Current Drug Targets - Volume 18, Issue 12, 2017

Background: Germinal matrix hemorrhage is a leading cause of mortality and morbidity from prematurity. This brain region is vulnerable to bleeding and re-bleeding within the first 72 hours of preterm life. Cerebroventricular expansion of blood products contributes to the mechanisms of brain injury. Consequences include lifelong hydrocephalus, cerebral palsy, and intellectual disability. Unfortunately little is known about the therapeutic needs of this patient population. Objectives: This review discusses the mechanisms of germinal matrix hemorrhage, the animal models utilized, and the potential therapeutic targets. Conclusion: Potential therapeutic approaches identified in pre-clinical investigations include corticosteroid therapy, iron chelator administration, and transforming growth factor-β pathway modulation, which all warrant further investigation. Thus, effective preclinical modeling is essential for elucidating and evaluating novel therapeutic approaches, ahead of clinical consideration.

Hematoma expansion (HE), defined as a greater than 33% increase in intracerebral hemorrhage (ICH) volume within the first 24 hours, results in significant neurological deficits, and enhancement of ICH-induced primary and secondary brain injury. An escalation in the use of oral anticoagulants has led to a surge in the incidences of oral anticoagulation-associated ICH (OAT-ICH), which has been associated with a greater risk for HE and worse functional outcomes following ICH. The oral anticoagulants in use include vitamin K antagonists, and direct thrombin and factor Xa inhibitors. Fibrinolytic agents are also frequently administered. These all act via differing mechanisms and thus have varying degrees of impact on HE and ICH outcome. Additionally, antiplatelet medications have also been increasingly prescribed, and result in increased bleeding risks and worse outcomes after ICH. Aspirin, thienopyridines, and GPIIb/IIIa receptor blockers are some of the most common agents in use clinically, and also have different effects on ICH and hemorrhage growth, based on their mechanisms of action. Recent studies have found that reduced platelet activity may be more effective in predicting ICH risk, hemorrhage expansion, and outcomes, than antiplatelet agents, and activating platelets may thus be a novel target for ICH therapy. This review explores how dysfunctions or alterations in the coagulation and platelet cascades can lead to, and/or exacerbate, hematoma expansion following intracerebral hemorrhage, and describe the mechanisms behind these effects and the drugs that induce them. We also discuss potential future therapy aimed at increasing platelet activity after ICH.

Background: Early hematoma growth is not uncommon in patients with intracerebral hemorrhage. It is a devastating complication that independently predicts poor outcome. The early hematoma enlargement is usually defined as an absolute increase in hematoma volume of greater than 33% on repeat CT scan. To date, no ideal animal model can mimic the exact pathophysiological process of early hematoma growth. Objective: This review of early hematoma enlargement in primary intracerebral hemorrhage discusses definitions, pathophysiology, risk factors, and novel treatment options aimed at improving outcomes. Conclusion: Novel imaging predictors such as CT angiography spot sign and CT blend sign may predict early hematoma growth in patients with intracerebral hemorrhage. Monitoring and modulation of blood pressure may improve outcomes. Rapid reduction of blood pressure to <140 mm Hg may be safe in patients with intracerebral hemorrhage.

Background: Intracranial hemorrhage is characterized by the blood vessel rupture and subsequent hematoma expansion. It is the least treatable stroke subtype, resulting in higher morbidity and mortality per incidence than ischemic stroke. Recent studies have observed lower than normal levels of plasma fibrinogen in patients of intracerebral hemorrhage. Furthermore, in other cases of severe hemorrhage, plasma fibrinogen levels have been identified as an indicator of prognosis. Current clinical management of cerebral hemorrhage includes adjunctive therapies and possible surgical evacuation. However, a possible therapeutic target for intracranial hemorrhage is fibrinogen. During intracranial hemorrhage with hematoma expansion, fibrinogen levels are rapidly depleted and thus are in need of replacement. Maintaining high levels of fibrinogen can promote rapid clotting and reduction of hematoma expansion. Objectives: Within this review, we examine the role of fibrinogen in intracranial hemorrhage and evaluate the use of fibrinogen replacement therapies for maintaining normal levels of this key hemostatic protein. The pros and cons are discussed and an opinion of the most appropriate fibrinogen replacement therapy for intracranial hemorrhage is made. Conclusion: It is concluded that fibrinogen concentrate seems to be the most suitable therapy for elevating plasma fibrinogen for the treatment of intracranial hemorrhage with hematoma expansion.

