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Traumatic brain injury (TBI) is still the leading cause of disability in young adults worldwide. The major mechanisms – diffuse axonal injury, cerebral contusion, ischemic neurological damage, and intracranial hematomas have all been shown to be associated with mitochondrial dysfunction in some form. Mitochondrial dysfunction in TBI patients is an active area of research, and attempts to manipulate neuronal/astrocytic metabolism to improve outcomes have been met with limited translational success. Previously, several preclinical and clinical studies on TBI induced mitochondrial dysfunction have focused on opening of the mitochondrial permeability transition pore (PTP), consequent neurodegeneration and attempts to mitigate this degeneration with cyclosporine A (CsA) or analogous drugs, and have been unsuccessful. Recent insights into normal mitochondrial dynamics and into diseases such as inherited mitochondrial neuropathies, sepsis and organ failure could provide novel opportunities to develop mitochondria-based neuroprotective treatments that could improve severe TBI outcomes. This review summarizes those aspects of mitochondrial dysfunction underlying TBI pathology with special attention to models of penetrating traumatic brain injury, an epidemic in modern American society.

Apoptosis after traumatic brain injury has been shown to be a major factor influencing prognosis and outcome. Endoplasmic reticulum stress may be involved in mitochondrial mediated neuronal apoptosis. Therefore, endoplasmic reticulum stress has become an important mechanism of secondary injury after traumatic brain injury. In this study, a rat model of traumatic brain injury was established by lateral fluid percussion injury. Fluorescence assays were used to measure reactive oxygen species content in the cerebral cortex. Western blot assays were used to determine expression of endoplasmic reticulum stress-related proteins. Hematoxylin-eosin staining was used to detect pathological changes in the cerebral cortex. Transmission electron microscopy was used to measure ultrastructural changes in the endoplasmic reticulum and mitochondria. Our results showed activation of the endoplasmic reticulum stress-related unfolded protein response. Meanwhile, both the endoplasmic reticulum stress response and mitochondrial apoptotic pathway were activated at different stages post-traumatic brain injury. Furthermore, pretreatment with the endoplasmic reticulum stress inhibitor, salubrinal (1 mg/kg), by intraperitoneal injection 30 minutes before injury significantly inhibited the endoplasmic reticulum stress response and reduced apoptosis. Moreover, salubrinal promoted recovery of mitochondrial function and inhibited activation of the mitochondrial apoptotic pathway post-traumatic brain injury. These results suggest that endoplasmic reticulum stress might be a key factor for secondary brain injury post-traumatic brain injury.

Traumatic brain injury (TBI) can result in poor functional outcomes and death, and overall outcomes are varied. Growth factors, such as angiopoietin-1 (Ang-1), vascular endothelial growth factor (VEGF), and granulocyte-colony stimulating factor (G-CSF), play important roles in the neurological functions. This study investigated the relationship between serum growth factor levels and long-term outcomes after TBI. Blood samples from 55 patients were collected at 1, 3 and 7 days after TBI. Blood samples from 39 healthy controls were collected as a control group. Serum Ang-1, G-CSF, and VEGF levels were measured using ELISA. Patients were monitored for 3 months using the Glasgow Outcome Scale-Extended (GOSE). Patients having a GOSE score of > 5 at 3 months were categorized as a good outcome, and patients with a GOSE score of 1-5 were categorized as a bad outcome. Our data demonstrated that TBI patients showed significantly increased growth factor levels within 7 days compared with healthy controls. Serum levels of Ang-1 at 1 and 7 days and G-CSF levels at 7 days were significantly higher in patients with good outcomes than in patients with poor outcomes. VEGF levels at 7 days were remarkably higher in patients with poor outcomes than in patients with good outcomes. Receiver operating characteristic analysis showed that the best cut-off points of serum growth factor levels at 7 days to predict functional outcome were 1,333 pg/mL for VEGF, 447.2 pg/mL for G-CSF, and 90.6 ng/mL for Ang-1. These data suggest that patients with elevated levels of serum Ang-1, G-CSF, and decreased VEGF levels had a better prognosis in the acute phase of TBI (within 7 days). This study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1800018251) on September 7, 2018.

Traumatic brain injury (TBI) remains one of the leading causes of death and disability in young adults worldwide. Despite growing evidence and advances in our knowledge regarding the multifaceted pathophysiology of TBI, the underlying mechanisms, though, are still to be fully elucidated. Whereas initial brain insult involves acute and irreversible primary damage to the brain, the processes of subsequent secondary brain injury progress gradually over months to years, providing a window of opportunity for therapeutic interventions. To date, extensive research has been focused on the identification of druggable targets involved in these processes. Despite several decades of successful pre-clinical studies and very promising results, when transferred to clinics, these drugs showed, at best, modest beneficial effects, but more often, an absence of effects or even very harsh side effects in TBI patients. This reality has highlighted the need for novel approaches that will be able to respond to the complexity of the TBI and tackle TBI pathological processes on multiple levels. Recent evidence strongly indicates that nutritional interventions may provide a unique opportunity to enhance the repair processes after TBI. Dietary (poly)phenols, a big class of compounds abundantly found in fruits and vegetables, have emerged in the past few years as promising agents to be used in TBI settings due to their proven pleiotropic effects. Here, we give an overview of the pathophysiology of TBI and the underlying molecular mechanisms, followed by a state-of-the-art summary of the studies that have evaluated the efficacy of (poly)phenols administration to decrease TBI-associated damage in various animal TBI models and in a limited number of clinical trials. The current limitations on our knowledge concerning (poly)phenol effects in TBI in the pre-clinical studies are also discussed.

