransmission and synaptophysin expression. It is important to note that PPI disruption and serum increases in cytokines induced by prenatal LPS exposure were both reversed by HAL. Taken together, these results demonstrate the critical influence of prenatal immune events on the functioning of adult nervous and immune systems, in association with the putative role of the immune system in the development of behavior relevant to schizophrenia.Neuropsychopharmacology (2007) 32, 1791–1804; doi:10.1038/sj.npp.1301292; published online 20 December 2006 [ABSTRACT FROM AUTHOR]

Studies the transforming growth factor-beta and ischemic brain injury. Fundamental hallmarks of neuronal death in stroke; Transforming growth factor-beta signaling pathway; Molecular mechanisms by which transforming growth factor-beta rescues neurons from excitotoxic neuronal death.

Tissue-plasminogen activator (t-PA) is now available for the treatment of thrombo-embolic stroke but adverse effects have been reported in some patients, particularly hemorrhaging. In contrast, the results of animal studies have indicated that t-PA could increase neuronal damage after focal cerebral ischemia. Here we report for the first time that t-PA potentiates signaling mediated by glutamatergic receptors by modifying the properties of the N-methyl-D-aspartate (NMDA) receptor. When depolarized, cortical neurons release bio-active t-PA that interacts with and cleaves the NR1 subunit of the NMDA receptor. Moreover, the treatment with recombinant t-PA leads to a 37% increase in NMDA-stimulated fura-2 fluorescence, which may reflect an increased NMDA-receptor function. These results were confirmed in vivo by the intrastriatal injection of recombinant-PA, which potentiated the excitotoxic lesions induced by NMDA. These data provide insight into the regulation of NMDA-receptor-mediated signaling and could initiate therapeutic strategies to improve the efficacy of t-PA treatment in man. [ABSTRACT FROM AUTHOR]

The introduction of recombinant tissue-type plasminogen activator (tPA) revolutionized stroke treatment, but experimental studies have suggested potential toxic effects of this molecule on various components of the CNS. Two new studies have added further insight into the complex CNS effects of tPA following traumatic brain injury and brain ischaemia. [ABSTRACT FROM AUTHOR]