Background: Cerebral hemorrhagic stroke, including intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and hemorrhagic transformation after cerebral infarction, is a major medical emergency in the neurology, neurosurgery, emergency and other clinical departments. The pathophysiological mechanisms of these cerebral hemorrhagic diseases have not been fully elucidated, and there are no effective pharmacological and molecular treatments against these diseases. Matrix metalloproteinase-9 (MMP-9), also known as collagenase B, is one of the most important members of the matrix metalloproteinases (MMPs) family. Objective: This article reviews the role of MMP-9 in the pathogenesis of diseases such as brain hemorrhage, hemorrhagic transformation after cerebral infarction, SAH, and brain injury. Results: The expression levels of MMP-9 in brain tissue increased after cerebral hemorrhage and related to the prognosis of brain hemorrhage. MMP-9 is related to post-thrombolytic hemorrhagic transformation after cerebral infarction. Inhibition of MMP-9 can reduce secondary brain injury after brain hemorrhage. MMP-9 aggravates the early brain injury and cerebral vasospasm after SAH. Conclusion: MMP-9 is involved in the pathological process of hemorrhagic stroke through a variety of mechanisms and is closely related to prognosis after cerebral hemorrhagic stroke.

Background: Hematoma expansion is a detrimental event of intracerebral hemorrhage (ICH) which results in progressive neurologic deteriorations and poor outcomes. Objective: To summariz the current understanding of the mechanisms underlying hematoma expansion and discuss the potential approaches of treatment and prevention. Results: Although the exact mechanism of hematoma expansion is unclear, accumulating evidences suggest that multiple clinical markers such as coagulation/hemostasis dysfunction, higher blood pressure and BRAIN scores, higher serum glucose and/or glycosylated hemoglobin A1c, serum creatinine, Factor XIII and international normalized ratio (INR), lower serum cholesterol or LDL cholesterol, and fibrinogen, may be correlated with incidents of hematoma expansion. Furthermore, activation of several molecular pathways (i.e. plasma kallikrein, von Willebrand factor, N-methyl-Daspartate and its receptor, cytokines/ adipokines, cellular fibronectin and apolipoprotein E2 allele) may lead to hematoma expansion. Conclusion: Prospective study for hematoma expansion How to predict the patients Who are at highest risk of hematoma expansion is more challengeable than restricting hematoma expansion itself following acute ICH. Seeking and detecting risk markers in plasma that can be intervened appropriately is meaningful for patients with potential hematoma expansion, which may contribute to improve clinical outcomes in patients suffering from ICH.

Background: Intracerebral hemorrhage (ICH), a subtype of stroke, brings high morbidity and mortality to human beings. Multiple studies indicated that neuroinflammation, excitotoxicity, oxidative stress, cytotoxicity resulted from the degradation products of blood clot play vital roles in ICH-induced secondary brain injury, which contributes to deterioration of neurological outcome. Prostaglandin E2 (PGE2), a type of prostanoids commonly up-regulated in these progresses, is proved to modulate numerous cellular and molecular processes by activating EP2 receptor after ICH. Objective: This review aim to discuss the PGE2 biosynthesis, downstream signaling pathway of EP2 receptor and the roles of EP2 receptor in ICH-induced brain damage, targeting to provide a potential effective therapeutic strategy. Methods: A large number of literatures on EP2 receptors and intracerebral hemorrhage were searched in PubMed, Medline, and Ebase. Results: Previous studies showed that EP2 receptor mediated double effects in ICH via activation of different signaling pathway. EP2 receptor could induce neuroprotection, spatial learning, and neuroplasticity via cAMP-PKA signaling pathway, while strengthen inflammation mainly through the cAMP-Epac pathway. In addition, the concentration level of cAMP might be the key factor that decides which downstream signaling pathway would be activated. Conclusion: In different phase of cerebral hemorrhage, EP2 receptor plays diverse effects in brain damage through different downstream signaling pathways.

Background: Among the central nervous system (CNS) disorders, diseases like ischemic and hemorrhagic stroke which are important health care problems as well as leading causes for emergency admissions, primarily affect neurovascular structure. Despite their high rate of mortality and morbidity, very few efficient treatment targets have been established until now. Objective: Blood-brain barrier (BBB) is the mostly effected structure in stroke as detected in both clinical studies and experimental settings. BBB is composed of endothelia, astrocyte end-foot, pericytes and basal lamina. Neurovascular unit, pericytes and BBB forming endothelia play significant pathophysiological roles in both ischemic and hemorrhagic stroke. Discussion: In this mini-review, the role of microcirculation and cells of blood-brain barrier in stroke pathophysiology will be discussed with a special emphasis based on pericytes. Pericytes are especially important for providing adequate microcirculatory supply according to needs of neuronal tissue and form one of the functionally important part of BBB and take role in neurovascular coupling. Understanding the role and disease producing mechanisms of neurovascular unit elements in different neurological conditions will provide novel targets for future treatments.

