Ray SK, Dixon CE, Banik NL: Molecular mechanisms in the pathogenesis of traumatic brain injury

Department of Neurology, Clinical Science Building, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 309, Charleston, SC 29425, USA.
Histology and histopathology (Impact Factor: 2.1). 11/2002; 17(4):1137-52.
Source: PubMed


Traumatic brain injury (TBI) is a serious neurodisorder commonly caused by car accidents, sports related events or violence. Preventive measures are highly recommended to reduce the risk and number of TBI cases. The primary injury to the brain initiates a secondary injury process that spreads via multiple molecular mechanisms in the pathogenesis of TBI. The events leading to both neurodegeneration and functional recovery after TBI are generalized into four categories: (i) primary injury that disrupts brain tissues; (ii) secondary injury that causes pathophysiology in the brain; (iii) inflammatory response that adds to neurodegeneration; and (iv) repair-regeneration that may contribute to neuronal repair and regeneration to some extent following TBI. Destructive multiple mediators of the secondary injury process ultimately dominate over a few intrinsic protective measures, leading to activation of cysteine proteases such as calpain and caspase-3 that cleave key cellular substrates and cause cell death. Experimental studies in rodent models of TBI suggest that treatment with calpain inhibitors (e.g., AK295, SJA6017) and neurotrophic factors (e.g., NGF, BDNF) can prevent neuronal death and dysfunction in TBI. Currently, there is still no precise therapeutic strategy for the prevention of pathogenesis and neurodegeneration following TBI in humans. The search continues to explore new therapeutic targets and development of promising drugs for the treatment of TBI.

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    • "SCI, which is characterized by primary physical damage and secondary damage, results in severe sequelae such as paralysis , intense pain, and progressive neurological damage. The primary injury is typically restricted to the specific area of vertebral fracture and is characterized by acute hemorrhage and ischemia, which serve as the foci from which secondary mechanisms of injury are induced (Ray et al., 2002; Simon et al., 2009). The secondary injury, which is characterized by further destruction of neuronal and glial cells, leads to a significant expansion of the injury site, and allows paralysis to extend to adjacent spinal cord segments. "
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    ABSTRACT: Spinal cord injury (SCI) is a devastating type of neurological trauma with limited therapeutic opportunities. The pathophysiology of SCI involves primary and secondary mechanisms of injury. Among all the secondary injury mechanisms, the inflammatory response is the major contributor and results in expansion of the lesion and further loss of neurologic function. Meanwhile, the inflammation directly and indirectly dominates the outcomes of SCI, including not only pain and motor dysfunction, but also preventingneuronal regeneration. Microglia and macrophages play very important roles in secondary injury. Microglia reside in spinal parenchyma and survey the microenvironment through the signals of injury or infection. Macrophages are derived from monocytes recruited to injured sites from the peripheral circulation. Activated resident microglia and monocyte-derived macrophages induce and magnify immune and inflammatory responses not only by means of their secretory moleculesand phagocytosis, but also through their influence on astrocytes, oligodendrocytes and demyelination. In this review, we focus on the roles of microglia and macrophages in secondary injury and how they contribute to the sequelae of SCI.
    Neural Regeneration Research 10/2014; 9(20):1787-1795. DOI:10.4103/1673-5374.143423 · 0.22 Impact Factor
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    • "TBI leads to important and deleterious neuroinflammation, as evidenced by edema, cytokine production, induction of nitric oxide synthase, and leukocyte infiltration. Strategies that block inflammatory and oxidative mediators have been shown to induce neuroprotective and anti-inflammatory effects after brain injury [2]. "
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    ABSTRACT: Aim: Traumatic brain injury (TBI) leads to important and deleterious inflammation, as evidenced by edema, cytokine production, induction of nitric oxide synthase, and leukocyte infiltration. After TBI, the activation of cerebral vascular endothelial cells plays a crucial role in the pathogenesis of inflammation. In this study, we hypothesized that the activation of cerebral vascular endothelial cells plays a crucial role in the pathogenesis of inflammation and outcome after TBI. It may represent a key cellular target for statin therapy. Methods: In our study, cortical contusions were induced, and the effect of continuous treatment of simvastatin on behavior and inflammation in adult rats following experimental TBI was evaluated. The treatment group received 15 mg/kg of simvastatin daily for 3 days. Neurological function was assessed with the grip test. Results: The results showed that the non-treatment control group had a significantly greater increase in ICAM-1 expression from pre-injury to the post-injury 72 h time point as compared to the expression in treatment group. The treatment group had better neurological function as evidenced in a grip test performed from baseline to 72 h. The analysis of a western blot test and pathology also demonstrated reduced ICAM-1 expression and a smaller area of damage and tissue loss. Conclusion: Our findings suggest that simvastatin could attenuate the activation of cerebral vascular endothelial inflammatory response and decrease the loss of neurological function and brain tissue.
    Annals of clinical and laboratory science 06/2014; 44(2):145-50. DOI:10.1155/2014/910260 · 0.91 Impact Factor
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    • "Brain injuries, caused by both external and internal forces, trigger a complex cascade of post-injury events that lead to pathophysiology. These events include failed cellular energetics leading to acidosis and the production of oxygen free radicals, excitotoxicity due to excessive glutamate signaling and increased intracellular free Ca2+, and increased cytokines/chemokines and the initiation of the inflammatory response [8]. Thus, pathophysiology in the brain is a secondary injury that develops as a consequence of a myriad of cellular and molecular mechanisms initiated after the primary injury. "
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    ABSTRACT: Hypothermia is considered a useful intervention for limiting pathophysiological changes after brain injury. Local hypothermia is a relatively safe and convenient intervention that circumvents many of the complications associated with systemic hypothermia. However, successful hypothermia treatment requires careful consideration of several factors including its practicality, feasibility, and associated risks. Here, we review the protective effects-and the cellular mechanisms that underlie them-of delayed and prolonged local hypothermia in rodent and canine brain injury models. The data show that the protective effects of therapeutic hypothermia, which mainly result from the modulation of inflammatory glial dynamics, are limited. We argue that decompressive craniectomy can be used to overcome the limitations of local brain hypothermia without causing histological abnormalities or other detrimental effects to the cooled area. Therefore, delayed and prolonged local brain hypothermia at the site of craniectomy is a promising intervention that may prove effective in the clinical setting.
    06/2014; 23(2):115-23. DOI:10.5607/en.2014.23.2.115
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