Current Pharmaceutical Design - Volume 23, Issue 15, 2017

Background: Besides the well-documented biochemical and electrophysiological effects, the mechanical stimuli also have prominent roles in the initiation and development of brain diseases but yet have been underestimated. To explore the role of mechanical stimuli and the followed mechanical-biochemical effects in the brain diseases. Method: In this review, we discussed the initiation and effect of mechanical stimuli and the surrounding topography in brain diseases, especially for the intracerebral hemorrhage (ICH), Alzheimer’s disease (AD), diffuse axonal injury (DAI) and primary brain tumors. The induced cascades of biological pathways by mechanical stimuli prior to and during the brain diseases were summarized. Strategies aiming to reduce the mechanical stimuli related damages or poor outcomes were also discussed, despite some could only prevent rather than cure. Literatures have indicated mechanical stimuli were the connection between the exogenous mechanotransduction and the inherent biochemical cascades. Therefore, we also reviewed in vitro models in the literatures that simulated the diverse range of mechanical stimuli, which connected the neural network with the tissue engineering, biomaterials and potential therapeutic strategies together. Results: At the microscopic and macroscopic levels, the hydrostatic pressure, tensile/compressive force, shear force, and even the roughness of topography from the physical surrounding exert the influence on the neural network not only by themselves but also through the interaction with other factors, e.g. biochemical or electrophysiological effects. Conclusion: In the clinical management, taking the undervalued mechanical stimuli and the followed mechanical- biochemical effects into consideration are important and inevitable in preventing and treating brain diseases.

Background: Intracerebral hemorrhage is one of the most common injuries in vehicle accidents. The aim of this paper is to survey the injury mechanism of intracerebral hemorrhage in vehicle accidents, including contusion, subarachnoid hemorrhage (SAH), subdural hematoma (SDH) and diffuse axonal injury (DAI). Methods: A condensed overview is given based on the published studies in biomechanical studies on intracerebral hemorrhage. Animal tests, cadaver tests, accident investigations and numerical simulation are the main method used for the mechanism studies. Results: Angular velocity and acceleration can be used to predict these injuries and they are the main causation of DAI. Intracranial pressure is the main causation of coup/contrecoup contusion. Shear stress and strain contribute to the rupture of bridging veins that result in SDH, SAH. Conclusion: Injury mechanism of intracerebral hemorrhage in vehicle accidents is complicated that with multiple causations. In-depth works need to be carried out in mechanism studies especially for child head injuries.

Background: Spontaneous non-traumatic intracerebral hemorrhage (ICH) has a worse prognosis than ischemic stroke. The purpose of this review was to update the reader on epidemiology, prognosis and secondary prevention strategies of ICH. Methods: We performed a selected review from the literature including recent original articles and meta-analyses. Results: ICH has an overall incidence of 24.6 per 100.000 patient years, which is considerably higher in Asian populations. Despite some progress in acute interventions and a great increase in clinical studies over the last decade, mortality of ICH remains high. In addition, survivors remain at increased risk of recurrent hemorrhagic as well as ischemic stroke. Conclusion: Knowledge on risk factors and prevention strategies can greatly decrease the incidence of ICH and improve prognosis of ICH survivors.

Background: Intracerebral hemorrhage (ICH) is a common type of stroke associated with high mortality and morbidity. Recent randomized controlled trials could not prove that the current strategies are effective at improving the final outcome of the ICH patients. Methods: Here we want to explore potential intervention targets for ICH based on the framework of the vascular neural network (VNN). In this review, a brief history of the evolution of stroke pathophysiology from humoral theory to VNN is discussed. Results: As current literature on pathophysiology of ICH is mainly focused on neuroprotection, here we want to evolve the central paradigm towards VNN. We stress mechanisms of vascular disruption and impaired blood flow harmony, which are clinically relevant but have received less attention in basic research. Conclusion: We propose that VNN could be a robust and practical paradigm in both ICH basic research and clinical practice.

Background: Spontaneous intracerebral hemorrhage (ICH) is the poorest prognosis of all stroke subtypes with a high mortality and morbidity. Although considerable progress has been made, no intervention is currently available to alter the outcome of patients with ICH, suggesting a new concept directing ICH study is urgently needed. Methods: Most ICH occurs in the deep area of the brain, the basal ganglion, whose blood supply is mainly from lenticulostriate arteries (LSAs). Thus, we focus on ICH occurring in this deep brain area. We summarize the structural and functional features of LSAs and the deep brain, and their interactions, which is essential for the pathogenesis, pathophysiology and management of ICH. Results: Here, we review the microanatomy, histological characters, hemodynamics and hypertensive pathology of LSAs. Especially, we look into the interactions between LSAs and their surrounding nerve tissues. The unique microanatomic, histological and hemodynamic features of LSAs underpin its high risk of rupture. The interactions between LSAs and the deep brain determine the pathophysiological process of ICH. Conclusion: LSAs and the circumferential deep brain are an interactive and mutually affected entity. We propose a new concept called lenticulostriate-artery neural complex (LNC) to integrate the structural, functional and pathological characteristics of this area, which would be a pragmatic paradigm in directing the future basic and clinical studies on ICH.

