Neuroprotection In Traumatic Brain Injury Research Articles

RACK1 promotes autophagy via the PERK signaling pathway to protect against traumatic brain injury in rats.

Neuronal cell death is a primary factor that determines the outcome after traumatic brain injury (TBI). We previously revealed the importance of receptor for activated C kinase (RACK1), a multifunctional scaffold protein, in maintaining neuronal survival after TBI, but the specific mechanism remains unclear. The aim of this study was to explore the mechanism underlying RACK1-mediated neuroprotection in TBI. TBI model was established using controlled cortical impact injury in Sprague-Dawley rats. Genetic intervention and pharmacological inhibition of RACK1 and PERK-autophagy signaling were administrated by intracerebroventricular injection. Western blotting, coimmunoprecipitation, transmission electron microscopy, real-time PCR, immunofluorescence, TUNEL staining, Nissl staining, neurobehavioral tests, and contusion volume assessment were performed. Endogenous RACK1 was upregulated and correlated with autophagy induction after TBI. RACK1 knockdown markedly inhibited TBI-induced autophagy, whereas RACK1 overexpression exerted the opposite effects. Moreover, RACK1 overexpression ameliorated neuronal apoptosis, neurological deficits, and cortical tissue loss after TBI, and these effects were abrogated by the autophagy inhibitor 3-methyladenine or siRNAs targeting Beclin1 and Atg5. Mechanistically, RACK1 interacted with PERK and activated PERK signaling. Pharmacological and genetic inhibition of the PERK pathway abolished RACK1-induced autophagy after TBI. Our findings indicate that RACK1 protected against TBI-induced neuronal damage partly through autophagy induction by regulating the PERK signaling pathway.

Human umbilical cord mesenchymal stem cell-derived exosomes provide neuroprotection in traumatic brain injury through the lncRNA TUBB6/Nrf2 pathway

Recently, human umbilical cord mesenchymal stem cell (HucMSC) is a new focus of research in neurological diseases, and the beneficial effect of HucMSC is mediated by paracrine factors which are transported by exosome. Our previous study has shown that HucMSC-derived exosome could provide neuroprotection after traumatic brain injury (TBI). However, the underlying mechanisms were not fully understood. In the present study, we found that administration of exosome suppressed TBI-induced inflammation and ferroptosis. In addition, exosome activated the long non-coding ribonucleic acid (lncRNA) TUBB6/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway after TBI. However, exosome partly failed to provide neuroprotection following TBI when TUBB6 was knockdown. Importantly, exosome treatment also decreased neuron cell death, suppressed inflammation, inhibited ferroptosis and activated the lncRNA TUBB6/Nrf2 pathway after TBI in vitro. Taken together, our results provided the first evidence that HucMSC-derived exosome played a key role in neuroprotection after TBI through the lncRNA TUBB6/Nrf2 pathway.

Ferrostatin‐1 and z‐VAD‐FMK Potentially Attenuated Iron‐mediated Neurotoxicity and Rescued Cognitive Function in Iron‐overloaded Rats

