Successive traumatic brain injuries (TBIs) exacerbate neuroinflammation and oxidative stress. No therapeutics exist for populations at high risk of repetitive mild TBIs (rmTBIs). We explored the preventative therapeutic effects of Immunocal®, a cysteine-rich whey protein supplement and glutathione (GSH) precursor, following rmTBI and repetitive mild-moderate TBI (rmmTBI). Populations that suffer rmTBIs largely go undiagnosed and untreated; therefore, we first examined the potential therapeutic effect of Immunocal® long-term following rmTBI. Mice were treated with Immunocal®prior to, during, and following rmTBI induced by controlled cortical impact until analysis at 2 weeks, 2 months, and 6 months following the lastrmTBI. Astrogliosis and microgliosis were measured in cortex at each time point and edema and macrophage infiltration by MRI were analyzedat2 months post-rmTBI. Immunocal® significantly reduced astrogliosis at2 weeks and2 months post-rmTBI.Macrophage activation was observed at 2 months post-rmTBI but Immunocal® had no significant effect on this endpoint. We did not observesignificantmicrogliosis or edema after rmTBI.The dosing regimen was repeated in mice subjected to rmmTBI; however, using this experimental paradigm, we examined the preventative therapeutic effects of Immunocal® at a much earlier timepoint because populations that suffer more severe rmmTBIs are more likely to receive acute diagnosis and treatment. Increases in astrogliosis, microgliosis, and serum neurofilament light (NfL), as well as reductions in the GSH:GSSG ratio, were observed 72 hours post-rmmTBI. Immunocal® only significantly reduced microgliosis after rmmTBI. In summary, we report that astrogliosis persists for 2 months post-rmTBI and that inflammation, neuronal damage, and altered redox homeostasis present acutely following rmmTBI. Immunocal® significantly limited gliosis in these models; however, its neuroprotection was partially overwhelmed by repetitive injury. Treatments that modulate distinct aspects of TBI pathophysiology, used in combination with GSH precursors like Immunocal®, may show more protection in these repetitive TBI models.Copyright © 2023. Published by Elsevier B.V.
