Ifeoma Mbue

Background: Traumatic Brain Injury (TBI) is defined as an injury caused by an external force.¹ The force can be mechanical, chemical, thermal, or electrical energy.¹ Traumatic brain injuries can be divided into two parts: primary injury and secondary injury. Primary injuries are the initial external force injury and secondary injuries are the changes in the brain after the injury i.e. neurotransmitter metabolism, inflammation, etc.¹ Prolonged secondary damage through glial cells, like astrocytes, plays a significant role in the development and progression of abnormal brain excitability/post-traumatic epilepsy.⁴ Normally, astrocytes clean up excess neurotransmitters, promote synapse formation & maintain the blood brain barrier. ⁵ Though, during a TBI, they become reactive and alter their gene expression by upregulating genes supporting inflammation, early response modifiers, and neuropeptide-amidating enzymes.⁶ They also release proinflammatory cytokines that promote the formation of epileptic networks. ⁶ Studies have seen that alterations in astrocytes contribute to the development of post-traumatic seizures and can be a good source for therapeutic options.

Objective: In this narrative review, we explored reactive astrocytes and how their alterations contribute to the development of post-traumatic seizures and can be a good source for therapeutic options.

Search Methods: An online search in the PubMed database was conducted from 2019-2024 using the following keywords: “astrocytes,” “abnormal brain excitability,” “post-traumatic epilepsy,” “reactive astrocytes.”

Results: A study found that mice that underwent a diffuse TBI had downregulation of essential proteins like GFAP which impaired homeostatic function and possibly initiated their epilepsy.⁵ This further confirmed that in different types of traumatic brain injury, reactive astrocytes are seen to contribute to post-traumatic epilepsy.⁵ miR155 & miR142 are microRNAs that are usually involved in regulating brain inflammation.⁸ miR155 was highly expressed in astrocytes in rat & human brains that underwent a TBI.  When astrocytes were incubated with a pro-inflammatory medium that overexpressed miR142, it further stimulated a proinflammatory state in the astrocytes by increasing the expression of miR155. Rats that underwent a TBI had increased expression of cleaved caspase-3 and apoptosis-related proteins. These apoptotic proteins were co-localized with AATF, a transcription factor that normally provides a cytoprotective response to apoptosis.⁷ AATF was highly expressed in astrocytes which further confirmed astrocytes role in post-traumatic epilepsy.⁷ For mice that underwent a TBI and developed post-traumatic epilepsy, they had an upregulation in genes typical of gliogenesis and glial development & differentiation, inflammation, and epileptogenesis.⁶ Pharmacological intervention using PP-4one demonstrated efficiency in reducing seizures in the rat model of PTE by suppressing astrocyte proliferation.⁹

Conclusions: Understanding the role of astrocytes in PTE is essential because of its involvement in maintaining the blood brain barrier. Prolonged atypical astrocytic response may be contributed by promoting apoptosis through AATF, and promoting inflammation through expression of miRNA 155 & 142.⁸ Analyzing transcriptional alterations in astrocytes provides an insight into what genes are turned on and promote PTE.⁶ AATF inhibition & PP-4one are great therapeutic targets to reduce astrocytic activation and therefore decrease abnormal brain excitability.^7,9

Works Cited:

1. Baracaldo-Santamaría D, Ariza-Salamanca DF, Corrales-Hernández MG, Pachón-Londoño MJ, Hernandez-Duarte I, Calderon-Ospina CA. Revisiting Excitotoxicity in Traumatic Brain Injury: From Bench to Bedside. Pharmaceutics. 2022;14(1):152. Published 2022 Jan 8. doi:10.3390/pharmaceutics14010152
2. Maas AIR, Menon DK, Manley GT, et al. Traumatic brain injury: progress and challenges in prevention, clinical care, and research. Lancet Neurol. 2022;21(11):1004-1060. Published Sep 29. doi:10.1016/S1474-4422(22)00309-X
3. Ladak AA, Enam SA, Ibrahim MT. A review of the molecular mechanisms of traumatic brain injury. World Neurosurgery. 2019;131:126-132. Published November 2019. doi:10.1016/j.wneu.2019.07.039
4. Doğanyiğit Z, Erbakan K, Akyuz E, Polat AK, Arulsamy A, Shaikh MohdF. The role of neuroinflammatory mediators in the pathogenesis of traumatic brain injury: a narrative review. ACS Chem Neurosci. 2022;13(13):1835-1848. Published 2022 June 22. doi:10.1021/acschemneuro.2c00196
5. Shandra O, Winemiller AR, Heithoff BP, et al. Repetitive Diffuse Mild Traumatic Brain Injury Causes an Atypical Astrocyte Response and Spontaneous Recurrent Seizures. J Neurosci. 2019;39(10):1944-1963. doi:10.1523/JNEUROSCI.1067-18.2018
6. Leonard J, Wei X, Browning J, et al. Transcriptomic alterations in cortical astrocytes following the development of post-traumatic epilepsy. Sci Rep. 2024;14(1):8367. Published 2024 Apr 10. doi:10.1038/s41598-024-58904-z
7. Wang W, Ma YM, Jiang ZL, Gao ZW, Chen WG. Apoptosis-antagonizing transcription factor is involved in rat post-traumatic epilepsy pathogenesis. Exp Ther Med. 2021;21(4):290. doi:10.3892/etm.2021.9721
8. Korotkov A, Puhakka N, Gupta SD, et al. Increased expression of miR142 and miR155 in glial and immune cells after traumatic brain injury may contribute to neuroinflammation via astrocyte activation. Brain Pathol. 2020;30(5):897-912. doi:10.1111/bpa.12865
9. Jin J, Shen X, Tian L, He G, Zhang Y. Pyrazolo[4,3-c]pyridine-4-one (PP-4-one) Exhibits Anti-Epileptogenic Effect in Rat Model of Traumatic Epilepsy by Mammalian Target of Rapamycin (mTOR) Signaling Pathway Downregulation. Med Sci Monit. 2020;26:e923919. Published 2020 Jul 20. doi:10.12659/MSM.923919