Background: Intracerebral hemorrhage (ICH) is one of the most common forms of cerebral hemorrhage, the morbidity and death of ICH is high worldwide. ICH can be spontaneous or caused by hypertension, coagulopathy, angiopathy, head trauma, bleeding disorders, tumors, or drug usage. ICH is the most serious and least treatable form of hemorrhagic stroke, with rapidly increasing hematoma size and often resulting in significant brain injury and long term neurological deficits. Surgical hematoma evacuation remains controversial. The currently therapy is mainly supportive with limited benefit. New therapeutic approaches are desperately needed. Methods: In this review, we provide an overview of the published literature concerning the pathophysiology leading to the ongoing neurologic damage, Emerging information of the physio-pathologic mechanisms of injury that occur after ICH is available from current animal models. Ideal therapeutic strategies should target on the pathophysiology of ICH. This review summarizes the recent advances in developing pharmaceutical agents in terms of therapeutic targets and effects in pre-clinical and clinical studies. Results: Recent animal and clinical studies have provided important information about the parallel and sequential deleterious mechanisms underlying ICH-induced brain injury and pharmacological agents targeting on these mechanisms. Neuroscientists have paid more attention to novel drug development that target on antioxidants, antiinflammatory, and anti-apoptosis for neuroprotection after ICH. Conclusion: Although ICH remains without an approved treatment proven to decrease morbidity and mortality, notable advances in the understanding of ICH pathophysiology and new drug development have been made in the last decade.

Background: Injury to cells adjacent to an intracerebral hemorrhage (ICH) is likely mediated at least in part by toxins released from the hematoma that initiate complex and interacting injury cascades. Pharmacotherapies targeting a single toxin or pathway, even if consistently effective in controlled experimental models, have a high likelihood of failure in a variable clinical setting. Nuclear factor erythroid-2 related factor 2 (Nrf2) regulates the expression of heme oxygenase-1 (HO-1) and multiple other proteins with antioxidant and antiinflammatory effects, and may be a target of interest after ICH. Methods: Studies that tested the effect of HO and Nrf2 in models relevant to ICH are summarized, with an effort to reconcile conflicting data by consideration of methodological limitations. Results: In vitro studies demonstrated that Nrf2 activators rapidly increased HO-1 expression in astrocytes, and reduced their vulnerability to hemoglobin or hemin. Modulating HO-1 expression via genetic approaches yielded similar results. Systemic treatment with small molecule Nrf2 activators increased HO-1 expression in perivascular cells, particularly astrocytes. When tested in mouse or rat ICH models, Nrf2 activators were consistently protective, improving barrier function and attenuating edema, inflammation, neuronal loss and neurological deficits. These effects were mimicked by selective astrocyte HO-1 overexpression in transgenic mice. Conclusion: Systemic treatment with Nrf2 activators after ICH is protective in rodents. Two compounds, dimethyl fumarate and hemin, are currently approved for treatment of multiple sclerosis and acute porphyria, respectively, and have acceptable safety profiles over years of clinical use. Further development of these drugs as ICH therapeutics seems warranted.

Background: Intracerebral hemorrhage (ICH) is the most lethal subtype of stroke, a leading cause of death and disability in developed countries. Therapeutic options are notably limited. There is no specific pharmacological treatment, and early surgery has few indications that represent only a small clinically relevant survival advantage. It is therefore mandatory to investigate repairing processes after ICH in order to develop related therapeutic strategies. Methods: The goal of this review is to discuss the current status of knowledge about the potential therapeutic role of endothelial progenitor cells (EPCs) in ICH, as well as the possible molecular mechanisms and future perspectives. Results: ICH is characterized by a primary vascular rupture, followed by a secondary vascular tearing due to the peripheral pressure exerted by the hematoma. Hypoperfusion may also play a role, although not as markedly as in ischemic stroke. In this context, the repairing of damaged vessels and the development of new ones seem logical therapeutic targets. Circulating EPCs have been suggested to play a major role in re-endothelization, angiogenesis and vasculogenesis. Congruently, EPC levels have been associated with good neurological and functional outcome as well as with reduced residual volume in patients with acute ICH. Conclusion: An EPC-based therapy, acting primarily through angiogenic mechanisms, may be a valid therapeutic option in ICH.

