Current Medicinal Chemistry - Volume 21, Issue 19, 2014

Atherosclerosis is a widespread disease of the arterial system that is generated by injury to the vasculature due to hypercholesterolemia, hypertension and inflammatory diseases. In the current review, we discuss the role of different risk factors, including obesity, hypertension and hypercholesterolemia in atherosclerosis, which may ultimately lead to either cardiovascular or cerebral complication. Inflammation plays a pivotal role in conjunction with obesity, hypertension and hypercholesterolemia in the etiology of atherosclerosis. We discuss the role of inflammation with regards to reactive oxygen species (ROS) linked to the specific risk factors. The role of nitric oxide (NO) in conjunction with ROS is also important. Correlations of inflammatory cytokines and their functions in the mentioned risk factors are also discussed. The risk factors may ultimately lead to ischemic events, including transient ischemic attacks (TIAs), thrombotic stroke and myocardial infarction. Importantly, it seems as if there is a combination of pathophysiological triggers that may eventually result in atherosclerosis. Therefore, atherosclerosis is not the result of only one risk factor, but a combination of various physiological processes such as homeostasis and the inflammatory response. Ultimately, each patient's risk profile is unique and determines their immediate risk for acute thrombotic events or lethal ischemia.

Ischemic stroke remains a leading cause of death worldwide. While the underlying causes of stroke remain poorly defined, brain inflammation appears to be a characteristic response to the vascular insult and there is growing evidence suggesting a cause-effect relationship between the inflammatory response and stroke-induced brain dysfunction and tissue injury. In this review, we summarize evidence that implicates leukocytes in the pathophysiology of stroke and address some of the mediators that contribute to the recruitment and activation of leukocytes in the post-ischemic brain. The products of leukocyte activation that may account for the deleterious effects of this cell population in stroke is also discussed. Recently tested compounds that afford protection against the neurological deficits and tissue injury induced by stroke are addressed within the context of potential development of novel strategies for stroke treatment.

CD147, a transmembrane glycoprotein, is expressed on all leukocytes, platelets, and endothelial cells. It has been implicated in a variety of physiological and pathological activities through interacting with multiple partners, including cyclophilins, monocarboxylate transporters, Caveolin-1, and integrins. While CD147 is best known as a potent inducer of extracellular matrix metalloproteinases (hence also called EMMPRIN), it can also function as a key mediator of inflammatory and immune responses. Increased expression of CD147 has been implicated in the pathogenesis of a number of diseases, such as asthma-mediated lung inflammation, rheumatoid arthritis, multiple sclerosis, myocardial infarction and ischemic stroke. Therapeutic targeting of CD147 has yielded encouraging effects in a number of experimental models of human diseases, suggesting CD147 as an attractive target for treatment of inflammation-related diseases. Here we review the current understanding of CD147 expression and functions in inflammatory and immune responses and potential implications for treatment of inflammatory disorders.

Ischemic stroke is caused by critical reductions in blood flow to brain or spinal cord. Microglia are the resident immune cells of the central nervous system, and they respond to stroke by assuming an activated phenotype that releases cytotoxic cytokines, reactive oxygen species, proteases, and other factors. This acute, innate immune response may be teleologically adapted to limit infection, but in stroke this response can exacerbate injury by further damaging or killing nearby neurons and other cell types, and by recruiting infiltration of circulating cytotoxic immune cells. The microglial response requires hours to days to fully develop, and this time interval presents a clinically accessible time window for initiating therapy. Because of redundancy in cytotoxic microglial responses, the most effective therapeutic approach may be to target the global gene expression changes involved in microglial activation. Several classes of drugs can do this, including histone deacetylase inhibitors, minocycline and other PARP inhibitors, corticosteroids, and inhibitors of TNFα and scavenger receptor signaling. Here we review the pre-clinical studies in which these drugs have been used to suppress microglial activation after stroke. We also review recent advances in the understanding of sex differences in the CNS inflammatory response, as these differences are likely to influence the efficacy of drugs targeting post-stroke brain inflammation.

Stroke is one of the most-frequent causes of death and the first cause of disability worldwide. Different mechanisms are related to the pathogenesis of stroke, involving multiple biological systems, which are often inter-connected. Besides age, hypertension is the most important risk factor for stroke and may also predispose to the development of more subtle cerebral damage based on arteriolar narrowing or pathological microvascular changes. Age and high blood pressure are responsible for silent structural and functional cerebral changes leading to white matter lesions and cognitive impairment. The clinical significance and pathological substrate of white matter lesions are not fully understood. Hypertensive patients have more white matter lesions, which are an important prognostic factor for the development of stroke, cognitive impairment, dementia and death, than normotensive people. Over the past 10 years, strong evidence has emerged that cerebral white matter lesions in hypertensive patients should be considered a silent early marker of brain damage. The mechanisms that would explain all these relationships remain to be elucidated, but available data suggest that arteriosclerosis of the penetrating brain vessels is the main factor in the pathogenesis of ischemic white matter lesions.

