Excessive oxygen and its chemical derivatives, namely reactive oxygen species (ROS), produce oxidative stress that has been known to lead to cell injury in ischemic stroke. ROS can damage macromolecules such as proteins and lipids and leads to cell autophagy, apoptosis, and necrosis to the cells. This review describes studies on the generation of ROS, its role in the pathogenesis of ischemic stroke, and recent development in therapeutic strategies in reducing oxidative stress after ischemic stroke.

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Stroke leads to inflammatory and immune response in the brain and immune organs. The gut or gastrointestinal tract is a major immune organ equipped with the largest pool of immune cells representing more than 70% of the entire immune system and the largest population of macrophages in the human body. The bidirectional communication between the brain and the gut is commonly known as brain–gut or gut–brain axis. Stroke often leads to gut dysmotility, gut microbiota dysbiosis, “leaky” gut, gut hemorrhage, and even gut-origin sepsis, which is often associated with poor prognosis. Emerging evidence suggests that gut inflammatory and immune response plays a key role in the pathophysiology of stroke and may become a key therapeutic target for its treatment. Ischemic brain tissue produces damage-associated molecular patterns to initiate innate and adaptive immune response both locally and systemically through the specialized pattern-recognition receptors (e.g., toll-like receptors). After stroke, innate immune cells including neutrophils, microglia or macrophages, mast cells, innate lymphocytes (IL-17 secreting γδ T-cell), and natural killer T-cell respond within hours, followed by the adaptive immune response through activation of T and B lymphocytes. Subpopulations of T-cells can help or worsen ischemic brain injury. Pro-inflammatory Th1, Th17, and γδ T-cells are often associated with increased inflammatory damage, whereas regulatory T-cells are known to suppress postischemic inflammation by increasing the secretion of anti-inflammatory cytokine IL-10. Although known to play a key role, research in the gut inflammatory and immune response after stroke is still in its initial stage. A better understanding of the gut inflammatory and immune response after stroke may be important for the development of effective stroke therapies. The present review will discuss recent advances in the studies of the brain–gut axis after stroke, the key issues to be solved, and the future directions.

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Stroke is a leading cause of death and long-term disabilities. Despite decades of extensive efforts in search of brain injury mechanisms and therapeutic interventions, pharmacological treatment is limited to the use of thrombolytic agent tissue plasminogen activator, which has limited therapeutic time window and potential side effect of intracranial hemorrhage. Over the past few years, endovascular thrombectomy with stent-retriever devices combined with advanced imaging modalities has transformed the standard of stroke care, offering an opportunity to improve the outcome in selected patients as late as 24 h after the onset of stroke. This mini-review summarizes the advancement in the treatment of ischemic stroke, from thrombolysis to thrombectomy and remaining challenges in the field.

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Every year, approximately 1.4 million US citizens visit emergency rooms for traumatic brain injuries. Formerly known as an acute injury, chronic neurodegenerative symptoms such as compromised motor skills, decreased cognitive abilities, and emotional and behavioral changes have caused the scientific community to consider chronic aspects of the disorder. The injury causing impact prompts multiple cell death processes, starting with neuronal necrosis, and progressing to various secondary cell death mechanisms. Secondary cell death mechanisms, including excitotoxicity, oxidative stress, mitochondrial dysfunction, blood–brain barrier disruption, and inflammation accompany chronic traumatic brain injury (TBI) and often contribute to long-term disabilities. One hallmark of both acute and chronic TBI is neuroinflammation. In acute stages, neuroinflammation is beneficial and stimulates an anti-inflammatory response to the damage. Conversely, in chronic TBI, excessive inflammation stimulates the aforementioned secondary cell death. Converting inflammatory cells from pro-inflammatory to anti-inflammatory may expand the therapeutic window for treating TBI, as inflammation plays a role in all stages of the injury. By expanding current research on the role of inflammation in TBI, treatment options and clinical outcomes for afflicted individuals may improve. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences.

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The central nervous system's (CNS) complicated design is a double-edged sword. On the one hand, the complexity is what gives rise to higher order thinking; but on the other hand, damage to the CNS evokes its unforgiving nature. The cerebrospinal fluid (CSF) circulation system is an intricate system embedded in and around the CNS that has been the topic of debate since it was first described in the 18^th century. It is underscored by the choroid plexus's distinct vascular network which has conventionally been seen as the most prominent structure in CSF production through a variety of active transporters and channels. Despite the ubiquity of this circulation system in vertebrates, some aspects remain understudied. Recent advances in scientific methodology and experimentation have proven to be effective tools for elucidating the mechanisms of the CSF circulation system and the pathological conditions associated with its malfunction. In this review, we capitulate the classical understanding of CSF physiology as well as a new, emerging theory on CSF production.

