Trauma-induced reactive gliosis is reduced after treatment with octanol and carbenoxolone

Andersson, H; Anderson, Michelle F.; Porritt, Michelle J.; Nodin, Christina; Blomstrand, Fredrik; Nilsson, Michael

doi:10.1179/1743132810y.0000000020

Cited by 8 publications

(8 citation statements)

References 26 publications

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“…We observed a decrease in GFAP immunoreactivity after siCx43 injection after jTBI (Figure 6). This decrease in GFAP is in accordance with an adult TBI study using antisense oligonucleotide pretreatment against Cx43 (Wu et al., 2013) and another study in which gap junction inhibitors, carbenoxolone and octanol, were administered in adult rats that underwent a stab wound to mimic brain injury (Andersson et al., 2011). Although the exact function and implication of changes in GFAP immunoreactivity is debated, it is commonly regarded to be associated with astrogliosis (Sofroniew, 2005; Sofroniew and Vinters, 2010).…”

Section: Discussionsupporting

confidence: 84%

“…Although TBI studies on astrocytic Cx43 are sparse, increased Cx43 has been associated with other brain pathologies (Chew et al., 2010). Ischemic stroke studies have reported beneficial results by specific inhibition of Cx43 in in vitro models (Chew et al., 2010) and general gap junction inhibition in vivo (Perez Velazquez et al., 2006; Andersson et al., 2011). Thus, siCx43 may be a unique and useful new technical approach to study in vivo the involvement of Cx43 as well as a potential therapeutic tool in other brain injury models as well.…”

Section: Discussionmentioning

confidence: 99%

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Small Interference RNA Targeting Connexin-43 Improves Motor Function and Limits Astrogliosis After Juvenile Traumatic Brain Injury

et al. 2019

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Juvenile traumatic brain injury (jTBI) is the leading cause of death and disability for children and adolescents worldwide, but there are no pharmacological treatments available. Aquaporin 4 (AQP4), an astrocytic perivascular protein, is increased after jTBI, and inhibition of its expression with small interference RNA mitigates edema formation and reduces the number of reactive astrocytes after jTBI. Due to the physical proximity of AQP4 and gap junctions, coregulation of AQP4 and connexin 43 (Cx43) expressions, and the possibility of water diffusion via gap junctions, we decided to address the potential role of astrocytic gap junctions in jTBI pathophysiology. We evaluated the role of Cx43 in the spread of the secondary injuries via the astrocyte network, such as edema formation associated with blood–brain barrier dysfunctions, astrogliosis, and behavioral outcome. We observed that Cx43 was altered after jTBI with increased expression in the perilesional cortex and in the hippocampus at several days post injury. In a second set of experiments, cortical injection of small interference RNA against Cx43 decreased Cx43 protein expression, improved motor function recovery, and decreased astrogliosis but did not result in differences in edema formation as measured via T2-weighted imaging or diffusion-weighted imaging at 1 day or 3 days. Based on our findings, we can speculate that while decreasing Cx43 has beneficial roles, it likely does not contribute to the spread of edema early after jTBI.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Small Interference RNA Targeting Connexin-43 Improves Motor Function and Limits Astrogliosis After Juvenile Traumatic Brain Injury

et al. 2019

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“…In general, reactive changes of glial cells are a hallmark of “gliosis” that is known to be induced in the CNS by numerous pathological conditions including traumatic (Andersson et al , 2011) or ischemic insults (Roy Choudhury et al , 2014) and in neurodegenerative diseases (Pekny & Pekna, 2014). As a predefined‐GO term for gliosis did not exist and in order to achieve a more integrative description of a reactive EGC phenotype, we created a non‐exclusive list of published genes regulated in reactive astrogliosis (Zamanian et al , 2012; Hara et al , 2017; Liddelow et al , 2017; Fujita et al , 2018; Mathys et al , 2019; Rakers et al , 2019; Schirmer et al , 2019).…”

Section: Discussionmentioning

confidence: 99%

A novel P2X2‐dependent purinergic mechanism of enteric gliosis in intestinal inflammation

et al. 2020

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Enteric glial cells (EGC) modulate motility, maintain gut homeostasis, and contribute to neuroinflammation in intestinal diseases and motility disorders. Damage induces a reactive glial phenotype known as "gliosis", but the molecular identity of the inducing mechanism and triggers of "enteric gliosis" are poorly understood. We tested the hypothesis that surgical trauma during intestinal surgery triggers ATP release that drives enteric gliosis and inflammation leading to impaired motility in postoperative ileus (POI). ATP activation of a p38-dependent MAPK pathway triggers cytokine release and a gliosis phenotype in murine (and human) EGCs. Receptor antagonism and genetic depletion studies revealed P2X2 as the relevant ATP receptor and pharmacological screenings identified ambroxol as a novel P2X2 antagonist. Ambroxol prevented ATPinduced enteric gliosis, inflammation, and protected against dysmotility, while abrogating enteric gliosis in human intestine exposed to surgical trauma. We identified a novel pathogenic P2X2dependent pathway of ATP-induced enteric gliosis, inflammation and dysmotility in humans and mice. Interventions that block enteric glial P2X2 receptors during trauma may represent a novel therapy in treating POI and immune-driven intestinal motility disorders.

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“…In recent years, its anti-inflammatory role has been raised in CNS. For instance, trauma-induced reactive gliosis could be alleviated by CBX [14]. Our study demonstrated that CBX is a protective drug against EAE.…”

Section: Discussionmentioning

confidence: 67%

The Effects of Carbenoxolone against Experimental Autoimmune Encephalomyelitis in a Mouse Model

Chen¹,

Hu²,

Li³

et al. 2020

Neuroimmunomodulation

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Introduction: Multiple sclerosis (MS) is a complex demyelinating disease involving central nervous system (CNS). It is still a challenge to secure an effective therapeutic strategy against this disease. Carbenoxolone (CBX) is a derivative of glycyrrhetinic acid, which is widely used in brain research for its gap-junction inhibition effects. Many researchers have observed CBX-mediated suppression of CNS inflammation in their studies. Objective: We want to further examine its anti-inflammation effects in CNS demyelinating disease like MS. Methods: Thus, our study applied an experimental autoimmune encephalomyelitis (EAE) mouse model and examined the effects of CBX on it. Results and Conclusions: We found that CBX significantly reversed the EAE severity and pathology in EAE. IL-17-secreting and IFN-γ-secreting CD4+ T lymphocytes were remarkably lower in the spleen of CBXtreated mice. Production of IL-23 and IL-17 from cortex in EAE animals was markedly reduced by CBX. Furthermore, CBX treatment increased the expression of brain-derived neurotrophic factor. This study provides evidence for the protective role of CBX against EAE.

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Trauma-induced reactive gliosis is reduced after treatment with octanol and carbenoxolone

Abstract: The present study demonstrates that two important components of reactive gliosis, cellular activation and proliferation, can be attenuated by octanol and carbenoxolone.

Cited by 8 publications

References 26 publications

Small Interference RNA Targeting Connexin-43 Improves Motor Function and Limits Astrogliosis After Juvenile Traumatic Brain Injury

Small Interference RNA Targeting Connexin-43 Improves Motor Function and Limits Astrogliosis After Juvenile Traumatic Brain Injury

A novel P2X2‐dependent purinergic mechanism of enteric gliosis in intestinal inflammation

The Effects of Carbenoxolone against Experimental Autoimmune Encephalomyelitis in a Mouse Model

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