Immunity and inflammation are key elements of the pathobiology of stroke, a devastating illness second only to cardiac ischemia as a cause of death worldwide. The immune system participates in the brain damage produced by ischemia, and the damaged brain, in turn, exerts an immunosuppressive effect that promotes fatal infections that threaten the survival of people after stroke. Inflammatory signaling is involved in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion to the late regenerative processes underlying post-ischemic tissue repair. Recent developments have revealed that stroke engages both innate and adaptive immunity. But adaptive immunity triggered by newly exposed brain antigens does not have an impact on the acute phase of the damage. Nevertheless, modulation of adaptive immunity exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. As immunomodulation is not devoid of deleterious side effects, a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.

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The immunology of stroke: from mechanisms to translation

Blood-brain barrier tight junction permeability and ischemic stroke.

Traumatic brain injury (TBI) is the leading cause of death in young adults and children. The treatment of TBI in the acute phase has improved substantially; however, the prevention and management of long-term complications remain a challenge. Blood-brain barrier (BBB) breakdown has often been documented in patients with TBI, but the role of such vascular pathology in neurological dysfunction has only recently been explored. Animal studies have demonstrated that BBB breakdown is involved in the initiation of transcriptional changes in the neurovascular network that ultimately lead to delayed neuronal dysfunction and degeneration. Brain imaging data have confirmed the high incidence of BBB breakdown in patients with TBI and suggest that such pathology could be used as a biomarker in the clinic and in drug trials. Here, we review the neurological consequences of TBI, focusing on the long-term complications of such injuries. We present the clinical evidence for involvement of BBB breakdown in TBI and examine the primary and secondary mechanisms that underlie such pathology. We go on to consider the consequences of BBB injury, before analyzing potential mechanisms linking vascular pathology to neuronal dysfunction and degeneration, and exploring possible targets for treatment. Finally, we highlight areas for future basic research and clinical studies into TBI.

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Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury

A great many aspects of neuronal physiology and pathology involve or affect the brain barriers. Recent insights into the role of the blood–brain barrier during development, and advances in our understanding of how it affects neurological disorders, have led to closer links between the two topics.

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Engaging neuroscience to advance translational research in brain barrier biology

Blood-brain barrier dysfunction and recovery after ischemic stroke.

Ischemic stroke is a devastating disease with a complex pathophysiology. Animal modeling of ischemic stroke serves as an indispensable tool first to investigate mechanisms of ischemic cerebral injury, secondly to develop novel antiischemic regimens. Most of the stroke models are carried on rodents. Each model has its particular strengths and weaknesses. Mimicking all aspects of human stroke in one animal model is not possible since ischemic stroke is itself a very heterogeneous disorder. Experimental ischemic stroke models contribute to our understanding of the events occurring in ischemic and reperfused brain. Major approaches developed to treat acute ischemic stroke fall into two categories, thrombolysis and neuroprotection. Trials aimed to evaluate effectiveness of recombinant tissue-type plasminogen activator in longer time windows with finer selection of patients based on magnetic resonance imaging tools and trials of novel recanalization methods are ongoing. Despite the failure of most neuroprotective drugs during the last two decades, there are good chances to soon have effective neuroprotectives with the help of improved preclinical testing and clinical trial design. In this article, we focus on various rodent animal models, pathogenic mechanisms, and promising therapeutic approaches of ischemic stroke.

Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia.

The blood-brain barrier is continuously open for several weeks following transient focal cerebral ischemia.

Post-ischemic blood–brain barrier leakage in rats: One-week follow-up by MRI

Ischemic tolerance defines transient resistance to lethal ischemia gained by a prior sublethal noxious stimulus (i.e., preconditioning). This adaptive response is thought to be an evolutionarily conserved defense mechanism, observed in a wide variety of species. Preconditioning confers ischemic tolerance if not in all, in most organ systems, including the heart, kidney, liver, and small intestine. Since the first landmark experimental demonstration of ischemic tolerance in the gerbil brain in early 1990's, basic scientific knowledge on the mechanisms of cerebral ischemic tolerance increased substantially. Various noxious stimuli can precondition the brain, presumably through a common mechanism, genomic reprogramming. Ischemic tolerance occurs in two temporally distinct windows. Early tolerance can be achieved within minutes, but wanes also rapidly, within hours. Delayed tolerance develops in hours and lasts for days. The main mechanism involved in early tolerance is adaptation of membrane receptors, whereas gene activation with subsequent de novo protein synthesis dominates delayed tolerance. Ischemic preconditioning is associated with robust cerebroprotection in animals. In humans, transient ischemic attacks may be the clinical correlate of preconditioning leading to ischemic tolerance. Mimicking the mechanisms of this unique endogenous protection process is therefore a potential strategy for stroke prevention. Perhaps new remedies for stroke are very close, right in our cells.

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Preconditioning-induced ischemic tolerance: a window into endogenous gearing for cerebroprotection

Publisher Summary Animal stroke models have played a unique role in understanding normal and ischemic brain metabolism and function. Sophisticated methods for the quantitative mapping of local cerebral blood flow, glucose utilization, and protein synthesis were developed and validated in rats. Rat is the commonly used species in experimental stroke studies and is one of the most suitable animals. The use of small animals for stroke research studies provides advantages of lower cost and greater acceptability from an ethical perspective compared to larger animals. In contrast, the disadvantage of using small animals is the lissencephalic morphology of their brains; whereas, large animals have gyrencephalic brains and considerable amount of neocortex like humans. Setting high standards for experimental studies will improve their relevance to human stroke and will help in the development of novel therapies for stroke. Scientists should be cautious not to over-interpret experimental data. The widespread use of novel technologies with stroke models has improved their utility. Many critical discoveries in the stroke field have stemmed from experimental models. Genetically manipulated animals have opened a new approach to stroke pathophysiology. This rapidly developing field holds great potential for improving stroke care, despite its already well recognized limitations.

Aysan Durukan

Papers

Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia.

The blood-brain barrier is continuously open for several weeks following transient focal cerebral ischemia.

Post-ischemic blood–brain barrier leakage in rats: One-week follow-up by MRI

Preconditioning-induced ischemic tolerance: a window into endogenous gearing for cerebroprotection

Animal models of ischemic stroke.