Microglial Activation in Stroke: Therapeutic Targets

Abstract

Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A4 analog: Protective mechanisms and long‐term effects on neurological recovery

“…Activation of microglia and macrophages by IL‐4, IL‐10, or tumor growth factor (TGF)β induces the M2 state, which is characterized by wound repair, debris clearance, and the release of anti‐inflammatory cytokines (Martinez & Gordon, 2014; Stein, Keshav, Harris, & Gordon, 1992). These opposing phenotypes play an important role in neuroinflammation and it is hypothesized that altering the activation of microglia and macrophages from the M1 side of the spectrum to the M2 side could be beneficial in ischemic stroke (Hu et al., 2012, 2015; Yenari, Kauppinen, & Swanson, 2010). …”

Pharmacological Modulation of Heat Shock Protein 70 (HSP70)—Dependent Mechanisms of Endogenous Neuroprotection in Conditions of Prenatal Chronic Alcoholism by Cerebrocurin and Tiocetam

“…Increased expression of the genes encoding heat shock proteins are regulated by transcription step. Heat shock proteins are called stress proteins, as increased expression of the corresponding genes is often observed in response to stress [3][4][5][6][7][8][9][10] . Their active participation in the most important processes of functioning cells suggests that these proteins play a key regulatory role in providing repair and degradation, and "failure" in the functioning of the "protein machine" -one of the causes of dysfunction and damage of organs and tissues.…”

Glial Cells, Inflammation and Heat Shock Proteins in Cerebral Ischemia

“…As a result, microglia can respond to diverse stresses by performing innate immune functions such as phagocytosis, and can release potentially beneficial factors such as glial-derived neurotrophic factor (GDNF). Microglia can release a host of factors to protect the CNS; however, when activated after ischemia by necrotic cell debris and other substances, they can produce free radicals, proinflammatory cytokines (IL-1 , TNF , IL-6 and interferon-), reactive oxygen species, matrix metalloproteinases and glutamate in an aberrant fashion (Lucin and Wyss-Coray, 2009;Yenari et al, 2010). Such compounds are instrumental in the subsequent activation of astrocytes (see below), induction of cell adhesion molecules and T-lymphocyte recruitment into the CNS following various injuries (Liu and Hong, 2003;Sweitzer et al, 2002).…”

“…Taken together, these studies suggest that inhibition of the post-ischemia inflammatory response is a viable option for stroke treatment. Although microglia quickly respond to ischemia by producing proinflammatory cytokines (Yenari et al, 2010), proliferating (Denes et al, 2007) and exhibiting an altered cell morphology , only a small percentage (1-8%) of the microglia in the corpus callosum and lesion penumbra, and no microglia in the lesion core, express Hsp72 early after focal ischemia (Soriano et al, 1994). This indicates that a robust increase in Hsp72 protein expression is not a normal aspect of the post-ischemic microglial phenotype.…”