Barrier mechanisms in neonatal stroke.

Clinical data continue to reveal that the incidence of perinatal stroke is high, similar to that in the elderly. Perinatal stroke leads to significant morbidity and severe long-term neurological and cognitive deficits, including cerebral palsy. Experimental models of cerebral ischemia in neonatal rodents have shown that the pathophysiology of perinatal brain damage is multifactorial. Cerebral vasculature undergoes substantial structural and functional changes during early postnatal brain development. Thus, the state of the vasculature could affect susceptibility of the neonatal brain to cerebral ischemia. In this review, we discuss some of the most recent findings regarding the neurovascular responses of the immature brain to focal arterial stroke in relation to neuroinflammation. We also discuss a possible role of the neonatal blood-CSF barrier in modulating inflammation and the long-term effects of early neurovascular integrity after neonatal stroke on angiogenesis and neurogenesis

Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration

Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy

Protective effects and potential mechanisms of Pien Tze Huang on cerebral chronic ischemia and hypertensive stroke

<p>Abstract</p> <p>Background</p> <p>Stroke caused by brain ischemia is the third leading cause of adult disability. Active prevention and early treatment of stroke targeting the causes and risk factors may decrease its incidence, mortality and subsequent disability. Pien Tze Huang (PZH), a Chinese medicine formula, was found to have anti-edema, anti-inflammatory and anti-thrombotic effects that can prevent brain damage. This study aims to investigate the potential mechanisms of the preventive effects of Pien Tze Huang on brain damage caused by chronic ischemia and hypertensive stroke in rats.</p> <p>Methods</p> <p>The effects of Pien Tze Huang on brain protein expression in spontaneously hypertensive rat (SHR) and stroke prone SHR (SHRsp) were studied with 2-D gel electrophoresis and mass spectrometric analysis with a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF)/TOF tandem mass spectrometer and on brain cell death with enzyme link immunosorbent assay (ELISA) and immunostaining.</p> <p>Results</p> <p>Pien Tze Huang decreased cell death in hippocampus and cerebellum caused by chronic ischemia and hypertensive stroke. Immunostaining of caspase-3 results indicated that Pien Tze Huang prevents brain cells from apoptosis caused by ischemia. Brain protein expression results suggested that Pien Tze Huang downregulated QCR₂in the electron transfer chain of mitochondria preventing reactive oxygen species (ROS) damage and possibly subsequent cell death (caspase 3 assay) as caused by chronic ischemia or hypertensive stroke to hippocampus and cerebellum.</p> <p>Conclusion</p> <p>Pien Tze Huang showed preventive effects on limiting the damage or injury caused by chronic ischemia and hypertensive stroke in rats. The effect of Pien Tze Huang was possibly related to prevention of cell death from apoptosis or ROS/oxidative damage in mitochondria.</p

Ischemic neurons recruit natural killer cells that accelerate brain infarction

Brain ischemia and reperfusion activate the immune system. The abrupt development of brain ischemic lesions suggests that innate immune cells may shape the outcome of stroke. Natural killer (NK) cells are innate lymphocytes that can be swiftly mobilized during the earliest phases of immune responses, but their role during stroke remains unknown. Herein, we found that NK cells infiltrated the ischemic lesions of the human brain. In a mouse model of cerebral ischemia, ischemic neuron-derived fractalkine recruited NK cells, which subsequently determined the size of brain lesions in a T and B cell-independent manner. NK cell-mediated exacerbation of brain infarction occurred rapidly after ischemia via the disruption of NK cell tolerance, augmenting local inflammation and neuronal hyperactivity. Therefore, NK cells catalyzed neuronal death in the ischemic brain

Molecular Biology of Atherosclerotic Ischemic Strokes

Among the causes of global death and disability, ischemic stroke (also known as cerebral ischemia) plays a pivotal role, by determining the highest number of worldwide mortality, behind cardiomyopathies, affecting 30 million people. The etiopathogenetic burden of a cerebrovascular accident could be brain ischemia (~80%) or intracranial hemorrhage (~20%). The most common site when ischemia occurs is the one is perfused by middle cerebral arteries. Worse prognosis and disablement consequent to brain damage occur in elderly patients or affected by neurological impairment, hypertension, dyslipidemia, and diabetes. Since, in the coming years, estimates predict an exponential increase of people who have diabetes, the disease mentioned above constitutes together with stroke a severe social and economic burden. In diabetic patients after an ischemic stroke, an exorbitant activation of inflammatory molecular pathways and ongoing inflammation is responsible for more severe brain injury and impairment, promoting the advancement of ischemic stroke and diabetes. Considering that the ominous prognosis of ischemic brain damage could by partially clarified by way of already known risk factors the auspice would be modifying poor outcome in the post-stroke phase detecting novel biomolecules associated with poor prognosis and targeting them for revolutionary therapeutic strategies

T cell–derived interleukin (IL)-21 promotes brain injury following stroke in mice

T lymphocytes are key contributors to the acute phase of cerebral ischemia reperfusion injury, but the relevant T cell–derived mediators of tissue injury remain unknown. Using a mouse model of transient focal brain ischemia, we report that IL-21 is highly up-regulated in the injured mouse brain after cerebral ischemia. IL-21–deficient mice have smaller infarcts, improved neurological function, and reduced lymphocyte accumulation in the brain within 24 h of reperfusion. Intracellular cytokine staining and adoptive transfer experiments revealed that brain-infiltrating CD4+ T cells are the predominant IL-21 source. Mice treated with decoy IL-21 receptor Fc fusion protein are protected from reperfusion injury. In postmortem human brain tissue, IL-21 localized to perivascular CD4+ T cells in the area surrounding acute stroke lesions, suggesting that IL-21–mediated brain injury may be relevant to human stroke

The role of the neuroprotective factor Npas4 in cerebral ischemia

Stroke is one of the leading causes of death and adult disability in the world. Although many molecules have been documented to have a neuroprotective effect, the majority of these molecules failed to improve the neurological outcomes for patients with brain ischemia. It has been proposed that neuroprotection alone may, in fact, not be adequate for improving the prognosis of ischemic stroke. Neuroprotectants that can regulate other processes which occur in the brain during ischemia could potentially be targets for the development of effective therapeutic interventions in stroke. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an activity-dependent transcription factor whose expression is induced in various brain insults, including cerebral ischemia. It has been shown that Npas4 plays an important role in protecting neurons against many types of neurodegenerative insult. Recently, it was demonstrated that Npas4 indeed has a neuroprotective role in ischemic stroke and that Npas4 might be involved in modulating the cell death pathway and inflammatory response. In this review, we summarize the current knowledge of the roles that Npas4 may play in neuroinflammation and ischemia. Understanding how ischemic lesion size in stroke may be reduced through modulation of Npas4-dependent apoptotic and inflammatory pathways could lead to the development of new stroke therapies.Fong Chan Choy, Thomas S. Klari, Simon A. Koblar and Martin D. Lewi