AbstractBackgroundOur study indicated that iron‐overloaded condition induced neurotoxicity in rats and cognitive impairment (1). Furthermore, neuronal deaths caused by apoptosis and ferroptosis, have been identified as one of the underlying mechanisms of neurotoxicity in iron‐overloaded condition (1, 2). Recently, a ferroptosis inhibitor; ferrostatin‐1 and a pan‐caspase inhibitor; z‐VAD‐FMK exerted neuroprotection in traumatic brain injury and intracerebral hemorrhagic brain. Nonetheless, the comparative efficacy of these cell death inhibitors on brain parameters and cognitive function in iron‐overloaded rats has not yet been investigated.MethodThirty male Wistar rats were divided into 2 groups to receive an intraperitoneal injection with 10% dextrose in normal saline solution (NSS) as a control group (n = 6) or 100 mg/kg iron dextran as an iron‐overloaded group (n = 24). After 4 weeks of injection, iron‐overloaded group was subdivided into 4 groups (n = 6/ group) to subcutaneously receive with the pharmacological interventions including 1) vehicle (10% DMSO in NSS), 2) deferoxamine (25 mg/kg), 3) ferrostatin‐1 (2 mg/kg), and 4) z‐VAD‐FMK (1 mg/kg). In contrast, rats in the control group were received vehicle. Those mice were received the assigned treatment for further 2 weeks. Behavioral tests including the Morris water maze test (hippocampal‐dependent memory) and novel object recognition test (hippocampal‐independent memory), were performed. At the end of experiments, systemic iron overload and brain parameters including blood‐brain tight junction proteins, brain iron, synaptic markers, and brain ferroptosis/apoptosis were determined.ResultNot only systemic iron overload, but iron‐overloaded rats exhibited blood‐brain barrier breakdown, brain iron overload, iron‐mediated brain toxicity including brain oxidative stress, loss of synaptic proteins, and brain ferroptosis/apoptosis, leading to cognitive impairment. Treatment with deferoxamine attenuated rats from systemic iron overload, brain pathologies, and hippocampal‐independent memory (Figure 1A), but failed to rescue hippocampal‐dependent memory in iron‐overloaded rats (Figure 1B). Interestingly, cell death inhibitors including ferrostatin‐1 and z‐VAD‐FMK provided superior neuroprotection than deferoxamine by attenuating loss of synaptic proteins and restoring cognitive function in hippocampal‐dependent and hippocampal‐independent manners (Figure 1A‐1C).ConclusionFerrostatin‐1 and z‐VAD‐FMK exerted neuroprotective effects and cognitive restoration in rats under iron‐overloaded condition, suggesting the novel therapeutic strategy using cell death inhibitors in brain following iron‐overloaded condition.

Endocannabinoid control of neuroinflammation in traumatic brain injury by monoacylglycerol lipase in astrocytes.

Endocannabinoid control of neuroinflammation in traumatic brain injury by monoacylglycerol lipase in astrocytes.

Advancing neuroprotection in traumatic brain injury: Maximizing the potential of the nuclear factor erythroid 2-related factor 2/nuclear factor kappa B pathway through insights from animal models

Traumatic brain injury (TBI) is a primary public health concern that can result in significant long-term disability and mortality. Neuroprotection strategies that can mitigate the effects of TBI are urgently needed. The nuclear factor erythroid 2-related factor 2 (Nrf-2)/nuclear factor kappa B (NF-κB) pathway has emerged as a promising TBI neuroprotection target because it regulates inflammation, oxidative stress, and mitochondrial dysfunction. This review summarizes the current preclinical evidence supporting the role of the Nrf-2/NF-κB pathway in TBI and the mechanisms underlying its regulation. Pharmacological and genetic approaches have been used to modulate the pathway in animal models of TBI, resulting in improved functional, histological, and molecular outcomes. The molecular mechanisms underlying the Nrf-2/NF-κB pathway in TBI involve regulating inflammation, oxidative stress, and mitochondrial dysfunction. The future studies should focus on identifying safe and effective agents for modulating this pathway, optimizing dosing regimens, and exploring combination therapies targeting multiple TBI pathways. While preclinical studies have shown promising results, further research is needed to determine the safety and efficacy of modulating the Nrf-2/NF-κB pathway in human TBI patients. Overall, the Nrf-2/NF-κB pathway represents a promising target for neuroprotection in TBI, and further research is needed to translate these preclinical findings into effective treatments for human patients.

Scientific Evidences of Calorie Restriction and Intermittent Fasting for Neuroprotection in Traumatic Brain Injury Animal Models: A Review of the Literature.