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The effectiveness of current management of critically ill stroke patients depends on rapid assessment of the type of stroke, ischemic or hemorrhagic, and on a patient's general clinical status. Thrombolytic therapy with recombinant tissue plasminogen activator (r-tPA) is the only effective treatment for ischemic stroke approved by the Food and Drug Administration (FDA), whereas no treatment has been shown to be effective for hemorrhagic stroke. Furthermore, a narrow therapeutic window and fear of precipitating intracranial hemorrhage by administering r-tPA cause many clinicians to avoid using this treatment. Thus, rapid and objective assessments of stroke type at admission would increase the number of patients with ischemic stroke receiving r-tPA treatment and thereby, improve outcome for many additional stroke patients. Considerable literature suggests that brain-specific protein biomarkers of glial [i.e. S100 calcium-binding protein B (S100B), glial fibrillary acidic protein (GFAP)] and neuronal cells [e.g., ubiquitin C-terminal hydrolase-L1 (UCH-L1), neuron-specific enolase (NSE), αII-spectrin breakdown products SBDP120, SBDP145, and SBDP150, myelin basic protein (MBP), neurofilament light chain (NF-L), tau protein, visinin-like protein-1 (VLP 1), NR2 peptide] injury that could be detected in the cerebrospinal fluid (CSF) and peripheral blood might provide valuable and timely diagnostic information for stroke necessary to make prompt management and decisions, especially when the time of stroke onset cannot be determined. This information could include injury severity, prognosis of short-term and long-term outcomes, and discrimination of ischemic or hemorrhagic stroke. This chapter reviews the current status of the development of biomarker-based diagnosis of stroke and its potential application to improve stroke care.

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Cerebral ischemia is among the leading causes of death worldwide. It is characterized by a lack of blood flow to the brain that results in cell death and damage, ultimately causing motor, sensory, and cognitive impairments. Today, clinical treatment of cerebral ischemia, mostly stroke and cardiac arrest, is limited and new neuroprotective therapies are desperately needed. The Sirtuin family of oxidized nicotinamide adenine dinucleotide (NAD ⁺)-dependent deacylases has been shown to govern several processes within the central nervous system as well as to possess neuroprotective properties in a variety of pathological conditions such as Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease, among others. Recently, Sirt1 in particular has been identified as a mediator of cerebral ischemia, with potential as a possible therapeutic target. To gather studies relevant to this topic, we used PubMed and previous reviews to locate, select, and resynthesize the lines of evidence presented here. In this review, we will first describe some functions of Sirt1 in the brain, mainly neurodevelopment, learning and memory, and metabolic regulation. Second, we will discuss the experimental evidence that has implicated Sirt1 as a key protein in the regulation of cerebral ischemia as well as a potential target for the induction of ischemic tolerance.

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Stroke is a main cause of mortality and morbidity worldwide. Despite the increasing development of innovative treatments for stroke, most are unsuccessful in clinical trials. In recent years, an encouraging strategy for stroke therapy has been identified in stem cells transplantation. In particular, grafting cells and their secretion products are leading with functional recovery in stroke patients by promoting the growth and function of the neurovascular unit – a communication framework between neurons, their supply microvessels along with glial cells – underlying stroke pathology and recovery. Mitochondrial dysfunction has been recently recognized as a hallmark in ischemia/reperfusion neural damage. Emerging evidence of mitochondria transfer from stem cells to ischemic-injured cells points to transfer of healthy mitochondria as a viable novel therapeutic strategy for ischemic diseases. Hence, a more in-depth understanding of the cellular and molecular mechanisms involved in mitochondrial impairment may lead to new tools for stroke treatment. In this review, we focus on the current evidence of mitochondrial dysfunction in stroke, investigating favorable approaches of healthy mitochondria transfer in ischemic neurons, and exploring the potential of mitochondria-based cellular therapy for clinical applications. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed.