Synaptic plasticity requires careful synchronization and coordination of neurons and glial cells via various mechanisms of intercellular communication. Among them, are those mediated by i) connexin gap junction channels (GJCs), ii) connexin hemichannels and iii) pannexin channels. Whereas GJCs directly communicate the cytoplasm of contacting cells and coordinate electric and metabolic activities, connexin hemichannels and pannexin channels serve as diffusional pathways for ions and small molecules between the intra- and extracellular compartments. A growing body of evidence has revealed that intercellular communication could be critical in the spread of protective and/or deleterious signals during stroke. Here, we review current findings on the regulation of connexin- and pannexin-based channels in ischemic stroke and how they contribute to cell damage observed in pathology. Depending on intensity of the ischemic event, brain region and connexin subtype expressed, GJCs may provide proper diffusion of energy metabolites and dissipation of toxic substances, whereas, in other circumstances, they could increase damage by spreading toxic molecules. Alternatively, connexin hemichannel and pannexin channel opening may favor the release of neurotoxic substances (e.g., glutamate), but in other cases, they may confer neuroprotection against an ischemic episode by the phenomenon of ischemic preconditioning. Development of new drug modulators using in silico devices for connexin and pannexin-based channels will be crucial for future therapies against stroke.

Mitochondria play a crucial role in multitude of cellular processes including energy production, calcium signaling, and apoptosis. This remarkable organelle constantly undergoes a complex cycle of fusion and fission, a crucial quality control system for maintaining homeostasis of the cell. Any impairment in this dynamic behavior is linked to a wide range of cellular abnormalities. Consistent with this concept, neuronal apoptosis often emanates in conjunction with rampant mitochondrial fragmentation. The mitochondrial dynamics are tightly regulated by a master mediator called Dynamin related protein 1 (Drp1), which in normal conditions facilitates mitochondrial fission. However, diverse stress conditions induce intensified translocation of cytosolic Drp1 to the mitochondria, contributing excessive fragmentation and concomitant apoptosis. Despite this knowledge, crucial questions such as how fission of the inner and outer mitochondrial membranes is coordinated and how these processes are linked to apoptosis and necrosis remain to be answered. This review focuses on delineating the mechanism of Drp1 activation and explores the pathophysiological importance of dysregulated mitochondrial fission with a special emphasis on ischemic stroke. Further, it also provides a new mechanistic link between ischemia and Drp1-mediated mitochondrial fission.

The vascular system distributes oxygen and nutrients to all tissues in the body. Additionally, the vascular system also functions in hosting and instructing tissue-specific stem and progenitor cells. Both cell- or blood-derived signals from the vascular system regulate stem cell properties in health and disease. Studies in animal models and in human disease have begun to uncover that signals from the vascular system are not merely maintaining the stem cell niche, but also instruct stem cells for repair mechanisms outside their niche. The present article focuses on recent findings about cell- or blood-derived factors in the vascular system supporting stem cell niche maintenance or activation for tissue homeostasis and repair. We highlight the fact that certain aspects of vascular - stem cell communication are conserved between stem cell niches in different tissues. Within this context, we will especially emphasize on a potential role of the altered vascular system after CNS disease in instructing stem cell fate. Understanding the communication between the vascular system and neural stem cells might support the development for new therapeutic approaches for CNS disease.

Mitochondrial dysfunction plausibly underlies the aging-associated brain degeneration. Mitochondria play a pivotal role in cellular bioenergetics and cell-survival. Oxidative stress consequent to chronic hypoperfusion induces mitochondrial damage, which is implicated as the primary cause of cerebrovascular accidents (CVA) mediated Alzheimer's disease (AD). The mitochondrial function deteriorates with aging, and the mitochondrial damage correlates with increased intracellular production of oxidants and pro-oxidants. The prolonged oxidative stress and the resultant hypoperfusion in the brain tissues stimulate the expression of nitric oxide synthase (NOS) enzymes, which further drives the formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The ROS and RNS collectively contributes to the dysfunction of the blood-brain barrier (BBB) and damage to the brain parenchymal cells. Delineating the molecular mechanisms of these processes may provide clues for the novel therapeutic targets for CVA and AD patients.