Current Medicinal Chemistry - Volume 21, Issue 18, 2014

Thrombomodulin (TM) is a membrane protein mainly expressed by endothelial cells. It is part of the anticoagulant protein C system but recently several effects were discovered which occur independently of protein C activation. TM binds thrombin and promotes the cleavage of protein C and the thrombin activatable fibrinolysis inhibitor (TAFI), thereby inhibiting coagulation and fibrinolysis. Additionally, it interferes with inflammation, stabilizes barrier function, and increases blood flow under pathological conditions. Recombinant soluble TM protects against tissue damage and partially restores normal function after ischemia in several organs. Recently, it was shown to reduce the infarct size in stroke models. Compared to other anticoagulant compounds the risk of bleeding seems to be smaller in animals and humans treated with soluble TM. With its multiple actions TM represents a new candidate for stroke treatment. In this review we focus on the effects of TM in coagulation, inflammation, and on its protective roles in the prevention of ischemic brain damage.

The neurovascular unit is now well accepted as a conceptual framework for investigating the mechanisms of ischemic stroke. From a molecular and cellular perspective, three broad mechanisms may underlie stroke pathophysiology – excitotoxicity, oxidative stress and inflammation. To date, however, most investigations of these basic mechanisms have focused on neuronal responses. In this mini-review, we ask whether these mechanisms of excitotoxicity, oxidative stress and inflammation can also be examined in terms of non-neuronal interactions in the neurovascular unit, including the release of extracellular vesicles for cell-cell signaling.

Stroke is a leading cause of human mortality and disability where most cases of stroke are ischemic. The central nervous system (CNS) is extremely vulnerable to ischemic stroke particularly due to its unique ability: synaptic transmission. Not only does elaborate synaptic transmission consume extravagant energy that constrains neuronal viability under ischemic conditions, but glutamate, the most predominant neurotransmitter in the CNS, also triggers several catastrophic signaling cascades at both synaptic and extrasynaptic sites when excessively released. These signaling cascades accelerate neuronal death and exacerbate cerebral injuries during ischemic stroke. In this review, we discuss the complete picture of synaptic and extrasynaptic glutamate signaling in ischemic stroke. We hope to provide substantial insights into potential therapies by reviewing recent discoveries that have advanced our understanding of the complex glutamate signaling mechanisms in ischemic stroke.

Role of calcium ion (Ca2+) in the functioning of neurons from their naive state to mature state is of vital importance. It controls functions such as neuronal functioning, neuronal ATP production, central nervous system migration and many others. Failure in Ca2+ homeostasis mechanisms and the resulting cellular Ca2+ ion load initiates a cascade of reactions involving various cytosolic enzymes and proteins. This total mechanism leads to the neuronal death. The ability of neurons to resist such death mechanisms fails as a result of extensive cell death signaling cascade reactions and later brings brain damage. The role of neuronal endoplasmic reticulum and protein channels like CaVs, TRP channels, and NMDAR as the mediators of cell damage and death has been evaluated in the studies related to cerebral ischemia. Here, we portray Ca2+ ion as one of the role players in neuronal death and cerebral damage following ischemia. The role of Ca2+ in neuronal functioning, its regulatory mechanisms and the failure of homeostatic mechanisms are discussed in detail.

Stroke is a frequent cause of long-term disability and death worldwide. Ischemic stroke is more commonly encountered compared to hemorrhagic stroke, and leads to tissue death by ischemia due to occlusion of a cerebral artery. Inflammation is known to result as a result of ischemic injury, long thought to be involved in initiating the recovery and repair process. However, work over the past few decades indicates that aspects of this inflammatory response may in fact be detrimental to stroke outcome. Acutely, inflammation appears to have a detrimental effect, and anti-inflammatory treatments have been been studied as a potential therapeutic target. Chronically, reports suggest that post-ischemic inflammation is also essential for the tissue repairing and remodeling. The majority of the work in this area has centered around innate immune mechanisms, which will be the focus of this review. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. A better understanding of the roles of the different immune cells and their temporal profile of damage versus repair will help to clarify more effective modulation of inflammation post stroke.

The evolution of ischemic brain damage is strongly affected by an inflammatory reaction that involves soluble mediators, such as cytokines and chemokines, and specialized cells activated locally or recruited from the periphery. The immune system affects all phases of the ischemic cascade, from the acute intravascular reaction due to blood flow disruption, to the development of brain tissue damage, repair and regeneration. Increased endothelial expression of adhesion molecules and blood-brain barrier breakdown promotes extravasation and brain recruitment of blood-borne cells, including macrophages, neutrophils, dendritic cells and T lymphocytes, as demonstrated both in animal models and in human stroke. Nevertheless, most anti-inflammatory approaches showing promising results in experimental stroke models failed in the clinical setting. The lack of translation may reside in the redundancy of most inflammatory mediators, exerting both detrimental and beneficial functions. Thus, this review is aimed at providing a better understanding of the dualistic role played by each component of the inflammatory/immune response in relation to the spatio-temporal evolution of ischemic stroke injury.