Objective: This review article focuses on the neuroprotective effect of drug-induced hypothermia in cerebrovascular diseases and discusses its related side effects. Method: A systematic literature search was performed using Pubmed and Embase electronic databases for a retrospective analysis. Results: Experimental studies have shown that drug-induced hypothermia alleviates brain damage and plays a neuroprotective role, thereby reducing mortality and ameliorating neurological deficits. Therefore, drug-induced hypothermia has an important research value and is worth further consideration in the clinical setting. However, drug-induced hypothermia is also associated with side effects, such as ventricular tachycardia, ventricular fibrillation, suppressed immune function, infection, electrolyte imbalance, glucose metabolism disorders, and skeletal muscle tremor. Existing drugs with cooling effects belong to the following categories: (1) dopamine receptor agonists; (2) cannabis; (3) opioid receptors; (4) vanilloid receptors; (5) vasopressins (potent neurotensin receptor agonists); (6) thyroid drugs; (7) adenosine drugs; and (8) purine drugs.

Objective: Intraventricular hemorrhage (IVH) is deemed to result in poor outcomes in patients with aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to explore the efficacy and safety of intraventricular injections of recombinant tissue plasminogen activator (rt-PA). Methods: We searched MEDLINE, EMBASE, and Cochrane Library from January 1980 to March 2015 for studies in English. The primary outcome was good functional improvement. The secondary outcomes were angiographic vasospasm, acute obstructive hydrocephalus, hemorrhage rate, and mortality. Results: Three observational studies and 3 randomized controlled trials (RCTs) with 217 patients were included in the present study. There is a significant difference in angiographic vasospasm (RR 0.58, 95% CI 0.16 to 0.85, P = 0.01). In the subgroup analysis, angiographic vasospasm (RR 0.37, 95% CI 0.38 to 0.88, P = 0.02) and acute obstructive hydrocephalus (RR 0.48, 95% CI 0.27 to 0.84, P = 0.01) showed significant differences in the observational studies. High dosage of rt-PA showed a significant difference in angiographic vasospasm (RR 0.60, 95% CI 0.38 to 0.97, P = 0.04). Sensitivity analysis showed that no significant differences were observed in all the outcomes after the Ramakrishna 2010 trial was excluded. Conclusion: Intraventricular rt-PA has no significant efficacy on the long-term functional recovery after aneurysmal SAH with IVH. However, high dosage of rt-PA might reduce the incidence of angiographic vasospasm. A feasible, large-scale, multi-center, placebo RCT is needed to confirm the present findings.

Introduction: Animal data suggest an association between neuroinflammation and secondary brain injury including axonal injury after aneurysmal subarachnoid hemorrhage (aSAH). We sought to study the association between brain extracellular interleukin (IL)-6 and TAU-protein levels as a surrogate marker for neuroinflammation and axonal injury in patients with poor grade aSAH. Methods: Prospectively collected data from 26 consecutive poor-grade aSAH patients with multimodal neuromonitoring including cerebral microdialysis (CMD) were retrospectively analyzed. IL-6 and TAU-protein levels were analyzed using ELISA from a single CMD-sample every 24 hours and correlated with brain metabolic and hemodynamic parameters. Patients were dichotomized to highgrade (N=10) or low-grade (N=16) neuroinflammation according to their median CMD-IL-6 levels. Data were analyzed using generalized estimating equations to account for multiple within-subject measurements. Results: Perilesional probe location (P=0.02) and aSAH related intracerebral hemorrhage (aICH) volume (P=0.003) at admission were associated with high-grade neuroinflammation. Brain extracellular TAU-protein levels (P=0.001), metabolic distress and delayed cerebral infarction (DCI; P=0.001) were linked to high-grade neuroinflammation. Relative or absolute phosphor-TAU levels were not correlated with CMD-IL-6 levels. High-grade neuroinflammation was a predictor for worse outcome three months after ictus, independently from probe location, initial Hunt grade and age (P=0.01). Conclusion: Neuroinflammation after aSAH is associated with intraparenchymal bleeding, deranged cerebral metabolism and TAU-protein release. The impact of potential anti-inflammatory treatment strategies on secondary brain injury after aSAH has to be investigated in future studies.

Background: Nosocomial infections are common in patients with spontaneous subarachnoid hemorrhage (SAH). The aim of this retrospective cohort study was to determine the incidence of infections during SAH and to evaluate the course of inflammation parameters and its implications for long term outcome. Objective: Ninety-nine consecutive coiled SAH patients were included. Laboratory and clinical parameters as well as culture positive infections were followed over the disease course. Long-term outcome was assessed at 6-month by the Glasgow Outcome score (GOS) and dichotomized in favorable (GOS>3) and unfavorable outcome (GOS≤3). Results: The most frequent infections were pulmonary (30.3%) urinary tract (25.3%), blood stream infections (20.2%) and ventriculitis (5.1%). The incidence of infections did not significantly differ between outcome groups. In contrast, patients with unfavorable outcome had a higher incidence of sepsis (46.7% versus 24.6%). C-reactive protein (CRP) and leukocytes were significantly higher in patients with unfavorable outcome. A CRP increase of 6 mg/dl or more in the first 3 days after SAH was independently associated with unfavorable outcome (OR 7.19 CI 1.7-30.52; p=0.008). Patients with an early CRP increase were more frequently treated with antimicrobial therapy in the first 3 days after admission which led to a significantly lower incidence of culture positive infections in the later course. Conclusion: A sharp CRP-increase in the acute phase of SAH could potentially aid the intensivist in the early identification of patients at high risk for neurological morbidity. Early antimicrobial treatment reduces the rate of patients showing culture positive infections in the course of the disease.

