engleski

Molecular mechanisms of traumatic brain injury

Traumatic brain injury (TBI) is frequent head injury, one of the leading causes of disability worldwide and a global health issue problem. TBI is defined as a direct physical impact to the head, and it elicits physical, cognitive, psychological, psychosocial and functional impairments. TBI can be associated with fatal outcome. In addition, TBI is related to high health care costs, long term rehabilitations, prolonged sick-leaves, and social and functional disability. The conflicts around the globe have facilitated the development of complications after TBI, especially in combat veterans, but also in civilians affected by conflicts and combat situations. The severity of TBI might vary from mild to severe form of TBI. The complications of TBI include cognitive dysfunction, post-traumatic epilepsy, headaches and other motor and sensory neurological impairments. There are two phases of TBI: primary (a head injury) and secondary (a biological response to primary TBI). The understanding of the pathophysiology of the secondary TBI is still unclear. Biological processes that develop after TBI are the result of the response of the organism to the primary TBI, and they include activation of the inflammatory mediators and secretion of neurotransmitters, the development of apoptosis or necrosis, and regenerative processes and altered synaptic plasticity. The first biological responses that develop after TBI include the intracranial hemorrhage, increased intracranial pressure, decreased cerebral blood flow, and consequent cerebral hypoxia and ischemia ; the release of pro-inflammatory mediators such as cytokines, chemokines, nitric oxide, prostaglandins, matrix metalloproteines, phosphatases, phospholipases and xanthin-oxidases ; release of excitotoxines (glutamate and aspartate), growth factors and catecholamines ; activation of microglia, astrocytes, and neurons ; activation and recruitment of systemic neutrophils and macophages, breakdown of the blood-brain barriers, activation of the complements ; and apoptosis. The inflammatory cascade involves the release of inflammatory cytokines (IL-6 and IL-10). Cerebral ischemia after blast injuries is accompanied by hypoperfusion, hyperemia and reduction in blood flow. Apoptosis, and the recovery or impairment of cognitive and behavioral functions, is regulated also by the complex biochemical cascades and by the different genes. Up- or down-regulation of the genes encoding for growth factors, transcription and signal transduction factors and nuclear proteins, cell cycle, apoptosis, metabolism, inflammation-related factors, and others, are found after TBI. Specifically, different gene polymorphisms may be involved in the pathological changes after TBI or in processes of healing. Genes that might have a role in the survival of TBI are genes that regulate inflammatory processes such as IL-6, since they have a role in the development of coronary of cerebral aneurysms, and the ruptures of these aneurysms ; gene for haemo-oxygenase -1 affects tissue redox homeostasis ; genes regulating the vascular response include hypoxia-inducible factor 1 and 2, vascular endothelial growth factor, glucose transporter -1, transferrin, transferrin receptor ; genes involved in neural, cognitive and behavioral response to TBI is apolipoprotein E ; gene that regulates apoptosis is p53 ; gene that is related to fronto-executive functioning is catechol-o-methyl.transferase (COMT), genes for the caspase family of the cysteine proteases, genes that are homologues to the oncogene Bcl-2, genes encoding for neurotrophic factors (brain-derived neurotropic factor or BDNF, nerve growth factor or NGF, neurotrophin 3, 4 and 5 or NT-3, NT-4 and NT-5) and their receptors, mobility group protein 1 (hmg-1 ), the regulator of G-protein signaling 2 (rgs-2 ), the transforming growth factor B inducible early growth response (tieg), the inhibitor of DNA binding 3 (id3 ), and the heterogeneous nuclear ribonucleoprotein H (hnrnp h), transcription factors (c-jun), and many others. The main goal in the TBI research is to improve the understanding of the underlying molecular mechanisms leading to the secondary TBI, to develop biomarkers that would be used to monitor the severity of injury, to develop new targets (new molecules) for the treatment and to have biomarkers that would follow the treatment response, to reduce mortality and physical, cognitive, psychological, psychosocial and functional impairments after TBI, and to improve the clinical outcome.

traumatic brain injury; immune and biochemical mediators; genes

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