Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions

Abstract

Studying the complex molecular mechanisms involved in traumatic brain injury (TBI) is crucial for developing new therapies for TBI. Current treatments for TBI are primarily focused on patient stabilization and symptom mitigation. However, the field lacks defined therapies to prevent cell death, oxidative stress, and inflammatory cascades which lead to chronic pathology. Little can be done to treat the mechanical damage that occurs during the primary insult of a TBI; however, secondary injury mechanisms, such as inflammation, blood-brain barrier (BBB) breakdown, edema formation, excitotoxicity, oxidative stress, and cell death, can be targeted by therapeutic interventions. Elucidating the many mechanisms underlying secondary injury and studying targets of neuroprotective therapeutic agents is critical for developing new treatments. Therefore, we present a review on the molecular events following TBI from inflammation to programmed cell death and discuss current research and the latest therapeutic strategies to help understand TBI-mediated secondary injury.

Gene Expression Signature of Traumatic Brain Injury

“…Unlike our analysis, effector memory T cells (Tem) populations were up-regulated in TBI (Ritzel et al, 2018 ). Immune responses in TBI are now considered both damaging and beneficial (Jarrahi et al, 2020 ). If regulated, the traumatized brain can benefit from inflammation.…”

Neuropathophysiological Mechanisms and Treatment Strategies for Post-traumatic Epilepsy

“…This resulting ionic imbalance depolarizes the postsynaptic cell membrane, causing a long-lasting increase in excitatory post-synaptic potential. Altered calcium signaling after TBI activates nitric oxide synthase (NOS), proteases, and lipases that trigger cell signaling cascades linked to excitotoxicity and cell death ( Weber, 2012 ; Jarrahi et al, 2020 ). Elevations in nitric oxide (NO) levels interferes with mitochondrial bioenergetics leading to energy depletion, further adding oxidative stress in neurons.…”

“…Dysfunctional endothelial cell signaling and activation of the immune cell response stimulates the release of proinflammatory mediators, such as ROS, matrix metalloproteinases (MMPs), bradykinins, prostaglandins, cytokines, tachykinins, and excitatory amino acids ( Paudel et al, 2019 ). The formation of intercellular adhesion molecule 1 and vascular cell adhesion protein 1/ERM complex with integrin, via Rac1, releases NADPH oxidase (enzyme involved in oxidative stress) in the endothelial cells generating ROS ( Cerutti and Ridley, 2017 ; Jarrahi et al, 2020 ). Elevations in ROS levels stimulate the release of MMP-2 and 9 causing damage to tight and gap junction proteins such as occludins, claudins and connexin-43.…”

“…Elevations in ROS levels stimulate the release of MMP-2 and 9 causing damage to tight and gap junction proteins such as occludins, claudins and connexin-43. A further rise in oxidative stress activates focal adhesion kinase, a non-receptor tyrosine kinase, and heat-shock protein 27, that results in receptor endocytosis and stress fiber formation within the cell ( Hemphill et al, 2011 ; Cerutti and Ridley, 2017 ; Jarrahi et al, 2020 ). In addition, vascular endothelial growth factor stimulated increase in Src increases phosphorylation of VE-cadherins via serine/threonine-protein kinase, which results in receptor endocytosis.…”

Effects of Memantine in Patients with Traumatic Brain Injury: A Systematic Review

“…Memantine was not only neuroprotective in animal models of cerebral and spinal cord ischemia but also in models of TBI [23][24][25][26][27][28][29][30][31]. Studies have also shown that blocking NMDAR function with antagonists such as amantadine, improve cognitive outcomes after mild TBI [32,33].…”