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Occludin is a key structural component of the blood–brain barrier (BBB) that has recently become an important focus of research in BBB damages. Many studies have demonstrated that occludin could regulate the integrity and permeability of the BBB. The function of BBB depends on the level of occludin protein expression in brain endothelial cells. Moreover, occludin may serve as a potential biomarker for hemorrhage transformation after acute ischemic stroke. In this review, we summarize the role of occludin in BBB integrity and the regulatory mechanisms of occludin in the permeability of BBB after ischemic stroke. Multiple factors have been found to regulate occludin protein functions in maintaining BBB permeability, such as Matrix metalloproteinas-mediated cleavage, phosphorylation, ubiquitination, and related inflammatory factors. In addition, various signaling pathways participate in regulating the occludin expression, including nuclear factor-kappa B, mitogen-activated protein kinase, protein kinase c, RhoK, and ERK1/2. Emerging therapeutic interventions for ischemic stroke targeting occludin are described, including normobaric hyperoxia, Chinese medicine, chemical drugs, genes, steroid hormones, small molecular peptides, and other therapies. Since occludin has been shown to play a critical role in regulating BBB integrity, further preclinical studies will help evaluate and validate occludin as a viable therapeutic target for ischemic stroke.

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Maintenance of adequate tissue perfusion through a dense network of cerebral microvessels is critical for the perseveration of normal brain function. Regulation of the cerebral blood flow has to ensure adequate delivery of nutrients and oxygen with moment-to-moment adjustments to avoid both hypo- and hyper-perfusion of the brain tissue. Even mild impairments of cerebral blood flow regulation can have significant implications on brain function. Evidence suggests that chronic stress and depression elicits multifaceted functional impairments to the cerebral microcirculation, which plays a critical role in brain health and the pathogenesis of stress-related cognitive impairment and cerebrovascular events. Identifying the functional and structural changes to the brain that are induced by stress is crucial for achieving a realistic understanding of how related illnesses, which are highly disabling and with a large economic cost, can be managed or reversed. This overview discusses the stress-induced alterations in neurovascular coupling with specific attention to cerebrovascular regulation (endothelial dependent and independent vasomotor function, microvessel density). The pathophysiological consequences of cerebral microvascular dysfunction with stress and depression are explored.

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Traumatic brain injury (TBI) is a worldwide medical problem, and currently, there are few therapeutic interventions that can protect the brain and improve functional outcomes in patients. Over the last several decades, experimental studies have investigated the pathophysiology of TBI and tested various pharmacological treatment interventions targeting specific mechanisms of secondary damage. Although many preclinical treatment studies have been encouraging, there remains a lack of successful translation to the clinic and no therapeutic treatments have shown benefit in phase 3 multicenter trials. Therapeutic hypothermia and targeted temperature management protocols over the last several decades have demonstrated successful reduction of secondary injury mechanisms and, in some selective cases, improved outcomes in specific TBI patient populations. However, the benefits of therapeutic hypothermia have not been demonstrated in multicenter randomized trials to significantly improve neurological outcomes. Although the exact reasons underlying the inability to translate therapeutic hypothermia into a larger clinical population are unknown, this failure may reflect the suboptimal use of this potentially powerful therapeutic in potentially treatable severe trauma patients. It is known that multiple factors including patient recruitment, clinical treatment variables, and cooling methodologies are all important in yielding beneficial effects. High-quality multicenter randomized controlled trials that incorporate these factors are required to maximize the benefits of this experimental therapy. This article therefore summarizes several factors that are important in enhancing the beneficial effects of therapeutic hypothermia in TBI. The current failures of hypothermic TBI clinical trials in terms of clinical protocol design, patient section, and other considerations are discussed and future directions are emphasized.

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While several large pivotal clinical trials recently revealed a substantial benefit of endovascular thrombectomy for acute ischemic stroke (AIS) caused by large-vessel occlusion, many patients still experience mediocre prognosis. Enlargement of the ischemic core, failed revascularization, incomplete reperfusion, distal embolization, and secondary reperfusion injury substantially impact the salvaging of brain tissue and the functional outcomes of AIS. Here, we propose novel concept of “Multiphase Adjuvant Neuroprotection” as a new paradigm that may help guide our search for adjunctive treatments to be used together with thrombectomy. The premise of multiphase adjuvant neuroprotection is based on the diverse and potentially nonoverlapping pathophysiologic mechanisms that are triggered before, during, and after thrombectomy therapies. Before thrombectomy, strategies should focus on preventing the growth of the ischemic core; during thrombectomy, improving recanalization while reducing distal embolization and maximizing reperfusion are of significant importance; after reperfusion, strategies should focus on seeking targets to reduce secondary reperfusion injury. The concept of multiphase adjuvant neuroprotection, wherein different strategies are employed throughout the various phases of clinical care, might provide a paradigm to minimize the final infarct size and improve functional outcome in AIS patients treated with thrombectomy. With the success of thrombectomy in selected AIS patients, there is now an opportunity to revisit stroke neuroprotection. Notably, if the underlying mechanisms of these neuroprotective strategies are identified, their role in the distinct phases will provide further avenues to improve patient outcomes of AIS.

