Differential expression of astrocytic connexins in a mouse model of prenatal alcohol exposure

Ramani, Meera; Mylvaganam, Shanthini; Krawczyk, Michał; Wang, Lihua; Zoidl, Christiane; Brien, James F.; Reynolds, James N.; Kapur, Bhushan; Poulter, Michael O.; Zoidl, Georg; Carlen, Peter L.

doi:10.1016/j.nbd.2016.02.022

Cited by 8 publications

(4 citation statements)

References 60 publications

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“…These data suggest that increased sensitivity to TNFα, in particular by astrocytes, is present in the PAE CNS, a concept recently supported by a study demonstrating that astrocytic connexin 43 (Cx43) in a mouse model of PAE is significantly upregulated that could underlie PAE-induced cerebral hyperexcitability [44]. Elevated Cx43 may reflect destabilized astrocytic responses to glutamate neurotransmission, as a separate report extended the role of basal Cx43 on astrocytes as a buffer for extracellular glutamate, which under neuropathic conditions or application of TNFα, Cx43 expression becomes significantly downregulated [40, 44]. Thus, while speculative, the astrocyte sensitivity to TNFα may be increased that synergizes with IL-1β in PAE offspring upon induction/early establishment of minor injury.…”

Section: Discussionmentioning

confidence: 74%

“…In support, a prior study demonstrated that TNFα triggers a cytokines cascade including IL-1β yielding adverse neuronal function [56], and it has been established that primed astrocytes in the degenerating brain produce exaggerated TNFα, IL-1β CCL2 protein [19]. These data suggest that increased sensitivity to TNFα, in particular by astrocytes, is present in the PAE CNS, a concept recently supported by a study demonstrating that astrocytic connexin 43 (Cx43) in a mouse model of PAE is significantly upregulated that could underlie PAE-induced cerebral hyperexcitability [44]. Elevated Cx43 may reflect destabilized astrocytic responses to glutamate neurotransmission, as a separate report extended the role of basal Cx43 on astrocytes as a buffer for extracellular glutamate, which under neuropathic conditions or application of TNFα, Cx43 expression becomes significantly downregulated [40, 44].…”

Section: Discussionmentioning

confidence: 99%

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Targeting the β2-integrin LFA-1, reduces adverse neuroimmune actions in neuropathic susceptibility caused by prenatal alcohol exposure

Sanchez

Noor

et al. 2019

acta neuropathol commun

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Recently, moderate prenatal alcohol exposure (PAE) was shown to be a risk factor for peripheral neuropathy following minor nerve injury. This effect coincides with elevated spinal cord astrocyte activation and ex vivo immune cell reactivity assessed by proinflammatory cytokine interleukin (IL) -1β protein expression. Additionally, the β2-integrin adhesion molecule, lymphocyte function-associated antigen-1 (LFA-1), a factor that influences the expression of the proinflammatory/anti-inflammatory cytokine network is upregulated. Here, we examine whether PAE increases the proinflammatory immune environment at specific anatomical sites critical in the pain pathway of chronic sciatic neuropathy; the damaged sciatic nerve (SCN), the dorsal root ganglia (DRG), and the spinal cord. Additionally, we examine whether inhibiting LFA-1 or IL-1β actions in the spinal cord (intrathecal; i.t., route) could alleviate chronic neuropathic pain and reduce spinal and DRG glial activation markers, proinflammatory cytokines, and elevate anti-inflammatory cytokines. Results show that blocking the actions of spinal LFA-1 using BIRT-377 abolishes allodynia in PAE rats with sciatic neuropathy (CCI) of a 10 or 28-day duration. This effect is observed (utilizing immunohistochemistry; IHC, with microscopy analysis and protein quantification) in parallel with reduced spinal glial activation, IL-1β and TNFα expression. DRG from PAE rats with neuropathy reveal significant increases in satellite glial activation and IL-1β, while IL-10 immunoreactivity is reduced by half in PAE rats under basal and neuropathic conditions. Further, blocking spinal IL-1β with i.t. IL-1RA transiently abolishes allodynia in PAE rats, suggesting that IL-1β is in part, necessary for the susceptibility of adult-onset peripheral neuropathy caused by PAE. Chemokine mRNA analyses from SCN, DRG and spinal cord reveal that increased CCL2 occurs following CCI injury regardless of PAE and BIRT-377 treatment. These data demonstrate that PAE creates dysregulated proinflammatory IL-1β and TNFα /IL-10 responses to minor injury in the sciatic-DRG-spinal pain pathway. PAE creates a risk for developing peripheral neuropathies, and LFA-1 may be a novel therapeutic target for controlling dysregulated neuroimmune actions as a consequence of PAE.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Targeting the β2-integrin LFA-1, reduces adverse neuroimmune actions in neuropathic susceptibility caused by prenatal alcohol exposure

