The pathophysiology of TBI is complex and involves a cascade of events that occur at the cellular and molecular levels. The process can be broadly categorized into primary and secondary injury mechanisms.
Secondary damages are often linked to the molecular mechanisms that occur post-TBI and ensure excitotoxicity, neuroinflammation and cytokine damage, oxidative damage, and eventual cell death as prominent mechanisms of cell damage.
Nevertheless, the molecular mechanism of TBI remains undefined. Differentially expressed (DE) lncRNAs, DEmRNAs and DEmiRNAs were selected between human TBI tissues and the adjacent histologically normal tissue by high-throughput sequencing. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis of overlapping DEmRNAs between predicted mRNAs of DEmiRNAs and DEmRNAs. The competitive endogenous RNA (ceRNA) network of lncRNA-miRNA-mRNA was established in light of the ceRNA theory. In the ceRNA network, the key lncRNAs were screened out. Then key lncRNAs related ceRNA subnetwork was constructed. After that, qRT-PCR was applied to validate the expression levels of hub genes. 114 DElncRNAs, 1807 DEmRNAs and 6 DEmiRNAs were DE in TBI. The TBI-related ceRNA network was built with 73 lncRNA nodes, 81 mRNA nodes and 6 miRNAs. According to topological analysis, two hub lncRNAs (ENST00000562897 and ENST00000640877) were selected to construct the ceRNA subnetwork. Subsequently, key lncRNA-miRNA-mRNA regulatory axes constructed by two lncRNAs including ENST00000562897 and ENST00000640877, two miRNAs including miR-6721-5p and miR-129-1-3p, two mRNAs including ketohexokinase (KHK) and cyclic nucleotide-gated channel beta1 (CNGB1), were identified. Furthermore, qRT-PCR results displayed that the expression of ENST00000562897, KHK and CNGB1 were significantly decreased in TBI, while the miR-6721-5p expression levels were markedly increased in TBI. The results of our study reveal a new insight into understanding the ceRNA regulation mechanism in TBI and select key lncRNA-miRNA-mRNA axes for prevention and treatment of TBI 1)
Ladak et al. presented a review highlighting the relation of each of these mechanisms with TBI, their mode of damaging brain tissue, and therapeutic correlation. They also mentioned the long-term sequelae and their pathophysiology of TBI focusing on Parkinson's, Alzheimer's disease, Epilepsy, and Chronic Traumatic Encephalopathy. Understanding the molecular mechanisms is important to realize the secondary and long-term sequelae that follow primary TBI and devise targeted therapy for quick recovery accordingly 2).
White matter Injury is an important contributor to long-term motor and cognitive dysfunction after traumatic brain injury. During brain trauma, acceleration, deceleration, torsion, and compression forces often cause direct damage to the axon tracts, and pathways that are triggered by the initial injury can trigger molecular events that result in secondary axon degeneration. White matter injury is often associated with altered mental status, memory deficits, and motor or autonomic dysfunction, and contributes to the development of chronic neurodegenerative diseases. The presence and proper functioning of oligodendrocyte precursor cells offer the potential for repair and recovery of injured white matter. The process of the proliferation, and maturation of oligodendrocyte precursor cells and their migration to the site of injury to replace injured or lost oligodendrocytes is known as oligodendrogenesis 3).
Mechanical Injury: The initial impact can cause direct damage to the brain tissue, leading to contusions, lacerations, and/or diffuse axonal injury (damage to the brain's white matter tracts). Coup-Contrecoup Injury: This occurs when the force of impact causes the brain to move within the skull, resulting in injuries at both the site of impact (coup) and the opposite side of the brain (contrecoup). Secondary Injury Mechanisms:
Ischemia and Hypoxia: The initial trauma can disrupt blood flow and oxygen delivery to the brain, leading to ischemia (insufficient blood supply) and hypoxia (low oxygen levels), exacerbating cell damage. Inflammatory Response: TBI triggers an inflammatory response, involving the release of inflammatory mediators and immune cells. While inflammation is a natural part of the healing process, excessive or prolonged inflammation can contribute to further damage. Excitotoxicity: The release of neurotransmitters, particularly glutamate, increases after TBI. Excessive glutamate can lead to excitotoxicity, causing damage to neurons by overstimulating receptors and promoting cell death. Cellular Apoptosis and Necrosis: Both programmed cell death (apoptosis) and uncontrolled cell death (necrosis) can occur, contributing to the loss of neurons and disruption of brain function. Blood-Brain Barrier Disruption: TBI can compromise the integrity of the blood-brain barrier, allowing the entry of toxins and inflammatory cells into the brain, further contributing to damage. Cascading Effects:
Oxidative Stress: TBI induces an increase in reactive oxygen species (ROS), leading to oxidative stress. This oxidative damage can affect cellular structures and exacerbate injury. Mitochondrial Dysfunction: TBI disrupts mitochondrial function, impairing energy production and contributing to cell death. Neurotransmitter Imbalance: Changes in neurotransmitter levels, including dopamine and serotonin, can affect neuronal communication and contribute to TBI-related symptoms. Understanding the pathophysiology of traumatic brain injury is crucial for developing effective therapeutic strategies and interventions aimed at mitigating both primary and secondary injury mechanisms. Research in this field continues to uncover new insights into the complex processes involved in TBI, with the goal of improving outcomes and minimizing long-term consequences.