The mitochondrion serves many functions in the central nervous system (CNS) and other organs beyond the well-recognized role of adenosine triphosphate (ATP) production. This includes calcium-dependent cell signaling, regulation of gene expression, synthesis and release of cytotoxic reactive oxygen species, and the release of cytochrome c and other apoptotic cell death factors. Traumatic injury to the CNS results in a rapid and, in some cases, sustained loss of mitochondrial function. One consequence of compromised mitochondrial function is induction of the mitochondrial permeability transition (mPT) state due to formation of the cyclosporine A sensitive permeability transition pore (mPTP). In this mini-review, we summarize evidence supporting the involvement of the mPTP as a mediator of mitochondrial and cellular demise following CNS traumatic injury and discuss the beneficial effects and limitations of the current ex-perimental strategies targeting the mPTP.

[This corrects the article DOI: 10.3389/fnagi.2024.1424312.].

Intracerebral hemorrhage (ICH) is a cerebrovascular disease with high mortality and morbidity, and the effective treatment is still lacking. We designed this study to investigate the therapeutic effects and mechanisms of melatonin on the secondary brain injury (SBI) after ICH. An in vivo ICH model was induced via autologous whole blood injection into the right basal ganglia in Sprague-Dawley (SD) rats. Primary rat cortical neurons were treated with oxygen hemoglobin (OxyHb) as an in vitro ICH model. The results of the in vivo study showed that melatonin alleviated severe brain edema and behavior disorders induced by ICH. Indicators of blood-brain barrier (BBB) integrity, DNA damage, inflammation, oxidative stress, apoptosis, and mitochondria damage showed a significant increase after ICH, while melatonin reduced their levels. Meanwhile, melatonin promoted further increasing of expression levels of antioxidant indicators induced by ICH. Microscopically, TUNEL and Nissl staining showed that melatonin reduced the numbers of ICH-induced apoptotic cells. Inflammation and DNA damage indicators exhibited an identical pattern compared to those above. Additionally, the in vitro study demonstrated that melatonin reduced the apoptotic neurons induced by OxyHb and protected the mitochondrial membrane potential. Collectively, our investigation showed that melatonin ameliorated ICH-induced SBI by impacting apoptosis, inflammation, oxidative stress, DNA damage, brain edema, and BBB damage and reducing mitochondrial membrane permeability transition pore opening, and melatonin may be a potential therapeutic agent of ICH.

Despite advances in the management of traumatic brain injury (TBI) in the intensive care unit (ICU), and the implementation of new diagnostic techniques and monitoring modalities, the rate of poor neurological outcomes remains high. Specialized neurocritical care units have been shown to improve outcomes. Guidelines have been developed, but most recommendations are based on low levels of evidence. This has led to substantial heterogeneity in clinical practice for many aspects of TBI management, including multimodal neuromonitoring indications, treatment of intra- and extra-cranial complications, and use of prognostic tools. New tools have recently emerged, such as biomarkers and the use of artificial intelligence, but further research is needed to establish their application in clinical practice. This narrative review aims to describe standards of practice for the management of TBI in the ICU, highlighting current evidence and knowledge gaps, to provide a pragmatic approach for clinicians caring for this population.

Intracerebral hemorrhage (ICH) is an important subtype of stroke with an unsatisfactory prognosis of high mortality and disability. Although many pre-clinical studies and clinical trials have been performed in the past decades, effective therapy that meaningfully improve prognosis and outcomes of ICH patients is still lacking. An active area of research is towards alleviating secondary brain injury after ICH through neuroprotective pharmaceuticals and in which minocycline is a promising candidate. Here, we will first discuss new insights into the protective mechanisms of minocycline for ICH including reducing iron-related toxicity, maintenance of blood-brain barrier, and alleviating different types of cell death from preclinical data, then consider its shortcomings. Finally, we will review clinical trial perspectives for minocycline in ICH. We hope that this summary and discussion about updated information on minocycline as a viable treatment for ICH can facilitate further investigations.

In patients with traumatic brain injury (TBI), calcium channel blockers (CCBs) may be used in the early phase to manage hypertension. However, these medications may exacerbate secondary brain injury via hypotension and cerebral vasodilation, blunting Cushing's reflex. We hypothesized that preoperative CCB use does not improve outcomes. A retrospective study (2017–2023) at a Level 1 Trauma Center includes adults undergoing craniotomy or craniectomy within 6 ​h of arrival. Patients were grouped by CCB exposure. Outcomes included mortality, Glasgow Outcome Scale (GOS), ICU days, hospital length of stay, and discharge location. Of 105 patients, 33 received CCBs. Groups were similar in injury severity and initial GCS. Preoperative CCB was linked to significantly higher mortality (46.9 ​% vs. 23.3 ​%, p ​= ​0.029) without significant GOS differences (p ​= ​0.135). Other outcomes showed no significant differences. Preoperative CCB use in TBI patients may be associated with higher mortality without improving outcomes. •TBI patients receiving preoperative CCBs showed significantly higher mortality.•Preoperative CCB use in TBI linked to non-significant change in functional outcomes.•Findings support cautious BP management and reevaluation of CCB use in TBI.