Neuroinflammatory Pathways and the Blood–Brain Barrier Interface in Post-Traumatic Epileptogenesis Following Moderate to Severe TBI
Keywords:
Traumatic Brain Injury, Post-Traumatic Epilepsy, Blood–Brain Barrier, Neuroinflammation, Epileptogenesis, Cytokines, Glial ActivationAbstract
Traumatic brain injury (TBI), particularly of moderate to severe intensity, is a major risk factor for the development of post-traumatic epilepsy (PTE), a condition characterized by recurrent unprovoked seizures that arise months or years after the initial injury. The pathophysiological mechanisms underlying this latency period remain elusive but are increasingly attributed to neuroinflammatory cascades and dysfunction of the blood–brain barrier (BBB). In this review, we analyze how neuroinflammatory responses interact with the BBB to contribute to epileptogenesis, integrating evidence from clinical, preclinical, and in vitro studies. We examine molecular mediators including cytokines, chemokines, and glial cell activation, and their influence on BBB permeability, ion homeostasis, and network hyperexcitability. This work highlights key gaps in the current literature and proposes future research directions targeting immune-BBB crosstalk as a therapeutic window for preventing epileptogenesis.
References
[1] Cacheaux, L. P., Ivens, S., David, Y., Lakhter, A. J., Bar-Klein, G., Shapira, M., Heinemann, U., Friedman, A., & Kaufer, D. "Transcriptome Profiling Reveals TGF-β Signaling Involvement in Epileptogenesis." Journal of Neuroscience, vol. 29, no. 28, 2009, pp. 8927–8935.
[2] Gorter, J. A., Iyer, A., & White, A. M. "Matrix Metalloproteinases in Epilepsy: Functional Roles and Therapeutic Implications." Neurobiology of Disease, vol. 75, 2015, pp. 14–24.
[3] Maroso, M., Balosso, S., Ravizza, T., Liu, J., Aronica, E., Iyer, A. M., Balestra, M., Bartfai, T., Aguzzi, A., Vezzani, A. "Toll-like Receptor 4 and High-Mobility Group Box-1 Are Involved in Ictogenesis and Can Be Targeted to Reduce Seizures." Nature Medicine, vol. 16, no. 4, 2010, pp. 413–419.
[4] Pitkänen, A., Engel, J., Jr., Pastell, J., Rethinasamy, M., & Löscher, W. "Roadmap for Antiepileptogenesis Research in the Post-Traumatic Epilepsy Model." Epilepsia, vol. 57, 2016, pp. 1–27.
[5] Riazi, K., Galic, M. A., Kentner, A. C., Reid, A. Y., Sharkey, K. A., & Pittman, Q. J. "Microglia-Dependent and -Independent Effects of LPS-Induced Systemic Inflammation on Hippocampal Synaptic Plasticity." Journal of Neuroscience, vol. 30, no. 46, 2010, pp. 15412–15423.
[6] Semple, B. D., Bye, N., Rancan, M., Ziebell, J. M., & Morganti-Kossmann, M. C. "Role of CCL2 (MCP-1) in Traumatic Brain Injury (TBI): Evidence from Clinical and Preclinical Studies." Journal of Cerebral Blood Flow & Metabolism, vol. 30, no. 5, 2010, pp. 769–782.
[7] Vezzani, A., Aronica, E., Ravizza, T., & Pittman, Q. J. "Epilepsy and Brain Inflammation in Disease Pathogenesis and Therapy." Nature Reviews Neurology, vol. 9, no. 5, 2013, pp. 263–275.
[8] Vezzani, A., Balosso, S., & Ravizza, T. "The Role of Cytokines in the Pathophysiology of Epilepsy." Brain, Behavior, and Immunity, vol. 25, no. 6, 2011, pp. 1126–1137.
[9] Vezzani, A., French, J., Bartfai, T., & Baram, T. Z. "The Role of Inflammation in Epilepsy." Nature Reviews Neurology, vol. 7, no. 1, 2011, pp. 31–40.
[10] Zetterberg, H., Smith, D. H., & Blennow, K. "Biomarkers of Mild Traumatic Brain Injury in Cerebrospinal Fluid and Blood." Nature Reviews Neurology, vol. 9, no. 4, 2013, pp. 201–210.
[11] Balosso, S., Liu, J., Bianchi, M. E., & Vezzani, A. "Disulfide HMGB1 Inhibits NMDA Receptors via a TLR4-Dependent Mechanism and Protects Against Seizures Induced by Kainic Acid in Mice." Neurobiology of Disease, vol. 69, 2014, pp. 117–123.
[12] Bar-Klein, G., Cacheaux, L. P., Kamintsky, L., Prager, O., Weissberg, I., Schoknecht, K., David, Y., Gidon, A., Friedman, A., & Kaufer, D. "Losartan Prevents Acquired Epileptogenesis in a Rat Model of Cerebral Blood–Brain Barrier Dysfunction." Annals of Neurology, vol. 75, no. 4, 2014, pp. 550–561.
