Abstract
Stroke is a major challenge in modern medicine and understanding the role of the neuronal extracellular matrix (NECM) in its pathophysiology is fundamental for promoting brain repair. Currently, stroke research is focused on the neurovascular unit (NVU). Impairment of the NVU leads to neuronal loss through post-ischemic and reperfusion injuries, as well as coagulatory and inflammatory processes. The ictal core is produced in a few minutes by the high metabolic demand of the central nervous system. Uncontrolled or prolonged inflammatory response is characterized by leukocyte infiltration of the injured site that is limited by astroglial reaction. The metabolic failure reshapes the NECM through matrix metalloproteinases (MMPs) and novel deposition of structural proteins continues within months of the acute event. These maladaptive reparative processes are responsible for the neurological clinical phenotype. In this review, we aim to provide a systems biology approach to stroke pathophysiology, relating the injury to the NVU with the pervasive metabolic failure, inflammatory response and modifications of the NECM. The available data will be used to build a protein–protein interaction (PPI) map starting with 38 proteins involved in stroke pathophysiology, taking into account the timeline of damage and the co-expression scores of their RNA patterns The application of the proposed network could lead to a more accurate design of translational experiments aiming at improving both the therapy and the rehabilitation processes.
Highlights
As life expectancy increases, vascular diseases are progressively rising as major causes of disability and death [1]
The damage to the blood–brain barrier (BBB) structure is the main harm to the neurovascular unit (NVU) during acute stroke, it allows the permeation of blood elements, normally confined to the systemic circulation
Minocycline has been showed to be effective in inhibiting poly(ADP-ribose) polymerase. This trial is a proof of concept for the results of a study that showed a possible role of minocycline in lowering matrix metalloproteinase 9 (MMP9) plasma levels following recombinant tissue plasminogen activator (rt-PA) treatment of stroke [119]
Summary
Vascular diseases are progressively rising as major causes of disability and death [1]. Various definitions of stroke have been assessed, the American Heart Association/American Stroke Association (AHA/ASA) delineated stroke as a CNS infarction within tissues of the brain, spinal cord or retina, due to ischemia [4] It should be confirmed through radiological, clinical and/or pathological evidence of permanent injury. This systems biology approach is essential to pave the way for an improvement in acute therapy and in the rehabilitation process. If the damage is superficial, instead of the formation of a cavity, the area could be infiltrated by granulomatous tissue comprehending macrophages and blood vessels where glial cells are obliterated [41] This macroscopic phenomenon is underlined by distinct molecular steps involving the NVU and NECM elements which interact with CNS resident and blood-derived immune cells [6]
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