Administration of all‐transretinoic acid after experimental traumatic brain injury is brain protective

Abstract

Background and Purpose: All-trans retinoic acid (ATRA) is a vitamin A metabolite, important in the developing and mature brain. Pre-injury ATRA administration ameliorates ischaemic brain insults in rodents. This study examined the effects of posttraumatic ATRA treatment in experimental traumatic brain injury (TBI). Experimental Approach: Male adult mice were subjected to the controlled cortical impact model of TBI or sham procedure and killed at 7 or 30 days post-injury (dpi). ATRA (10 mg kg−1, i.p.) was given immediately after the injury and 1, 2 and 3 dpi. Neurological function and sensorimotor coordination were evaluated. Brains were processed for (immuno-) histological, mRNA and protein analyses (qPCR and western blot). Key Results: ATRA treatment reduced brain lesion size, reactive astrogliosis and axonal injury at 7 dpi, and hippocampal granule cell layer (GCL) integrity was protected at 7 and 30 dpi, independent of cell proliferation in neurogenic niches and bloodbrain barrier damage. Neurological and motor deficits over time and the brain tissue loss at 30 dpi were not affected by ATRA treatment. ATRA decreased gene expression of markers for damage-associated molecular pattern (HMGB1), apoptosis (caspase-3 and Bax), activated microglia (TSPO), and reactive astrogliosis (GFAP, SerpinA3N) at 7 dpi and a subset of markers at 30 dpi (TSPO, GFAP). Conclusion and Implications: In experimental TBI, post-traumatic ATRA administration exerted brain protective effects, including long-term protection of GCL integrity, but did not affect neurological and motor deficits. Further investigations are required to optimize treatment regimens to enhance ATRA's brain protective effects and improve outcomes.

Pharmacologic Inhibition of ADAM10 Attenuates Brain Tissue Loss, Axonal Injury and Pro-inflammatory Gene Expression Following Traumatic Brain Injury in Mice

“…The CCI model was used to induce an experimental brain injury as described before ( Hummel et al, 2020 ). Briefly, after induction of anesthesia (isoflurane 4 Vol.%, maintenance 2.1 Vol.%) mice were attached to a stereotactic apparatus (Kopf Instruments) and a right parietal craniotomy was performed.…”

“…Behavioral tests were performed in a blinded and unbiased fashion 1 day before and 1 and 7 days after CCI using a neurological severity score (NSS). The NSS was modified from Tsenter et al (2008) and assesses the severity of neurological impairments ranging from 0 (no impairment) to 12, as described ( Hummel et al, 2020 ).…”

“…For immunoblotting, brain samples were collected during cryosectioning and homogenized in RIPA buffer and protein concentrations were determined by Lowry assay (BioRad). Immunoblotting and dot blot analysis were performed essentially as described ( Hummel et al, 2020 ). Briefly, 30 μg of protein for each sample was resolved by 10% SDS-PAGE.…”

“…Gene expression was quantified as outlined before ( Hummel et al, 2020 ). Briefly, RNA was extracted from brain tissue and reverse-transcribed into cDNA using RNeasy Kit and QuantiScript Reverse Transcription Kit (Qiagen), respectively.…”

“…Unfortunately, the pathophysiology of TBI is still incompletely understood and decades of animal research providing pharmacological targets for early therapeutic interventions have not been yet translated to the clinic. Given the complexity of TBI, the targeting of multiple secondary injury pathways has been proposed to better support neuronal survival and brain repair than targeting single factors ( Loane and Faden, 2010 ; Hummel et al, 2020 ). However, also the targeting of single factors can have profound implications when they are at the forefront of regulatory processes such as enzymes with a variety of substrates executing different biological effects.…”