It has widely been accepted that food restriction (FR) without malnutrition has multiple health benefits. Various calorie restriction (CR) and intermittent fasting (IF) regimens have recently been reported to exert neuroprotective effects in traumatic brain injury (TBI) through variable mechanisms. However, the evidence connecting CR or IF to neuroprotection in TBI as well as current issues remaining in this research field have yet to be reviewed in literature. The objective of our review was therefore to weigh the evidence that suggests the connection between CR/IF with recovery promotion following TBI. Medline, Google Scholar and Web of Science were searched from inception to 25 February 2022. An overwhelming number of results generated suggest that several types of CR/IF play a promising role in promoting post-TBI recovery. This recovery is believed to be achieved by alleviating mitochondrial dysfunction, promoting hippocampal neurogenesis, inhibiting glial cell responses, shaping neural cell plasticity, as well as targeting apoptosis and autophagy. Further, we represent our views on the current issues and provide thoughts on the future direction of this research field.

Commentary: Lactate, the Astrocyte-Neuron Lactate Shuttle, and Neuroprotection in Traumatic Brain Injury.

Commentary: Lactate, the Astrocyte-Neuron Lactate Shuttle, and Neuroprotection in Traumatic Brain Injury.

Can Ultrasound-Guided Xenon Delivery Provide Neuroprotection in Traumatic Brain Injury?

Traumatic brain injury (TBI) is associated with high mortality and morbidity in children and adults. Unfortunately, there is no effective management for TBI in the acute setting. Rodent studies have shown that xenon, a well-known anesthetic gas, can be neuroprotective when administered post-TBI. Gas inhalation therapy, however, the approach typically used for administering xenon, is expensive, inconvenient, and fraught with systemic side effects. Therapeutic delivery to the brain is minimal, with much of the inhaled gas cleared by the lungs. To bridge major gaps in clinical care and enhance cerebral delivery of xenon, this study introduces a novel xenon delivery technique, utilizing microbubbles, in which a high impulse ultrasound signal is used for targeted cerebral release of xenon. Briefly, an ultrasound pulse is applied along the carotid artery at the level of the neck on intravenous injection of xenon microbubbles (XeMBs) resulting in release of xenon from microbubbles into the brain. This delivery technique employs a hand-held, portable ultrasound system that could be adopted in resource-limited environments. Using a high-fidelity porcine model, this study demonstrates the neuroprotective efficacy of xenon microbubbles in TBI for the first time.

Evaluation of Progesterone Receptor Antagonist and Maxi-K Channel Agonist as Neuroprotective in Feeney's Weight Drop Model of TBI.

Neuroprotection in traumatic brain injury (TBI) is an unmet medical need. We evaluated two agents, aglepristone (progesterone receptor antagonist) and N-salicyloyltryptamine (STP) (activator of Maxi-K channel in GH3 cells), for neuroprotection in Feeney's weight drop model of TBI. Forty-eight male Wistar rats were divided into six groups (n = 8 per group). A battery of six neurobehavioral tests was evaluated at the end of the first week (EO1W), second week (EO2W), and third week (EO3W). In addition, histopathological and immunohistochemistry (BAX, Bcl-2, and M30 Cytodeath) tests were performed at EO3W. Aglepristone at 10 mg/kg showed significant neuroprotection compared to control as assessed by Rota-rod test at EO1W, VEFP right paw and 28-point neurobehavioral test at EO2W, MWM test at EO3W, and positive histopathological and IHC findings. Aglepristone at 20 mg/kg showed negative results as assessed by BAX expression, downregulation of Bcl-2, and positive M30 Cytodeath, thereby suggesting toxicity at higher doses. STP 100 mg/kg showed modest neuroprotective activity but failed to show a dose-response relationship at a dose of 50 mg/kg. The study shows that progesterone receptor antagonists have neuroprotection at lower doses and toxicity at higher doses.

Inhalational Gases for Neuroprotection in Traumatic Brain Injury.

Despite multiple prior pharmacological trials in traumatic brain injury (TBI), the search for an effective, safe, and practical treatment of these patients remains ongoing. Given the ease of delivery and rapid absorption into the systemic circulation, inhalational gases that have neuroprotective properties will be an invaluable resource in the clinical management of TBI patients. In this review, we perform a systematic review of both pre-clinical and clinical reports describing inhalational gas therapy in the setting of TBI. Hyperbaric oxygen, which has been investigated for many years, and some of the newest developments are reviewed. Also, promising new therapies such as hydrogen gas, hydrogen sulfide gas, and nitric oxide are discussed. Moreover, novel therapies such as xenon and argon gases and delivery methods using microbubbles are explored.

