Dear editor We read with great interest the recent study by Lozano et al1 published in the Neuropsychiatric Disease and Treatment. The recovery after traumatic brain injury (TBI) is related to severity of the initial injury (primary injury) and the presence of secondary injury.2 Evidences suggest that inflammation, oxidative stress, excitotoxicity, apoptosis, and neuroendocrine responses play an important role in the development of secondary brain injury.3 Therefore, an important part in the management of patients with TBI is trying to minimize the occurrence of deleterious secondary lesions. Lozano et al’s1 paper focused on the role of neuroinflammation in brain injury. Although some studies have described experimental drugs which may eventually have neuroprotective effects in patients with TBI,2–4 there is currently no approved pharmacological treatment for neuroinflammatory effects of the acute phase of the injury. The dissociation between experimental data with positive results and consecutive clinical trials with negative results leads to a dilemma for the treatment of patients with TBI. And, we agree with Lozano et al1 that further clarification of the neuroinflammatory mechanisms could be the basis for addressing the gap between bench and clinical results to provide better treatment and reduce death and sequelae of TBI. A strong point of the paper1 is the detailed description of signaling pathways of biochemical cascades of secondary injury in TBI, highlighting the metabolic and cellular processes. The discussion about cell death mechanisms is comprehensive and in simple language, which makes it accessible for clinical teams. The description of acute excitatory mechanisms, oxidative stress, and mitochondrial dysfunction is broad and interesting. Another prominent aspect in the review is the section “Neuroinflammation-based therapies”, which allows an analysis of the current status and perspectives for treatment of post-traumatic neuroinflammation. Our group has a particular interest in the role of MMPs, zinc-dependent peptides capable to break down most of the extracellular matrix components such as COL, ELN, and FN, in the mechanisms of enhancement of brain injury. As discussed by Lozano et al many processes in secondary injury depends on the integrity of the blood–brain barrier,5 an anatomical structure formed by tight junctions, basement membrane, podocyte and glial cells that prevents the passive transport of hydrophilic molecules larger than 500 Da between brain structures and blood.5,6 Experimental studies have shown that MMP-9 levels increase after TBI, breaking down basal lamina components and disrupting the blood–brain barrier.7 In animal studies, Wang et al8 demonstrated increased levels of MMP-9 after TBI which persisted for up to 1 week and such an increase also occurred in the contralateral hemisphere, suggesting that after trauma, changes in cerebral state are not restricted to the injured area. Suehiro et al7 found high levels of MMP-9 in TBI patients in the acute phase correlated with high levels of IL-6. They suggested that MMP-9 might play a role in the damage of TBI and be associated with inflammatory events post-TBI. Moreover, during normal development and physiological conditioning of the cell, activated metalloproteinases are required to break down extracellular matrix molecules to allow cell migration.6 In this context, metalloproteinases may also play a role in allowing the interaction of different types of cells during brain injury or repair. Inflammatory process, as reported by the authors, is a double-edged sword, good toward neuroregeneration and bad toward enhancing brain damage. The comprehension of the mechanisms that rule this subtle switch to one side or the other should be the goal of this group and others working in this challenging domain.
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