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

Abstract

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.

Modulation of Microglia Polarization through Silencing of NF-κB p65 by Functionalized Curdlan Nanoparticle-Mediated RNAi

“…Most reports administered siRNAs prior to the ischemic event, through local injection in the intracerebral cortex and lateral ventricle or intranasal administration using a commercial transfection reagent. SiRNA administration after ischemia or traumatic brain injury was also reported. − However, those research studies used invasive intracranial injection using a commercial transfection reagent. Although the beneficial effect of siRNA drugs in brain injury has been proved by these research studies, a targeted systemic siRNA delivery system is urgently needed for noninvasive delivery of siRNAs to a specific cell type in brain.…”

VISSA-PLS-DA-Based Metabolomics Reveals a Multitargeted Mechanism of Traditional Chinese Medicine for Traumatic Brain Injury

“…Survivors of TBI commonly live with neurocognitive deficits and physical disability and increased risk of neurodegenerative disease in the long term (Pattinson and Gill, 2018). Unfortunately, no drug has been approved in Phase III of clinical trials for treating TBI (Stocchetti et al., 2015) because of complex pathogenesis, such as burst reactive oxygen species, increased glutamate levels, destroyed blood–brain barrier (BBB), uncontrolled neuroinflammation, and obliterated synapse (Li et al., 2018; Ma et al., 2018; Ichkova et al., 2019). Thus, the consensus of multitarget intervention was formed as its therapeutic principle.…”

Do astrocytes act as immune cells after pediatric TBI?

“…Juvenile animals in moderate/severe CCI or FPI models present with neuronal tissue loss in cortex, corpus callosum, hippocampus and thalamus ( Delage et al, 2021 ). These anatomical changes result in long-term consequences on both motor and cognitive functions ( Giza et al, 2005 ; Ajao et al, 2012 ; Kamper et al, 2013 ; Ichkova et al, 2019 ). Recently, we developed a pediatric closed-head injuiy with long-term disorders (CHILD) model ( Fig.…”

“…Astrocytes exhibit significant GFAP-positive phenotypic changes post-injury in various preclinical pediatric TBI models ( Adelson et al, 2001 ; Clément et al, 2020 ; Fletcher et al, 2021 ; Huh et al, 2007 ; Huh et al, 2008 ; Ichkova et al, 2019 , 2020 ; Pop et al, 2013 ; Prins et al, 2010 ; Robinson et al, 2016 ; Rodriguez-Grande et al, 2018 ; Russell et al, 2014 ; Schober et al, 2019 . Table 1 lists studies focusing on astrocytic responses to TBI in pediatric preclinical models ( Fig.…”