Sestrin2 protects against traumatic brain injury by reinforcing the activation of Nrf2 signaling.

Sestrin2 (SESN2) is stress-inducible protein that confers cytoprotective effects against various noxious stimuli. Accumulating evidence has documented that SESN2 has potent anti-apoptosis and anti-oxidative stress functions. However, whether it provides neuroprotection in traumatic brain injury (TBI) models remains unexplored. The purpose of this study was to explore the regulatory effect of SESN2 on TBI using in vivo and in vitro models. We found that TBI resulted in a marked induction of SESN2 in the cerebral cortex tissues of mice. SESN2 overexpression in the brain by in vivo gene transfer significantly decreased neurological deficit, brain edema, and neuronal apoptosis of mice with TBI. Moreover, the overexpression of SESN2 significantly decreased the oxidative stress induced by TBI in mice. In vitro studies of TBI demonstrated that SESN2 overexpression decreased apoptosis and oxidative stress in scratch-injured cortical neurons. Notably, SESN2 overexpression increased the nuclear levels of nuclear factor-erythroid 2-related factor 2 (Nrf2) and enhanced the activation of Nrf2 antioxidant signaling in in vivo and in vitro models of TBI. In addition, the inhibition of Nrf2 significantly abolished SESN2-mediated neuroprotective effects in vivo and in vitro. In conclusion, these results of our work demonstrate that SESN2 protects against TBI by enhancing the activation of Nrf2 antioxidant signaling.

Upregulation of C Terminus of Hsc70-Interacting Protein Attenuates Apoptosis and Procoagulant Activity and Facilitates Brain Repair After Traumatic Brain Injury.

Traumatic brain injury (TBI) could highly induce coagulopathy through breaking the dynamic balance between coagulation and fibrinolysis systems, which may be a major contributor to the progressive secondary injury cascade that occurs after TBI. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibition is reported to exert neuroprotection in TBI, making it a potential regulatory target involved in TBI-induced coagulation disorder. PTEN level is controlled in a major way by E3 ligase-mediated degradation through the ubiquitin–proteasome system. The C terminus of Hsc70-interacting protein (CHIP) has been shown to regulate proteasomal degradation and ubiquitination level of PTEN. In the present study, CHIP was overexpressed and knocked down in mouse brain microvascular endothelial cells (bEnd.3) and tissues during the early phase of TBI. In vitro cell proliferation, cell apoptosis, migration capacity, and invasion capacity were determined. The changes of procoagulant and apoptosis molecules after TBI were also detected as well as the micrangium density and blood–brain barrier permeability after in vivo TBI. In vitro results demonstrated that CHIP overexpression facilitated bEnd.3 cell proliferation, migration, and invasion and downregulated cell apoptosis and the expressions of procoagulant molecules through promoting PTEN ubiquitination in a simulated TBI model with stretch-induced injury treatment. In vivo experiments also demonstrated that CHIP overexpression suppressed post-TBI apoptosis and procoagulant protein expressions, as well as increased microvessel density, reduced hemorrhagic injury, and blood–brain barrier permeability. These findings suggested that the upregulation of CHIP may attenuate apoptosis and procoagulant activity, facilitate brain repair, and thus exerts neuroprotective effects in TBI.

