(M-517) Inhibition of p38 MAPK Phosphor-signaling Ameliorates Cytokine Correlated Depressive-like Behavioral Induced by Repetitive Mild Traumatic Brain Injury

Introduction:: Background and Introduction: Post-concussion syndrome associated with long-term functional impairments (i.e., depression, anxiety) is observed frequently among patients who experienced mild traumatic brain injury (mTBI). Moreover, repetitive injuries within the “window of vulnerability” leads to exacerbated consequences compared to a single mTBI. Increasing evidence suggests that brain inflammatory processes consisting of phospho-signaling pathways mediate functional consequences experienced by patients with mTBI. We previously reported that phosphorylation of the pro-inflammatory signaling molecule p38 MAPK was linked to worse functional outcomes following a weight-drop mouse model of repetitive mTBI. Given the close link between depression and multiple psychiatric and cognitive symptoms after mTBI, addressing depressive symptoms becomes a crucial therapeutic aspect for individuals with mTBI. As functional and pathological outcomes are closely associated, we hypothesized that acute inhibition of p38 MAPK phosphorylation will ameliorate depressive-like behavior in correlation with molecular markers of pathology in mice with repetitive mTBI.

Materials and Methods:: Materials and Methods: Adult male and female C57/BL6 mice were intraperitoneally injected with the p38 MAPK inhibitor SB239063 or vehicle 30-mins following each of the 5 once-daily weight-drop closed head injuries (CHIs) or sham injuries. Depressive-like behavior was evaluated by Tail Suspension Test (TST) within 4-weeks after the final CHI followed by brain tissue collection and Luminex multiplexed ELISA on bulk tissue samples for expression of 32 cytokines. GFAP is measured by sandwiched ELISA. All animal protocols were approved by the Institutional Animal Care and Use Committee from Emory University.


Results, Conclusions, and Discussions:: Results and Discussions: Our study demonstrated that rmTBI induced a significant increase in depressive-like behavior, as indicated by the significant elevation of the TST immobility time observed after five once-daily CHIs (5xCHI; 5xCHI + vehicle: 200.4 ± 28.6 vs sham + vehicle: 177.9 ± 13.0, t-test, p < 0.05). Such depressive-like behavior was ameliorated by acute inhibition of p38α/β phosphorylation via SB239063 (5xCHI + SB: 170.7 ± 28.5 vs 5xCHI + vehicle: 200.4 ± 28.6, t-test, p < 0.05); sham + SB: 156.5 ± 39.6 vs sham = vehicle: 177.9 ± 13.0, p = 0.13). To determine the combined effect of the drug on functional outcomes and markers of inflammation, we correlated cytokines with TST immobility time and GFAP expression from 5xCHI mice exposed to either vehicle or SB239063. Three of our cytokines (MIP-1a, VEGF, IL-2) were correlated with TST immobility time among the 5xCHI SB239063/vehicle group 4-weeks post final CHI (Pearson correlation, p < 0.05; Figure 1 a-b). Such correlations were not found among the sham injury SB239063/vehicle group (Pearson correlation, MIP-1a: p = 0.86, VEGF: p = 0.89, IL-2: p = 0.76; Figure 1 b) Notably, all three of these cytokines were also significantly correlated with cortical GFAP expression 4-weeks post final CHI among the 5xCHI SB239063/vehicle group (Pearson correlation, p< 0.05), suggesting a potential mechanism underlying rmTBI-induced depressive-like behavior involving p38 MAPK phosphorylation, cytokine expression, and astrocyte reactivity.



Conclusions: These findings demonstrate that transient inhibition of p38 MAPK signaling can attenuate depressive-like behavior following mTBI. The observed correlation between cytokine expressions, astrocyte reactivity, and depressive-like behavior suggests a potential link between depressive-like behavior and brain immune signaling. Together, these data underscore the therapeutic potential of targeting the p38 MAPK signaling pathway for treating rmTBI-induced depression.




Acknowledgements (Optional): : Acknowledgment: This project was supported by the National Institutes of Health R01 NS115994

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