Background: Neural stem/progenitor cells (NSPCs)-based treatment is a potential therapeutic approach for stroke. MicroRNAs (miRNAs) have been recently verified as promoters or suppressors in the regulation of NSPCs. However, the underlying mechanisms regulating cell biological behaviors of NSPCs remain largely unknown. Methods: we retrieved papers focusing on potential roles and mechanisms of miRNAs in the regulation of NSPCs, and paid a special attention to clinical therapeutic potentials of miRNAs in stroke patients. This narrative review provides a comprehensive and critical landscape of this issue. Results: We summarize the most recent studies on the roles and mechanisms of miRNAs in regulating the proliferation, differentiation and migration of NSPCs and fully discuss the potential clinical implications of miRNAs interacting with NSPCs in stroke patients. Conclusion: Promising but full of hurdles, miRNAs have been confirmed to play a critical role in regulating NSPCs. Clinical potentials of miRNAs are huge in treating stroke patients receiving NSPCs-based therapy, which can be used as biomarkers for the diagnosis and prognosis, and as targets for controlling the proliferation, differentiation and migration of NSPCs.

Background: Stroke remains the second commonest cause of death and leading cause of adult disability worldwide. Ischemic events account for nearly 85% of all strokes, and hemorrhages account for nearly 15%. Stroke intervention and recovery have been identified as the important factors in the functional outcome of patients with completed stroke. However, the only FDA approved treatment for ischemic strokes is tissue plasminogen activator, and no effective targeted therapy for hemorrhagic stroke exists yet. Methods: The goal of this work is to review the brain drug delivery systems (BDDS) used for stroke intervention and recovery. Results: Many novel BDDS have been developed for the use of stroke intervention and recovery, including nanoparticles, hydrogels, fibers, liposomes, and so on, which could improve the permeability of blood-brainbarrier (BBB), short half-life, stability in vivo, and reduce adverse effects of drugs. Conclusion: Combined with new drug targets in the treatment of stroke, BDDS will provide more effective therapeutics for stroke intervention and recovery.

Cutaneous scars (particularly hypertrophic and keloid scars), not only can cause adverse cosmetic problems, but also can be associated with emotional distress such as anxiety and depression. Comparing with other surgical treatments, patients who do not opt for or cannot opt for invasion therapies are more eligible for using the topical anti-scarring agents. In this mini-review, we have researched for and collected the data between October 2005 and October 2015, in PubMed and Web of Science, and identified those agents including silicone-based products, imiquimod, corticosteroids, 5-fluorouracil, bleomycin, mitomycin, and plant extracts such as onion extract, asiaticoside, aloe vera, vitamin E, and so on. Besides, we have listed these popular products in commercial market with their useful information. We have also described the combined process according to our clinical experience. However, to establish the more effective treatment among different types of topical agents or their combined process, large, well-designed head-to-head comparisons between individual and combined preparations in relevant patient populations are urgently needed.

In the present study, nineteen new fluoro-benzimidazole derivatives, including nifuroxazide analogs, were synthesized by microwave-supported reactions and tested against a panel of pathogenic microorganisms consisting of resistant strains. The synthesized compounds were characterized and identified by FT-IR, 1H- and 13C-NMR, mass spectroscopy, and elemental analyses, respectively. In vitro antimicrobial and cytotoxic effects of the synthesized compounds were determined by microdilution and by [3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide] (MTT) assay. The compound 4-[5(6)-fluoro-1H-benzimidazol-2-yl)-N'-(2- methylbenzylidene)]benzohydrazide (18) showed particularly high inhibitory activity against the gastro-intestinal pathogens, such as Escherichia coli O157:H7, Escherichiacoli ATCC 8739, Escherichia coli ATCC 35218 and Salmonella typhimurium ATCC 13311 standard strains, with minimum inhibitory concentrations (MIC90) ranging from 0.49–0.98 μg/mL. The microbial panel contained a total of ten pathogens including Klebsiella sp., Mycobacterium sp., MRSA, etc., for which the level of inhibitory activity measured was higher than that exhibited by the tested concentrations (MIC > 1000 μg/mL). In vitro cytotoxicity results revealed that the inhibitory concentration (IC50) value (210.23 μg/mL) of compound 18 against CCD 841 CoN cells (human intestinal epithelial cell line) is about 430 times higher than its MIC90 value against the tested Escherichia coli strains. Furthermore, the docking study of compound 18 suggested that its structure is very compatible with the active site pocket of the phosphofructokinase-2 enzyme.