Elias Perli

Introduction: Traumatic Brain Injury (TBI) is a change in normal brain function caused by an external insult. More than 3 million people in the United States suffer a TBI annually, accounting for around 300,000 hospitalizations and 50,000 fatalities per year.^1,4 One notable sequela of TBI is Posttraumatic Epilepsy (PTE). PTE is a neurological disorder where late spontaneous recurrent seizures develop following a TBI. Epileptogenesis may begin after the TBI and become suppressed months/years after the brain insult occurred; potentially delaying diagnosis of PTE after the primary brain trauma. PTEs make up around 20% of symptomatic epilepsies, and 5-6% of all epilepsies in general.^2,4 Current long-term PTE treatment is limited to the acute use of antiepileptic drugs (AEDs), prompting the need to investigate non-neuronal targets/mechanisms other than ion channels, such as: microglia, enzymes, oxidative stress molecules, and genetics.⁶ Novel research has shown microglial polarization plays a crucial role in neuroinflammation, as seen in PTE, and it may present a new therapeutic target on PTE’s chronic inflammation and long-term treatment.¹ Methods: literature-review study conducted by collecting data from PubMed using the MeSH Database to look for articles in the field of PTE due to TBI. Research articles were filtered to exclusively include those published in the last five years, and our research comprised a total of six basic science/translational research articles, five review articles, and two clinical research studies. Results: different mice studies showed that microglial depletion prevents inflammatory and neuropathology-associated gene expression at subacute and chronic time points after injury, while acute changes were microglia independent.¹ Inhibition and deletion of NOX2 diminishes the M1 (pro-inflammatory) phenotype while increasing the M2 (anti-inflammatory) phenotype of microglia.⁷ Resveratrol promotes M2 polarization by knocking down PGC-1a and coactivation of the STAT6 and STAT3 pathways.⁸ Rosiglitazone-induces PPAR-gamma activation and promoted microglia polarization to the M2 phenotype, reducing the inflammatory response, attenuating axonal injury and improving neurological function.⁹ Conclusions: Studies have shown that chronic disruption of microglial homeostasis may underlie neurodegenerative diseases following TBI and is linked to development of PTE.  Post-injury, microglia can be polarized into two major phenotypes: proinflammatory (M1) and anti-inflammatory (M2) phenotype. Current management of PTE due to TBI focuses on preventing signs of secondary injury, and there exists mixed consensus on the use of AEDs. Studying microglial polarization in neuroinflammation could provide new treatments oriented toward the expression of M2 microglial phenotype to improve PTE’s long-term effects.

1. Witcher KG, Bray CE, Chunchai T, Zhao F, O’Neil SM, Gordillo AJ, Campbell WA, McKim DB, Liu X, Dziabis JE, Quan N, Eiferman DS, Fischer AJ, Kokiko-Cochran ON, Askwith C, Godbout JP. Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia. J Neurosci. 2021 Feb 17;41(7):1597-1616. doi: 10.1523/JNEUROSCI.2469-20.2020. Epub 2021 Jan 15. PMID: 33452227; PMCID: PMC7896020. (Primary Article)
2. SzuJI, Patel DD, Chaturvedi S, Lovelace JW, Binder DK. Modulation of posttraumatic epileptogenesis in aquaporin-4 knockout mice. Epilepsia. 2020;61:1503–1514. https://doi.org/10.1111/ epi.16551.
3. Therajaran P, Hamilton JA, O’Brien TJ, Jones NC, Ali I. Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity. Epilepsia. 2020;61:203–215.
4. Xu T, Yu X, Ou S, Liu X, Yuan J, Huang H, Yang J, He L, Chen Y. Risk factors for posttraumatic epilepsy: A systematic review and meta-analysis. Epilepsy Behav. 2017 Feb;67:1-6. doi: 10.1016/j.yebeh.2016.10.026. Epub 2017 Jan 8. PMID: 28076834.
5. Symonds, Joseph D.a,b; Zuberi, Sameer M.a,b; Johnson, Michael R.c Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment, Current Opinion in Neurology: April 2017 – Volume 30 – Issue 2 – p 193-199 doi: 10.1097/WCO.0000000000000433.
6. Sharma S, Tiarks G, Haight J and Bassuk AG (2021) Neuropathophysiological Mechanisms and Treatment Strategies for Post-traumatic Epilepsy. Front. Mol. Neurosci. 14:612073. doi: 10.3389/fnmol.2021.612073.
7. Wang J, Ma MW, Dhandapani KM, Brann DW. Regulatory role of NADPH oxidase 2 in the polarization dynamics and neurotoxicity of microglia/macrophages after traumatic brain injury. Free Radic Biol Med. 2017 Dec;113:119-131. doi: 10.1016/j.freeradbiomed.2017.09.017. Epub 2017 Sep 21. PMID: 28942245.
8. Yang X, Xu S, Qian Y, Xiao Q. Resveratrol regulates microglia M1/M2 polarization via PGC-1α in conditions of neuroinflammatory injury. Brain Behav Immun. 2017 Aug;64:162-172. doi: 10.1016/j.bbi.2017.03.003. Epub 2017 Mar 6. PMID: 28268115.
9. Wen L, You W, Wang H, Meng Y, Feng J, Yang X. Polarization of Microglia to the M2 Phenotype in a Peroxisome Proliferator-Activated Receptor Gamma-Dependent Manner Attenuates Axonal Injury Induced by Traumatic Brain Injury in Mice. J Neurotrauma. 2018 Oct 1;35(19):2330-2340. doi: 10.1089/neu.2017.5540. Epub 2018 Jun 7. PMID: 29649924.