Background: Subarachnoid hemorrhage (SAH) following rupture of an intracranial is associated with high mortality and morbidity. The late deterioration of the patient's neurological status or late cognitive dysfunctions even after secure clipping or decent endovascular treatment which is defined as delayed ischemic neurological deficits recently has been attributed to vasospasm. Due to the failure of specific anti-vasospastic agents in clinical trials researchers focused to explore new pathological mechanisms to be responsible for the delayed deterioration of the patients suffering from SAH. Early brain injury (EBI), as a new term in the SAH research area has been the focus of scientist for the past couple of years. Objective: The goal of this study is to review the common mechanisms of early brain injury and vasospasm. Results: The acute events following SAH, such as increased intracranial pressure and decreased cerebral blood flow, causing global cerebral ischemia initiate a cascade of pathological changes including inflammation, lipid peroxidation, cell death and blood brain barrier disruption. Conclusion: The more insight we gain into the EBI we realize that there are a bunch of common mechanisms between EBI and vasospasm. In the SAH management, a therapy targeting these early injuries may also reduce the later developing pathological neurological complications.

Background: Fever is common in neurocritical care patients and is associated with poor outcome. Targeted temperature management (TTM), i.e. therapeutic hypothermia or controlled normothermia, after acute brain injury has been studied as a neuroprotectant for several decades. In contrast to pharmacological agents with specific targets TTM affects multiple pathophysiological mechanisms and is primarily thought to attenuate secondary brain injury. Most promising results have been obtained from experimental studies on cerebral ischemia or traumatic brain injury showing beneficial effects of hypothermia on structural and functional outcome. Objective: The aim of this systematic review of the literature is to provide an overview on preclinical and clinical data on the use of TTM for intracerebral hemorrhage (ICH). The impact of TTM on structural changes and functional outcome after induced and spontaneous ICH will be summarized. Results and Discussion: A positive influence of hypothermia has been observed in animal models of spontaneous ICH improving, among others, perihematomal edema, blood-brain barrier integrity, inflammation and thrombin-induced injury. However, results regarding functional outcome are conflicting. Little data is available on the effect of TTM after spontaneous ICH in humans. Single-center observational studies have shown reduced perihematomal edema under mild hypothermia and an association with favorable outcome. However, these beneficial effects on mortality and functional outcome have not been confirmed in randomized studies so far. Thus, results from ongoing, prospective randomized-controlled trials are highly anticipated.

Background: Hemorrhagic transformation (HT) is a common and natural complication after acute ischemic stroke. The only FDA-approved treatment so far for acute ischemic stroke is rapid reperfusion with recombinant tissue plasminogen activator (rtPA). Although it has been shown to exaggerate the risk and severity of HT and to be associated with increased morbidity and mortality. Objective: The aim of this review is to discuss the multifactorial pathophysiology of hemorrhagic transformation, promising interventional targets, and pharmacological treatment options. Results and Conclusion: Understanding HT is essential to restore cerebral blood flow to ischemic brain by reperfusion therapy without causing this complication and additional brain injury. Therefore methods for the prevention and treatment of HT are needed. Although experimental studies showed promising results, clinical translation remains unsatisfactory to date.

Background: Ca2 influx plays an essential role in the physiological and pathophysiologic processes of several nervous system diseases. The transient receptor-potential channels (TRPCs) form a family of voltage –sensitive calcium ion channels. Objective: In this review, we will discuss the importance of transient receptor potential canonical (TRPC) channels, which is a crucial family of calcium channels. This article reviews the role of TRPC channels in the pathogenesis of diseases such as brain hemorrhage, hemorrhagic transformation after cerebral infarction, subarachnoid hemorrhage, and brain injury. Results: TRPC has especially high expression in the central nervous system (CNS), and was involved in several physiological functions. The TRPC family is associated with cerebral vasospasm after subarachnoid hemorrhage, neuronal damage after intracerebral hemorrhage, NMDA cytotoxicity in cerebral ischemia, nervous system tumors, neurodegenerative diseases, neural addiction and other diseases. Conclusion: The TRPC family has rich functionality and is widely distributed, with different functions in various nervous system diseases.