Neuroprotective effects of food restriction in a rat model of traumatic brain injury – the role of glucocorticoid signaling

ABSTRACT Objective: Traumatic brain injury (TBI) is one of the most common causes of neurological damage in young and middle aged people. Food restriction (FR) has been shown to act neuroprotectively in animal models of stroke and TBI. Indeed, our previous studies showed that FR attenuates inflammation, through suppression of microglial activation and TNF-α production, suppresses caspase-3-induced neuronal cell death and enhances neuroplasticity in the rat model of TBI. Glucocorticoids (GCs) play a central role in mediating both molecular and behavioral responses to food restriction. However, the exact mechanisms of FR neuroprotection in TBI are still unclear. The goal of the present study was to examine whether FR exerts its beneficial effects by altering the glucocorticoid receptor (GR) signaling alone and/or together with other protective factors. Methods: To this end, we examined the effects of FR (50% of regular daily food intake for 3 months prior to TBI) on the protein levels of total GR, GR phosphoisoform Ser232 (p-GR) and its transcriptional activity, as well as 11β-HSD1, NFκB (p65) and HSP70 as factors related to the GR signaling. Results: Our results demonstrate that FR applied prior to TBI significantly changes p-GR levels, and it’s transcriptional activity during the recovery period after TBI. Moreover, as a pretreatment, FR modulates other protective factors in response to TBI, such as 11β-HSD1, NF-κB (p65) and HSP70 that act in parallel with GR in it’s anti-inflammatory and neuroprotective effects in the rat model of brain injury. Conclusion: Our results suggest that prophylactic FR represents a potent non-invasive approach capable of changing GR signalling, together with other factors related to the GR signaling in the model of TBI.

Intranasal wnt-3a alleviates neuronal apoptosis in early brain injury post subarachnoid hemorrhage via the regulation of wnt target PPAN mediated by the moonlighting role of aldolase C

Neuronal apoptosis is one of the main pathophysiological events in the early brain injury (EBI) post subarachnoid hemorrhage (SAH). Wnt-3a, one of the endogenous wnt ligands crucial in neurogenesis, has been proven to be efficacious in neuroprotection in traumatic brain injury and ischemic stroke. The glycolytic enzyme aldolase C and ribosome biogenesis protein PPAN were revealed to be linked to wnt signaling pathway. The aim of the study was to explore the antiapoptotic effects of intranasal wnt-3a through Frizzled-1 (Frz-1)/aldolase C/PPAN pathway in SAH. Approaches for assessment included SAH grade, Garcia test, brain water content evaluation, rotarod test, Morris water maze test, Western blot, immunofluorescence and transmission electron microscopy. The results showed that wnt-3a improved the neurological scores, brain water content and long-term neurobehavioral functions after SAH. Wnt-3a increased the level of Frz-1, aldolase C, β-catenin, PPAN and the Bcl-2/Bax ratio; and decreased the level of axin and cleaved caspase-3 (CC-3). The anti-apoptotic effect of wnt-3a was further evidenced by TUNEL staining and subcellular structure imaging. Frz-1 siRNA and aldolase C siRNA offset the effects of wnt-3a; and restoration of aldolase C by aldolase C CRISPR in Frz-1 siRNA preconditioned SAH rats salvaged the level of Frz-1, aldolase C, PPAN and reduced axin and CC-3. In summary, intranasal administration of wnt-3a alleviates neuronal apoptosis through Frz-1/aldolase C/PPAN pathway in the EBI of SAH rats. The feasible intranasal route and the long-lasting neuroprotective property of wnt-3a is of great clinical relevance.

Transplantation of mesenchymal stem cells overexpressing interleukin-10 induces autophagy response and promotes neuroprotection in a rat model of TBI.