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Sulforaphane (SFN) is a phytochemical found in cruciferous vegetables. It has been shown to have many protective effects against many diseases, including multiple types of cancer. SFN is a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response element (ARE) genetic pathway. Upregulation of Nrf2-ARE increases the availability of multiple antioxidants. A substantial amount of preclinical research regarding the ability of SFN to protect the nervous system from many diseases and toxins has been done, but only a few small human trials have been completed. Preclinical data suggest that SFN protects the nervous system through multiple mechanisms and may help reduce the risk of many diseases and reduce the burden of symptoms in existing conditions. This review focuses on the literature regarding the protective effects of SFN on the nervous system. A discussion of neuroprotective mechanisms is followed by a discussion of the protective effects elicited by SFN administration in a multitude of neurological diseases and toxin exposures. SFN is a promising neuroprotective phytochemical which needs further human trials to evaluate its efficacy in preventing and decreasing the burden of many neurological diseases.

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Acute brain injuries, including ischemic and hemorrhagic stroke, as well as traumatic brain injury (TBI), are major worldwide health concerns with very limited options for effective diagnosis and treatment. Stroke and TBI pose an increased risk for the development of chronic neurodegenerative diseases, notably chronic traumatic encephalopathy, Alzheimer's disease, and Parkinson's disease. The existence of premorbid neurodegenerative diseases can exacerbate the severity and prognosis of acute brain injuries. Apoptosis involving caspase-3 is one of the most common mechanisms involved in the etiopathology of both acute and chronic neurological and neurodegenerative diseases, suggesting a relationship between these disorders. Over the past two decades, several clinical biomarkers of apoptosis have been identified in cerebrospinal fluid and peripheral blood following ischemic stroke, intracerebral and subarachnoid hemorrhage, and TBI. These biomarkers include selected caspases, notably caspase-3 and its specific cleavage products such as caspase-cleaved cytokeratin-18, caspase-cleaved tau, and a caspase-specific 120 kDa αII-spectrin breakdown product. The levels of these biomarkers might be a valuable tool for the identification of pathological pathways such as apoptosis and inflammation involved in injury progression, assessment of injury severity, and prediction of clinical outcomes. This review focuses on clinical studies involving biomarkers of caspase-3-mediated pathways, following stroke and TBI. The review further examines their prospective diagnostic utility, as well as clinical utility for improved personalized treatment of stroke and TBI patients and the development of prophylactic treatment chronic neurodegenerative disease.

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The cessation (ischemia) and restoration (reperfusion) of cerebral blood flow after cardiac arrest (CA) induce inflammatory processes that can result in additional brain injury. Therapeutic hypothermia (TH) has been proven as a brain protective strategy after CA. In this article, the underlying pathophysiology of ischemia-reperfusion brain injury with emphasis on the role of inflammatory mechanisms is reviewed. Potential targets for immunomodulatory treatments and relevant effects of TH are also discussed. Further studies are needed to delineate the complex pathophysiology and interactions among different components of immune response after CA and identify appropriate targets for clinical investigations.

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There are currently no adequate treatments for white-matter injury, which often follows central nervous system maladies and their accompanying neurodegenerative processes. Indeed, the white matter is compromised by the deterioration of the blood–brain barrier and the demyelination of neuronal axons. Key repairs to the white matter are mediated by oligodendrocyte lineage cells after damaging events. Oligodendrocytes are supported by other cells in the neurovascular unit and these cells collaborate in processes such as angiogenesis, neurogenesis, and oligodendrogenesis. Understanding the various interactions between these cells and oligodendrocytes will be imperative for developing reparative therapies for impaired white matter. This minireview will discuss how oligodendrocytes and oligodendrocyte lineage cells mend damage to the white matter and restore brain function ensuing neural injury.