Sanchez

Noor

et al. 2019

acta neuropathol commun

View full text Add to dashboard Cite

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“…Additionally, modulation of GJA1–20k expression has been reported during pathological stressors, including chemically induced hypoxia and cardiac ischemia (Basheer et al, 2018; Basheer et al, 2017; Ul-Hussain et al, 2014). The GJA1–20k fragment was also found in a model of fetal alcohol spectrum disorder (FASD) (Ramani et al, 2016). Although some signaling pathways have been implicated, the cellular mechanisms regulating changes in Gja1 translation are unknown.…”

Section: Introductionmentioning

confidence: 96%

Dynamic UTR Usage Regulates Alternative Translation to Modulate Gap Junction Formation during Stress and Aging

et al. 2019

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“…Gap junction (GJ)-mediated coupling occurs among satellite glial cells and is facilitated by GJ proteins composed of two hemichannels (HC), including connexins (Cx), pannexin (Px) and innexin (Inx) ( 4 , 5 ). Previous studies have indicated that Px1 affects the activation of astrocytes by regulating the release of ATP and the flow of calcium ( 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

Carbenoxolone has the potential to ameliorate acute incision pain in rats

2021

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Carbenoxolone (CBX) is primarily used to relieve various types of neuropathic and inflammatory pain. However, little is known concerning the role of CBX in acute pain and its functional mechanisms therein and this was investigated in the present study. Rats underwent toe incision and behavioral tests were performed to assess mechanical hypersensitivity. The expression levels of pannexin 1 (Px1) and connexin 43 (Cx43) were detected using western blot analysis 2, 4, 6 or 24 h after toe incision, and the expression of TNF-α, IL-1β and P substance (SP) was determined by ELISA; Px1 and Cx43 expression was also examined by immunofluorescence staining. At 2, 6 and 12 h post-toe incision, the postoperative pain threshold was significantly reduced, which was subsequently recovered at 2 and 6 h post-surgery following pretreatment with CBX or pannexin 1 mimetic inhibitory peptide. CBX reduced Px1 levels at 4 and 24 h post-incision. However, Cx43 levels were reduced by CBX as little as 2 h post-surgery. Furthermore, CBX not only distinctly decreased the levels of Px1 and Cx43, but also reduced the co-localization of Px1 or Cx43 with glial fibrillary acidic protein, 2 h after incision. It was also observed that the protein levels of inflammatory makers (IL-1β, SP and TNF-α) showed a tendency to decline at 2, 4, 6 and 24 h after incision. Collectively, the expression of Px1 and Cx43 in astrocytes may be involved in pain behaviors diminished by CBX, and CBX potentially reduces acute pain by decreasing Px1 and Cx43 levels. Px1 and Cx43 from spinal astrocytes may serve important roles in the early stages and maintenance of acute pain, while preoperative injection of CBX has the potential to relieve hyperalgesia.

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Differential expression of astrocytic connexins in a mouse model of prenatal alcohol exposure

Cited by 8 publications

References 60 publications

Targeting the β2-integrin LFA-1, reduces adverse neuroimmune actions in neuropathic susceptibility caused by prenatal alcohol exposure

Targeting the β2-integrin LFA-1, reduces adverse neuroimmune actions in neuropathic susceptibility caused by prenatal alcohol exposure

Dynamic UTR Usage Regulates Alternative Translation to Modulate Gap Junction Formation during Stress and Aging

Carbenoxolone has the potential to ameliorate acute incision pain in rats

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