Neuroinflammation after Intracerebral Hemorrhage and Potential Therapeutic Targets

Abstract

Spontaneous intracerebral hemorrhage (ICH) is a catastrophic illness causing significant morbidity and mortality. Despite advances in surgical technique addressing primary brain injury caused by ICH, little progress has been made treating the subsequent inflammatory cascade. Pre-clinical studies have made advancements identifying components of neuroinflammation, including microglia, astrocytes, and T lymphocytes. After cerebral insult, inflammation is initially driven by the M1 microglia, secreting cytokines (e.g., interleukin-1β [IL-1β] and tumor necrosis factor-α) that are involved in the breakdown of the extracellular matrix, cellular integrity, and the blood brain barrier. Additionally, inflammatory factors recruit and induce differentiation of A1 reactive astrocytes and T helper 1 (Th1) cells, which contribute to the secretion of inflammatory cytokines, augmenting M1 polarization and potentiating inflammation. Within 7 days of ICH ictus, the M1 phenotype coverts to a M2 phenotype, key for hematoma removal, tissue healing, and overall resolution of inflammation. The secretion of anti-inflammatory cytokines (e.g., IL-4, IL-10) can drive Th2 cell differentiation. M2 polarization is maintained by the secretion of additional anti-inflammatory cytokines by the Th2 cells, suppressing M1 and Th1 phenotypes. Elucidating the timing and trigger of the anti-inflammatory phenotype may be integral in improving clinical outcomes. A challenge in current translational research is the absence of an equivalent disease animal model mirroring the patient population and comorbid pathophysiologic state. We review existing data and describe potential therapeutic targets around which we are creating a bench to bedside translational research model that better reflects the pathophysiology of ICH patients.

INT-777 Improves Cognitive Impairment after Sepsis by Attenuating Neuroinflammation Through the TGR5/cAMP/PKA/CREB Signaling Axis in Rats

“…First, although TGR5 plays a role in neuroprotection through different mechanisms, such as resistance to apoptosis, oxidative stress resistance, and the maintenance of bloodbrain barrier integrity, in this study, the role of TGR5 in only neuroin ammation was studied. Second, our study showed that TGR5 is also minimally expressed on astrocytes, and the current study con rms that astrocytes are also strongly associated with neuroin ammation [45], and we intend to further evaluate the effect of INT-777 treatment on astrocytes in neuroin ammation in a follow-up study. Third, INT-777 was administered at 1 hour after CLP, and whether the administration of INT-777 within a time frame of 3 hours, 6 hours or longer after CLP would still have a signi cant neuroprotective effect was not evaluated, although this information would be more valuable for clinical application.…”

Protective Effect of CXCR4 Antagonist CX807 in a Rat Model of Hemorrhagic Stroke

“…After the onset of ICH, a series of neurodegenerative and inflammatory cascade reactions are turned on. These include disruption of the blood–brain barrier, upregulation of chemokines, activation of microglia, mobilization of peripheral lymphocytes to the lesioned brain, apoptosis, and cell death [ 1 ]. As inflammation is closely associated with degeneration in the brain, anti-inflammatory agents may reduce brain damage and improve outcomes in ICH patients.…”

Pharmacological Activation of RXR-α Promotes Hematoma Absorption in a PPAR-γ-Dependent Pathway After Intracerebral Hemorrhage

“…Microglia and monocytes/macrophages are vital to maintaining homeostasis, acting as phagocytes to scavenge for debris in the CNS after ICH. Targeting these cells may be an ideal therapeutic strategy for stroke [9]. Besides, immuno uorescence staining showed that RXR-α was expressed in microglia/macrophages, astrocytes, and neurons.…”

“…Various mechanisms are involved in the regulation of tissue healing, hematoma removal, and in ammation resolution. One of the essential mechanisms, especially concerning the neuroin ammation that is incurred by post-hemorrhagic secondary brain injuries, is related to the conversion of the classical activation phenotype (M1) to the alternative activation phenotype (M2) [9]. In the CNS, M2-like microglia/macrophages are e cient phagocytes [42].…”

“…In the central nervous system (CNS), microglia/macrophages serve as the main phagocytes involved in the defense against brain damage, including ICH, through the phagocytosis of red blood cells and the removal of tissue debris [4,8]. Microglia/macrophages can be activated by hematoma components, such as thrombin and neurotoxins after tissue damage occurs [9]. It has been found that microglia/macrophages of the brain may dynamically be activated into two polarized states, termed the classical M1-like phenotype and the alternative M2-like phenotype [10].…”