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Tissue plasminogen activator (tPA) thrombolysis continues to be the gold standard therapy for ischemic stroke. Due to the time-limited treatment window, within 4.5 h of stroke onset, and a variety of potentially deadly complications related to delayed administration, particularly hemorrhagic transformation (HT), clinical use of tPA is limited. Combination therapies with other interventions, drug or nondrug, have been hypothesized as a logical approach to enhancing tPA effectiveness. Here, we discuss various potential pharmacological and nondrug treatments to minimize adverse effects, primarily HT, associated with delayed tPA administration. Pharmacological interventions include many that support the integrity of the blood–brain barrier (i.e., atorvastatin, batimastat, candesartan, cilostazol, fasudil, and minocycline), promote vascularization and preserve cerebrovasculature (i.e., coumarin derivative IMM-H004 and granulocyte-colony stimulating factor), employing other mechanisms of action (i.e., oxygen transporters and ascorbic acid). Nondrug treatments are comprised of stem cell transplantation and gas therapies with multi-faceted approaches. Combination therapy with tPA and the aforementioned treatments demonstrated promise for mitigating the adverse complications associated with delayed tPA treatment and rescuing stroke-induced behavioral deficits. Therefore, the conjunctive therapy method is a novel therapeutic approach that can attempt to minimize the limitations of tPA treatment and possibly increase the therapeutic window for ischemic stroke treatment.

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Stroke is a major cause of neurological disability and death in industrialized nations. Therapeutic hypothermia has been shown to protect the brain from ischemia, stroke, and other acute neurological insults at the laboratory level. It has been shown to improve neurological outcome in certain clinical settings including anoxic brain injury due to cardiac arrest and hypoxic-ischemic neonatal encephalopathy. Hypothermia seems to affect multiple aspects of brain physiology and it is likely that multiple mechanisms underlie its protective effect. Understanding the events that occur in the ischemic brain during hypothermia might help lead to an understanding of how to protect the brain against acute injuries.

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Aneurysmal subarachnoid hemorrhage (SAH) typically carries a poor prognosis. Growing evidence indicates that overabundant production of nitric oxide (NO) may be responsible for a large part of the secondary injury that follows SAH. Although SAH modulates the activity of all three isoforms of nitric oxide synthase (NOS), the inducible isoform, NOS-2, accounts for a majority of NO-mediated secondary injuries after SAH. Here, we review the indispensable physiological roles of NO that must be preserved, even while attempting to downmodulate the pathophysiologic effects of NO that are induced by SAH. We examine the effects of SAH on the function of the various NOS isoforms, with a particular focus on the pathological effects of NOS-2 and on the mechanisms responsible for its transcriptional upregulation. Finally, we review interventions to block NOS-2 upregulation or to counteract its effects, with an emphasis on the potential therapeutic strategies to improve outcomes in patients afflicted with SAH. There is still much to be learned regarding the apparently maladaptive response of NOS-2 and its harmful product NO in SAH. However, the available evidence points to crucial effects that, on balance, are adverse, making the NOS-2/NO/peroxynitrite axis an attractive therapeutic target in SAH.

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In this paper, our review series on cerebrovascular disease anatomy, physiology, and pathology ends with a thorough discussion of the most significant cerebrovascular pathology: stroke. This discussion proceeds through two layers of organization. First, stroke is divided up into its main etiologic categories (ischemic stroke/transient ischemic attack, hemorrhagic stroke, and ischemic to hemorrhagic transformation). Then, the epidemiological, pathophysiological, clinical, and therapeutic (employed currently as well as emerging) aspects of each etiology are explored; emphasis is placed upon the therapeutic aspects. Finally, once we have covered all aspects of each etiologic category, we end our review with a defense of the thesis that there is much hope for the future of stroke treatment to be derived from familiarity with the literature on emerging therapies.

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Ischemic stroke is a leading cause of death and disability. Fear of intracranial hemorrhage (ICH) has been the primary reason for withholding tissue plasminogen activator (tPA) and thrombectomy, the only two widely accepted treatments for ischemic stroke. Thrombolysis treatment is only allowed in a very narrow time window (within 4.5–6 h). However, so far, other than the time window guideline, there is no reliable indicator available in the clinic to predict ICH before thrombolysis treatment. Recently, extensive research efforts have been devoted to the development of reliable indicators to predict ICH and safely guide the thrombolysis treatment. Accumulating evidence suggests that ischemic brain regions with a compromised blood–brain barrier (BBB) before tPA treatment develop ICH at the later time during thrombolytic reperfusion. Assessing BBB damage before thrombolysis could potentially help predict the risk of ICH after thrombolysis. This article reviews the literature reports on BBB damage biomarkers that have been developed in recent years, including biochemical markers such as BBB structural proteins, circulating brain microvascular endothelial cells, plasma albumin, and brain parenchyma proteins, as well as image markers such as magnetic resonance imaging assessment for BBB damage.