Autophagy, including mitophagy, is critical for neuroprotection in traumatic brain injury (TBI). Transplantation of mesenchymal stem cells (MSCs) provides neuroprotection and induces autophagy by increasing anti‐inflammatory cytokines, such as interleukin‐10 (IL‐10). To evaluate these effects of IL10 that are released by MSCs, we genetically engineered MSCs to overexpress IL10 and compared their effects to unaltered MSCs following transplantation near the site of induced TBIs in rats. Adult, male Sprague‐Dawley rats were divided into four groups: Sham + vehicle, TBI + vehicle, TBI + MSCs‐IL‐10 and TBI + MSCs‐GFP. Thirty‐six hours post‐TBI, the first two groups received vehicle (Hanks balance salt solution), whereas last two groups were transplanted with MSCs‐IL‐10 or MSCs‐GFP. Three weeks after transplantation, biomarkers for neurodegenerative changes, autophagy, mitophagy, cell death and survival markers were measured. We observed a significant increase in the number of dead cells in the cortex and hippocampus in TBI rats, whereas transplantation of MSCs‐IL‐10 significantly reduced their numbers in comparison to MSCs alone. MSCs‐IL‐10 rats had increased autophagy, mitophagy and cell survival markers, along with decreased markers for cell death and neuroinflammation. These results suggest that transplantation of MSCs‐IL‐10 may be an effective strategy to protect against TBI‐induced neuronal damage.

Neuroprotection in Traumatic Brain Injury: Mesenchymal Stromal Cells can Potentially Overcome Some Limitations of Previous Clinical Trials

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. In the last 30 years several neuroprotective agents, attenuating the downstream molecular and cellular damaging events triggered by TBI, have been extensively studied. Even though many drugs have shown promising results in the pre-clinical stage, all have failed in large clinical trials. Mesenchymal stromal cells (MSCs) may offer a promising new therapeutic intervention, with preclinical data showing protection of the injured brain. We selected three of the critical aspects identified as possible causes of clinical failure: the window of opportunity for drug administration, the double-edged contribution of mechanisms to damage and recovery, and the oft-neglected role of reparative mechanisms. For each aspect, we briefly summarized the limitations of previous trials and the potential advantages of a newer approach using MSCs.

Neuroprotection in traumatic brain injury.

Traumatic brain injury (TBI) has a high incidence worldwide and is associated with significant morbidity and mortality. TBI has enduring implications in several domains and limits overall quality of life even in the survivors. Assessment of failures of different strategies attempted at improving outcomes in traumatic brain injury is required. Several neuroprotective strategies have been studied to limit the morbidity and mortality associated with TBI. Various approaches, both pharmacologic and surgical, have been tried. In this article, we will review the epidemiology of TBI, the impact of secondary brain injury on outcomes and different strategies in traumatic brain injury. Furthermore, discussion into failure of different strategies and necessary future approach will be discussed. TBI remains a challenging condition to intervene on due to its heterogeneity. Future work should incorporate a multi-disciplinary as well as multi-center approach to target specific subset of patient population.

Nrf2-ARE signaling provides neuroprotection in traumatic brain injury via modulation of the ubiquitin proteasome system

The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway exhibits protective effects in a variety of neurological diseases. However, the role of this pathway in traumatic brain injury (TBI) is not fully understood. This study investigates whether the Nrf2-ARE pathway provides neuroprotection following TBI via regulation of the ubiquitin proteasome system (UPS), and examines the involvement of this pathway in redox homeostasis. We found that activation the Nrf2-ARE pathway can mitigate secondary brain injury induced by TBI. Furthermore, we found that inhibiting the Nrf2-ARE pathway weakened the UPS following TBI. Treatment of TBI with the proteasome inhibitor, MG132, increased neuronal apoptosis, and evidence of brain water content was found. These data suggest that the Nrf2-ARE pathway provides neuroprotection following TBI via modulation of the UPS. In addition, the results indicated that the content of glutathione (GSH) was significantly increased after activation of Nrf2, and the level of ROS decreased; however, this effect contradictory in the Nrf2 knockout mice. Further studies found that treatment with the ROS agonist, ferric ammonium citrate (FAC), resulted in additional damage exerted by the ubiquitin proteasome pathways, and a significant increase in the amount of ubiquitinated proteins. In contrast, the activity of the ubiquitin proteasome pathways was vastly enhanced, and the level of ubiquitination proteins was significantly decreased following treatment with the inhibitor, N-acetylcysteine (NAC). The above mentioned results were also verified in in vitro experiments. In conclusion, the activation the Nrf2-ARE pathway improves neurological impairment caused by TBI via modulation of the UPS, and the redox homeostasis is one of the vital regulatory mechanisms.

Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Mediates Neuroprotection in Traumatic Brain Injury at Least in Part by Inactivating Microglia.

BackgroundMicroglial activation has been reported to be involved in traumatic brain injury (TBI). Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a significant role in protecting against TBI-induced secondary brain injury. However, the exact mechanism is not clearly understood. The present study aimed to explore whether Nrf2 protects against TBI partly by regulating microglia function.Material/MethodsMicroglia cells were isolated from C57BL/6 mouse brains (postnatal day 1–3). The expression of Nrf2 was suppressed by transfection with Nrf2-specific small interfering RNA (siRNA), and overexpressed by transfections with pcDNA3.1-Nrf2. The expression of Nrf2 was confirmed by real-time PCR and Western blotting. After transfection, cell viability, phagocytic ability, and the expression of pro-inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-6) were determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) colorimetric assay, phagocytosis assay, and enzyme-linked immunosorbent assay (ELISA), respectively.ResultsmRNA and protein expression levels of Nrf2 were significantly reduced by transfection with Nrf2-specific siRNA (both P<0.05) but were elevated by transfection with pcDNA3.1-Nrf2 (both P<0.01). The cell viability, phagocytic ability, and the expression of TNF-α and IL-6 were all significantly reduced by overexpression of Nrf2 but were significantly increased by silencing of Nrf2 compared with the control group.ConclusionsOur results suggest that Nrf2 protects against TBI, at least part by regulating microglia function.

The nature of the destructive, compensatory and regenerative processes in the brain of rats after experimental moderate traumatic brain injury and the possibility of their pharmacological correction.

Background. The most important task of intensive care patients with traumatic brain injury is prevention and treatment of secondary brain injury, including cerebral ischemia secondary, and neuroprotection, which reduces the impact of secondary damaging factors and allows the nerve cells to escape death. One of the most promising ways of neuroprotection in traumatic brain injury can be neurotrophic therapy. Among the drugs used as neuroprotective agents cerebrolysin occupies a special place. Objective. The aim of this work was to study the effect of the drug cerebrolysin on the morphological changes of brain structures in the early posttraumatic period. Methods. To simulate a traumatic brain injury spring drummer was used, it was experimentally calibrated to apply rats moderate injury. At the time of injury animals were briefly pressed to the foam lining, achieved than horizontal arrangement surface of the cranial vault. In the first subgroup of the main group of animals applied injury secondary to severe without further therapy cerebrolysin. In the second subgroup of the main group after the application of the medium-heavy injury in an experimental neuroprotective therapy used Cerebrolysin (0.1 ml once within 10 days). Calculated absolute number or percentage of 100 cells observed in 10 fields of view of the microscope intact pathologically altered neurons and glial cells. Results. Under the recovery and regeneration (day 21) due to the neuroprotective therapy after traumatic brain injury modeling moderate severity in both hemispheres an increase of normal neurons was observed, it was expressed in the absence of significant differences in this indicator when compared with the control. The same trend was observed on the 14th day after the injury, but occurs only in the damaged hemisphere. On day 21 compared to control a decline of the total number of neurons changed, the values of this index approaches the value 1 day after the injury. Morphometric analysis showed a reduction in the bulk density of the nucleus is 7, and 21 days of experimental traumatic brain injury in the group without treatment. In Cerebrolysin group on day 14 and 21, the bulk density of the nucleus closer to the control parameters. The same trend was observed in relation to the bulk density of ribosomes and neurofibrillary. In case of injury of moderate severity in the group without a neuroprotectant during the entire study period there is a diffuse lesion of the brain studied departments mostly damaged hemisphere, which appeared resistant dystrophic and destructive changes of the neurons without significant signs of pronounced reparative regeneration in the regenerative posttraumatic period. Conclusion. When using a neuroprotectant cerebrolysin marked increase in intact neurons, which was celebrated not only in the injured, but also in the contralateral hemisphere on the day 21st of the experiment. In this case an increase amount of glial cells was also seen.