Abstract
Ischemic stroke is one of the leading causes of morbidity and mortality globally. Hundreds of clinical trials have proven ineffective in bringing forth a definitive and effective treatment for ischemic stroke, except a myopic class of thrombolytic drugs. That, too, has little to do with treating long-term post-stroke disabilities. These studies proposed diverse options to treat stroke, ranging from neurotropic interpolation to venting antioxidant activity, from blocking specific receptors to obstructing functional capacity of ion channels, and more recently the utilization of neuroprotective substances. However, state of the art knowledge suggests that more pragmatic focus in finding effective therapeutic remedy for stroke might be targeting intricate intracellular signaling pathways of the ‘neuroinflammatory triangle’: ROS burst, inflammatory cytokines, and BBB disruption. Experimental evidence reviewed here supports the notion that allowing neuroprotective mechanisms to advance, while limiting neuroinflammatory cascades, will help confine post-stroke damage and disabilities.
Highlights
Stroke follows heart diseases and cancer as the highest global cause of mortality
The instant and primary damage to the brain cells are followed by neuroinflammatory cascade entailing bursts of reactive oxygen species (ROS), release of a variety of signaling cytokines, and damage to the cerebral microvasculature, as well as disruption of the blood-brain barrier (BBB) [6,7,8,9]
Non-availability of clinically reliable therapeutic interventions for limiting stroke-related morbidities and mortalities puts the significance of clinical trials into question
Summary
Stroke follows heart diseases and cancer as the highest global cause of mortality. It is the leading cause of permanent disabilities [1]. INF-g binding with INFG1 part brings INFG2 in to proximity with INFG1 in such a way that, intracellularly, Jak and Jak phosphorylate each other’s two receptor domains These receptor domains act as docking points for STATs to bind with respective JAKs. The activated STAT dissociates and forms a homodimeric complex functioning as a transcription factor inducing the expression of variety of protein signals in various cell types. This sIL-6R-a and IL-6 complex has a very high affinity to membrane bound gp130 (present on the cell membrane of distant glial and neuronal cells), causing activation of intracellular tyrosin-kinases, such as Janus kinase (JAK), which in-turn activates two pathways: activation of JAKSTAT pathway (upregulate the synthesis of iNOS, T cell differentiation)and the RAS-RAF-MAPK pathway [112,113,114] Both these mechanisms lead to expression of genes which are associated with producing inflammatory outcomes [115]. IL-6 induces excess production of vascular endothelial growth factor (VEGF), leading to enhanced vascular permeability, which is one of the many pathological features of inflammatory lesions in the brain [116]
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