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Stroke is an important cause of morbidity and mortality worldwide. Development of novel neuroprotectants is of paramount importance. This review seeks to summarize the recent evidence for the role of the endocannabinoid signaling system in stroke pathophysiology, as well as the evidence from preclinical studies regarding the efficacy of cannabinoids as neuroprotective therapies in the treatment of stroke. Recent evidence from rodent models implicating cannabinoid 1 receptor (CB1R), cannabinoid 2 receptor (CB2R), and CB1R and CB2R co-antagonism as neuroprotective strategies in stroke are reviewed. Rodent evidence for the therapeutic role of the endocannabinoid system in treating poststroke depression is reviewed. Finally, evidence for the role of cannabidiol, a publicly available cannabinoid that does not bind directly to known endocannabinoid receptors, as a stroke neuroprotectant is also reviewed. The review closes with a consideration of the role of human cannabinoid abuse in stroke and considers future directions for research on endocannabinoid-based stroke therapeutics.

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Vinpocetine (VPN) is a synthetic ethyl-ester derivative of the alkaloid apovincamine from Vinca minor leaves. VPN is a selective inhibitor of phosphodiesterase type 1 (PDE1) that has potential neurological effects through inhibition of voltage-gated sodium channel and reduction of neuronal calcium influx. VPN has noteworthy antioxidant, anti-inflammatory, and anti-apoptotic effects with inhibitory effect on glial and astrocyte cells during and following ischemic stroke (IS). VPN is effective as adjuvant therapy in the management of epilepsy; it reduces seizure frequency by 50% in a dose of 2 mg/kg/day. VPN improves psychomotor performances through modulation of brain monoamine pathway mainly on dopamine and serotonin, which play an integral role in attenuation of depressive symptoms. VPN recover cognitive functions and spatial memory through inhibition of hippocampal and cortical PDE1 with augmentation of cyclic adenosin monophosphate and cyclic guanosin monophosphate ratio, enhancement of cholinergic neurotransmission, and inhibition of neuronal inflammatory mediators. Therefore, VPN is an effective agent in the management of IS and plays an integral role in the prevention and attenuation of poststroke epilepsy, depression, and cognitive deficit through direct cAMP/cGMP-dependent pathway or indirectly through anti-inflammatory and antioxidant effects.

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In this paper, which is the first in a three-part series that reviews cerebrovascular anatomy, pathogenesis, and stroke, we lay the anatomical foundation for the rest of the series. Beginning with its origin in the branches of the aorta, we start by describing the arterial system. This system is partitioned into two major divisions (anterior and posterior circulations) that differ significantly in features and pathogenic potential. The systems, and the major branches that comprise them, are described. Description of the arterial system proceeds to the point of the fulfillment of its function. This function, the exchange of gases and nutrients with the cerebral parenchyma, is the subject of a subsequent section on the microcirculation and blood–brain barrier. Finally, the cerebral venous system, which is composed of cerebral veins and dural venous sinuses, is described. Thus, an anatomical context is supplied for the discussion of cerebrovascular disease pathogenesis provided by our second paper.

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The advent of mechanical thrombectomy and increasing alteplase use have transformed the care of patients with acute ischemic stroke. Patients with major arterial occlusions with poor outcomes now have a chance of returning to independent living in more than half of the cases. However, many patients with these severe strokes suffer major disability despite these therapies. The search is ongoing for agents that can be combined with thrombectomy to achieve better recovery through halting infarct growth and mitigating injury after ischemic stroke. Several studies in animals and humans have demonstrated that therapeutic hypothermia (TH) offers potential to interrupt the ischemic cascade, reduce infarct volume, and improve functional independence. We performed a literature search to look up recent advances in the use of TH surrounding the science, efficacy, and feasibility of inducing TH in modern stroke treatments. While protocols remain controversial, there is a real opportunity to combine TH with the existing therapies to improve outcome in adults with acute ischemic stroke.

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