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Neuroinflammatory Mechanisms of Post-Traumatic Epilepsy

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Neuroinflammatory Mechanisms of Post-Traumatic Epilepsy Mukherjee et al. Journal of Neuroinflammation (2020) 17:193 https://doi.org/10.1186/s12974-020-01854-w REVIEW Open Access Neuroinflammatory mechanisms of post- traumatic epilepsy Sanjib Mukherjee1†, Gabriel M. Arisi2*†, Kaley Mims3, Gabriela Hollingsworth3, Katherine O’Neil3 and Lee A. Shapiro1* Abstract Background: Traumatic brain injury (TBI) occurs in as many as 64–74 million people worldwide each year and often results in one or more post-traumatic syndromes, including depression, cognitive, emotional, and behavioral deficits. TBI can also increase seizure susceptibility, as well as increase the incidence of epilepsy, a phenomenon known as post-traumatic epilepsy (PTE). Injury type and severity appear to partially predict PTE susceptibility. However, a complete mechanistic understanding of risk factors for PTE is incomplete. Main body: From the earliest days of modern neuroscience, to the present day, accumulating evidence supports a significant role for neuroinflammation in the post-traumatic epileptogenic progression. Notably, substantial evidence indicates a role for astrocytes, microglia, chemokines, and cytokines in PTE progression. Although each of these mechanistic components is discussed in separate sections, it is highly likely that it is the totality of cellular and neuroinflammatory interactions that ultimately contribute to the epileptogenic progression following TBI. Conclusion: This comprehensive review focuses on the neuroinflammatory milieu and explores putative mechanisms involved in the epileptogenic progression from TBI to increased seizure-susceptibility and the development of PTE. Keywords: Traumatic brain injury, TBI, Astrocytes, Microglia, Cytokines, Chemokines, Epileptogenesis, Inflammation Introduction are lacking, as is a clear mechanistic understanding of Traumatic brain injury (TBI) occurs in as many as 64-74 the epileptogenic factors that may contribute to the on- million people worldwide each year [1]. TBI severity set of PTE. ranges from mild to severe, and may cause post- While injury type and severity appear to partially pre- traumatic syndromes, including depression, cognitive, dict PTE susceptibility, similar injuries in people do not emotional, and behavioral deficits. TBI may also cause always cause PTE [2]. Lesion location may influence the post-traumatic seizures (PTS), increase seizure risk of PTE, as temporal lobe lesions following TBI are susceptibility and increase the incidence of epilepsy, a related to both a high incidence of early seizures and phenomenon known as post-traumatic epilepsy (PTE). longitudinal development of PTE [3]. Penetrating lesions Despite intensive research, biomarkers and treatments in motor areas and the parietal lobe are also associated with an increased risk of PTE [4]. Importantly, some risk factors have been suggested to be neuropathologically * Correspondence: [email protected]; [email protected] †Sanjib Mukherjee and Gabriel M. Arisi contributed equally to this work. relevant in PTE development in humans, such as age, 2Department of Physiology, Federal University of Sao Paulo – Escola Paulista early seizures after TBI, and trauma severity [5]. de Medicina, Sao Paulo, Brazil Following TBI, a neuroinflammatory response is rap- 1Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA idly initiated and mounting evidence from human and Full list of author information is available at the end of the article animal studies support a pro-epileptogenic role of the © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mukherjee et al. Journal of Neuroinflammation (2020) 17:193 Page 2 of 11 neuroinflammatory response in the development of PTE seizure medications like levetiracetam and phenytoin [6]. In general, following TBI, there is a rapid release of [32], such treatments do not necessarily ameliorate the inflammatory cytokines, chemokines and complement risk to develop PTE [33, 34]. Recurrent spontaneous sei- proteins. This immune response signals a variety of zures that define PTE are resistant to anti-epileptic treat- cellular mediators and also can initiate the acute phase ments in about one-third of patients [34–36], and the response [7–13]. Following these signals, astrocytes and side-effects from anti-epileptic drugs are found to be resident microglial cells are induced to become acti- more severe in PTE patients [37]. Thus, understanding vated, proliferate, and migrate to the injury site [14, 15]. the pro-epileptogenic mechanisms of TBI is vital for the Peripheral immune cells are also described to infiltrate diagnosis and treatment of PTE and for improving into the brain in response to TBI. Once this immune/ quality-of-life measures in these patients. neuroimmune response is activated to re-establish tissue homeostasis, these immune cells remove debris and Astrocytes and PTE: support cell, inflammatory identify potentially pathogenic signaling. Interestingly, mediator, or pathological nexus? while the most intense neuroinflammatory response Transformative studies have re-defined the classical role occurs relatively early (within hours and days after the of astrocytes in the brain. Astrocytes were initially con- injury), a low-level of neuroinflammation often chronic- sidered to be primarily support cells [38], sub serving ally persists [14, 16–20]. Both the acute/early and the neuronal function and helping to maintain brain homeo- chronic neuroinflammation have been implicated in stasis. Although there was early recognition of the role epileptogenesis, and herein, the evidence for pro- of astrocytes in the response to injury [21], in the de- epileptogenic contributions of neuroinflammation will cades since, the extensive roles that astrocytes play in be reviewed. the pathogenic inflammatory response continues to be Some of the earliest neuropathological reports recog- appreciated and explored [39]. Thus, it is abundantly nized that a progressive gliosis at the site of a brain clear, that far from their classification as merely support injury was a major component of the development of an cells, astrocytes are actively and directly involved in mul- epileptogenic focus [4, 21]. Accumulating evidence con- tiple aspects of neuronal function. tinues to support glial scarring and other neuroinflam- Astrocytes are the most abundant cell type in the brain matory mechanisms in PTE. In 2004, the founding of [40] and are now known to be involved in regulating ion the Journal of Neuroinflammation by Drs. Sue T. Griffin homeostasis, maintaining blood-brain barrier function, and Robert E. Mrak, provided a platform that sparked a metabolizing neurotransmitters, as well as providing reinvigorated focus on mechanisms of neuroinflamma- nutrient and energy support for neuronal function. tion in neuropathological disorders. To pay tribute to Astrocytes are key components in learning and memory, Dr. Mrak’s role in ushering in a new era of neuroscience, sleep, and other fundamental brain functions [41, 42] an overarching review of neuroinflammation following and are important components of the neuroinflamma- TBI is discussed, with a specific focus on neuroinflam- tory response. matory mechanisms that can promote seizures, epilepto- Astrocytes play a key role in regulating neuronal activ- genesis and the development of PTE. ity, energizing neuronal metabolism by exchanging neur- onal pyruvate for astrocytic lactate, and increasing Etiology and incidence of PTE NADH levels in neurons [43]. Astrocytes are active in The incidence of epilepsy is estimated to be approxi- neuronal information processing, and their processes en- mately 0.5–2% of the general population. This incidence velop thousands of synapses to control neuronal activity rate increases to approximately 5–7% in patients who through neurotransmitter uptake and release [41, 42]. experienced a precipitating head injury [22–24] and/or Astrocytes also regulate the availability of glutamate and have been hospitalized for TBI [2, 25, 26]. A greater in- GABA in the synaptic cleft, thereby modulating synaptic jury severity has been correlated with a higher PTE risk transmission [44–46]. Thus, there are numerous [27], and this risk increases up to 10-fold in military pa- mechanisms by which astrocytes might contribute to tients with penetrating head wounds. At the extreme, post-traumatic epileptogenesis. Here, we focus on those some estimates have suggested that the incidence of mechanisms that are related to neuroinflammation.
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