Blood–brain barrier, reperfusion injury, and hemorrhagic transformation in acute ischemic stroke

Abstract

It has been more than a century since Paul Ehrlich, in 1885, and later his student Edwin Goldmann, proposed that a barrier existed between the CNS and the peripheral circulation.1 While studying the limited permeation of potassium ferrocyanate into the brain in 1900, Lewandowsky coined the term bluthirnschranke, blood–brain barrier (BBB).1 The BBB is considered the gatekeeper of the CNS, whose main role is to maintain the fragile homeostasis of the brain designed by segregating the CNS from the systemic circulation. The BBB is composed of endothelial cells, pericytes, astrocytes, neurons, and the extracellular matrix (ECM), which are collectively known as the neurovascular unit (NVU). BBB endothelial cells lack fenestrations, have tight junctions (TJs), have minimal pinocytotic activity, and express a number of enzymes capable of degrading both harmful and therapeutic molecules. They also have increased mitochondrial content, which is required for the multiple energy-dependent processes involved in nutrient support and protection of the brain.1,–,3 Pericytes are vascular smooth-muscle-lineage cells that occur as solitary cells embedded in the basement membrane of microvessels and have their own characteristic morphology.4 Both the endothelial cells and pericytes are surrounded by the basal lamina, which is 30- to 40-nm contiguous with the plasma membranes of astrocyte end-feet. The basal lamina supports and anchors cells via adhesion receptors and regulates intercellular communication. Astrocytes play a very important role not only in BBB support and its maintenance but also in neuron–NVU interactions. Under conditions of ischemia, there is a disruption of the bidirectional communication between microvessels and neurons with the participation of the intervening astrocytes.3 The greater the distance between the microvessels and the neurons [(m − n) distance], the higher the likelihood of being prone to ischemic injury.3 Microglial cells are basically the macrophages of …