Glial Cells Response in Stroke

Abstract

As the second-leading cause of death, stroke faces several challenges in terms of treatment because of the limited therapeutic interventions available. Previous studies primarily focused on metabolic and blood flow properties as a target for treating stroke, including recombinant tissue plasminogen activator and mechanical thrombectomy, which are the only USFDA approved therapies. These interventions have the limitation of a narrow therapeutic time window, the possibility of hemorrhagic complications, and the expertise required for performing these interventions. Thus, it is important to identify the contributing factors that exacerbate the ischemic outcome and to develop therapies targeting them for regulating cellular homeostasis, mainly neuronal survival and regeneration. Glial cells, primarily microglia, astrocytes, and oligodendrocytes, have been shown to have a crucial role in the prognosis of ischemic brain injury, contributing to inflammatory responses. They play a dual role in both the onset as well as resolution of the inflammatory responses. Understanding the different mechanisms driving these effects can aid in the development of therapeutic targets and further mitigate the damage caused. In this review, we summarize the functions of various glial cells and their contribution to stroke pathology. The review highlights the therapeutic options currently being explored and developed that primarily target glial cells and can be used as neuroprotective agents for the treatment of ischemic stroke.

Keywords: Blood–brain barrier; Glial cells; Ischemic stroke; Neuroprotection; Therapeutic target.

Fig. 1

Glial cell crosstalk in cerebral ischemia: after cerebral ischemia, there is the release of DAMPs, cellular content, and debris from dying cells that initiate microglial activation in response to inflammatory activity. This leads to microglial polarization through which two different phenotypes, namely M1 and M2 show pro-inflammatory and anti-inflammatory activity, respectively. M1 contributes to pro-inflammatory activity (detrimental) by releasing IL-6, IL-1β, IFN-ϒ, TNF-α, IL-15, IL-18, IL-23, ROS/NOS whereas M2 contributes to be an anti-inflammatory activity (protective) by releasing IL-4, IL-10, IL-13, IGF-1, TGF-β, BDNF, and vasoactive proteins. M2 also promotes phagocytic activity. Astrocytes will be activated by the inflammatory activity of microglia and bring about reactive astrogliosis forming reactive astrocytes which are also categorized as A1, i.e., pro-inflammatory, and A2, i.e., anti-inflammatory (neuroprotective) phenotypes. These reactive astrocytes have also a detrimental effect on oligodendrocytes. Oligodendrocyte regulation is also mediated by the two-fold role of microglia, i.e., inflammatory mediators released by activated microglia (M1 phenotype) cause damage to oligodendrocytes and inhibit OPC proliferation whereas M2 phenotype help in OPC proliferation and oligodendrocyte differentiation. DAMP damaged associated molecular pattern, IL interleukin, IFN interferon, ROS reactive oxygen species, NOS nitric oxide synthase, IGF insulin-like growth factor, TGF transforming growth factor, BDNF brain-derived neurotrophic factor, OPC oligodendrocyte progenitor cell. ( Adapted from Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License, https://smart.servier.com/)

Fig. 2

Pathology behind BBB disruption after ischemia: following ischemia, there is initiation molecular cascades that results in the production of inflammatory cytokines, toxic free radicals (ROS/RNS), proteases like MMPs along with altered production of angiogenic factors such as VEGF. Activation of proteases leads to disruption of the neurovascular unit (NVU), which plays a crucial role in normal brain functioning. The NVU includes astrocytes, endothelial cells that are connected by tight junctions, pericytes, neurons, and ECM surrounding the blood vessels. Microglia, which are resident immune cells in the brain, also play a vital role in NVU control. The tight junction is impaired in this pathological condition as the tight junction proteins such as occluding, claudin, ZOs are degraded. That ultimately leads to the disrupted basement membrane and lastly causes BBB disruption. ROS reactive oxygen species, RNS reactive nitrogen species, MMP matrix metalloproteinases, VEGF vascular endothelial growth factor, ECM extracellular matrix, ZO zonula occludens. ( Adapted from Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License, https://smart.servier.com/)

Fig. 3

Drugs targeting microglial activation and polarization: one of the first events after brain ischemia is microglial activation where microglia undergoes morphological changes from ramified state to amoeboid state. Once activated they get polarized into M1 and M2 phenotypes which decides the fate of inflammatory reaction. Different drugs are being tested which acts on these events and can be used as neuroprotective agents to treat ischemia. Ginsenoside is one of the drugs that inhibit microglial activation, as well as polarization into the M1 phenotype which furthers, inhibits the release of pro-inflammatory cytokines such as IL-6, IL-1β, IFN-ϒ, TNF-α, IL-15, IL-18, IL-23. Protocatechuic acid too inhibits the microglial switch to M1. Electroacupuncture therapy, Rapamycin, and ABIN1, all inhibit the release of pro-inflammatory cytokines mentioned earlier. Minocycline switches M1 phenotype to M2 through inhibition of caspase 3/7 as well as reducing cell death through the STAT1/6 pathway. There are some drugs such as Metformin. l-3-n-Butylpthalide, PACAP (pituitary adenylate cyclase-activating polypeptide), and melatonin which activates the M2 phenotype which releases anti-inflammatory cytokines like IL-4, IL-10, IL-13, IGF-1, TGF-β, BDNF thereby attenuating the post-stroke inflammatory response. ( Adapted from Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License, https://smart.servier.com/)