Pediatric mild traumatic brain injury (mTBI) is a growing public health crisis, increasingly complicated by comorbidities such as high-fat diet (HFD) consumption, which can impair CNS health and exacerbate chronic mTBI outcomes. mTBI pathology involves a primary impact followed by a secondary injury phase characterized by neuroinflammation and cell death. As there are no approved pharmacotherapies for TBI, there is an urgent need to develop therapeutics that can mitigate the damaging effects of secondary injury. Nuclear factor kappa B (NF-kB) is a transcription factor implicated in adverse inflammatory states when upregulated following CNS injury. We developed a novel biologic, SynB1-ELP-p50i, which consists of an elastin-like polypeptide (ELP) carrier delivering a specific NF-kB inhibitor (p50i). SynB1-ELP-p50i acts by mimicking the NF-kB nuclear localization signal, preventing NF-kB transport to the nucleus. We hypothesized that SynB1-ELP-p50i would accumulate in the brain parenchyma at levels sufficient to inhibit NF-kB in vitro, reduce neuroinflammatory mRNA expression, and that administration of SynB1-ELP-p50i would improve cognitive deficits induced by mTBI. Long-Evans rats were assigned to normal diet or HFD groups at postnatal day 20 (PND20), and mTBI or sham injury was induced at PND30 using the translationally relevant CHIMERA TBI model. Rats received 50 milligrams/kilogram SynB1-ELP-p50i or saline post-injury. Behavioral outcomes were assessed with the Morris water maze (MWM), and neuroinflammatory markers were measured using RT-qPCR and single-nucleus RNA sequencing (snRNA-seq). Data were analyzed using two-way ANOVAs with Tukey’s post-hoc tests. Biodistribution experiments revealed that SynB1-ELP-p50i accumulated at injury sites (F(1, 25) = 8.151, p < 0.001), effectively exploiting mTBI-induced blood-brain barrier disruption. SynB1-ELP-p50i-treated chow-fed rats showed reduced spatial memory deficits compared to HFD subjects and vehicle controls 3 hours post injury (F(1, 26) = 5.862, p < 0.05). RT-qPCR confirmed increased expression of Aif1 (F(1,21) = 7.056, p < 0.05) and Gfap (F(1,21) = 13.36, p < 0.01) post-injury. These findings indicate that mTBI triggers acute cognitive deficits and neuroinflammation, pathologies that are exacerbated by HFD exposure. Crucially, SynB1-ELP-p50i accumulated in the brain following injury and mitigated acute memory deficits in chow-fed animals, supporting NF-κB inhibition as a promising therapeutic strategy for TBI. Ongoing studies are now assessing the viability of SynB1-ELP-p50i as a pharmacotherapy for severe TBI. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Haskell et al. (Fri,) studied this question.