It has a massive personal and socioeconomic impact, as it is a disease with high morbidity and mortality. Both young and old people are affected, as a result of traffic or sports accidents as well as due to falls at home. The term TBI encompasses various clinical pictures, differing considerably in cause, prognosis, and therapy. What they all have in common is the pathophysiological cascade that develops immediately after the initial trauma and can persist for several days and weeks. In this phase, medical treatment, whether surgical or pharmacological, attempts to reduce the consequences of the primary damage 4).
Pathophysiological changes arising after primary brain injury lead to the secondary brain injury 5) 6) 7).
Neuroendocrine dysfunction occurs often in the acute phase of moderate-to-severe traumatic brain injury, more commonly in patients with severe traumatic brain injury, patients with pressure effects and low Glasgow Outcome Scale.
Autonomic impairment, as measured by heart rate variability and baroreflex sensitivity, is significantly associated with increased mortality after traumatic brain injury. These effects, though partially interlinked, seem to be independent of age, trauma severity, intracranial pressure, or autoregulatory status, and thus represent a discrete phenomenon in the pathophysiology of traumatic brain injury. Continuous measurements of heart rate variability and baroreflex sensitivity in the neuromonitoring setting of severe traumatic brain injury may carry novel pathophysiological and predictive information 8).
Traumatic brain injury (TBI) induces transient cell membrane disruptions that lead to redistribution of ions and neurotransmitters, altering the membrane potential. During the acute phase (≤1 hour) after TBI, there is a massive release of glutamate from presynaptic terminals, which disrupts ionic equilibrium on postsynaptic membranes. The amount of potassium (K+) released increases with injury severity, as measured by microdialysis 9) 10).
Mild Fluid percussion (FP) injury produced a 1.4- to 2.2-fold increase in extracellular [K+] levels that was blocked by tetrodotoxin (a neurotoxin that prevents brain cell firing), suggesting that this rise in [K+] is related to neuronal firing. More severe injuries produced greater increases (4.3- to 5.9-fold) in [K+] that were tetrodotoxin-resistant. Administration of kynurenic acid, an antagonist of excitatory amino acids, attenuated the [K+] increase in a dose-dependent manner, suggesting that the K+ surge is dependent on excitatory neurotransmitters. In order for brain cells to fire again, ionic equilibrium must be re-established, which requires ATP (cellular energy) 11).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820255/
Traumatic brain injury (TBI) induces glial activation and neuroinflammation in the hippocampus, resulting in acute and chronic hippocampal dysfunction.
After TBI, cerebral vascular endothelial cells play a crucial role in the pathogenesis of inflammation.
Following TBI, various mediators are released which enhance vasogenic and/or cytotoxic brain edema. These include glutamate, lactate, H(+), K(+), Ca(2+), nitric oxide, arachidonic acid and its metabolites, free oxygen radicals, histamine, and kinins. Thus, avoiding cerebral anaerobic metabolism and acidosis is beneficial to control lactate and H(+), but no compound inhibiting mediators/mediator channels showed beneficial results in conducted clinical trials, despite successful experimental studies.
Heuvel et al., investigated the role of EI affecting these responses unfolding after TBI. We used a blunt, weight-drop approach to model TBI in mice. Male mice were pre-administered with ethanol or vehicle to simulate EI. The neuroinflammatory response in the hippocampus was assessed by monitoring the expression levels of >20 cytokines, the phosphorylation status of transcription factors and the phenotype of microglia and astrocytes. We used AS1517499, a brain-permeable STAT6 inhibitor, to elucidate the role of this pathway in the EI/TBI interaction. We showed that TBI causes the elevation of IL-33, IL-1β, IL-38, TNF-α, IFN-α, IL-19 in the hippocampus at 3h time point and concomitant EI results in the dose-dependent downregulation of IL-33, IL-1β, IL-38, TNF-α and IL-19 (but not of IFN-α) and in the selective upregulation of IL-13 and IL-12. EI is associated with the phosphorylation of STAT6 and the transcription of STAT6-controlled genes. Moreover, ethanol-induced STAT6 phosphorylation and transcriptional activation can be recapitulated in vitro by concomitant exposure of neurons to ethanol, depolarization and inflammatory stimuli (simulating the acute trauma). Acute STAT6 inhibition prevents the effects of EI on IL-33 and TNF-α, but not on IL-13 and negates acute EI beneficial effects on TBI-associated neurological impairment. Additionally, EI is associated with reduced microglial activation and astrogliosis as well as preserved synaptic density and baseline neuronal activity 7 days after TBI and all these effects are prevented by acute administration of the STAT6 inhibitor concomitant to EI. EI concomitant to TBI exerts significant immunomodulatory effects on cytokine induction and microglial activation, largely through the activation of STAT6 pathway, ultimately with beneficial outcomes 12).