Progress in research on the role of clinical nutrition in treating traumatic brain injury affecting the neurovascular unit.

The neurovascular unit (NVU) is composed of neurons, glial cells, and blood vessels. NVU dysfunction involves the processes of neuroinflammation, and microcirculatory disturbances, as well as neuronal injury after traumatic brain injury (TBI). Traditional anti-inflammatory drugs have limited efficacy in improving the prognosis of TBI. Thus, treatments that target NVU dysfunction may provide a breakthrough. A large number of clinical studies have shown that the nutritional status of patients with TBI was closely related to their conditions and prognoses. Nutrient complexes and complementary therapies for the treatment of TBI are therefore being implemented in many preclinical studies. Importantly, the mechanism of action for this treatment may be related to repair of NVU dysfunction by ensuring adequate omega-3 fatty acids, curcumin, resveratrol, apigenin, vitamins, and minerals. These nutritional supplements hold promise for translation to clinical therapy. In addition, dietary habits also play an important role in the rehabilitation of TBI. Poor dietary habits may worsen the pathology and prognosis of TBI. Adjusting dietary habits, especially with a ketogenic diet, may improve outcomes in patients with TBI. This article discusses the impact of clinical nutrition on NVU dysfunction after TBI, focusing on nutritional complexes and dietary habits.

Nano-PSO Administration Attenuates Cognitive and Neuronal Deficits Resulting from Traumatic Brain Injury.

Traumatic Brain Injury (TBI), is one of the most common causes of neurological damage in young populations. It is widely considered as a risk factor for neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's (PD) disease. These diseases are characterized in part by the accumulation of disease-specific misfolded proteins and share common pathological features, such as neuronal death, as well as inflammatory and oxidative damage. Nano formulation of Pomegranate seed oil [Nano-PSO (Granagard TM)] has been shown to target its active ingredient to the brain and thereafter inhibit memory decline and neuronal death in mice models of AD and genetic Creutzfeldt Jacob disease. In this study, we show that administration of Nano-PSO to mice before or after TBI application prevents cognitive and behavioral decline. In addition, immuno-histochemical staining of the brain indicates that preventive Nano-PSO treatment significantly decreased neuronal death, reduced gliosis and prevented mitochondrial damage in the affected cells. Finally, we examined levels of Sirtuin1 (SIRT1) and Synaptophysin (SYP) in the cortex using Western blotting. Nano-PSO consumption led to higher levels of SIRT1 and SYP protein postinjury. Taken together, our results indicate that Nano-PSO, as a natural brain-targeted antioxidant, can prevent part of TBI-induced damage.

Neural stem cell therapy in conjunction with curcumin loaded in niosomal nanoparticles enhanced recovery from traumatic brain injury.

Despite a great amount of effort, there is still a need for reliable treatments of traumatic brain injury (TBI). Recently, stem cell therapy has emerged as a new avenue to address neuronal regeneration after TBI. However, the environment of TBI lesions exerts negative effects on the stem cells efficacy. Therefore, to maximize the beneficial effects of stem cells in the course of TBI, we evaluated the effect of human neural stem/progenitor cells (hNS/PCs) and curcumin-loaded niosome nanoparticles (CM-NPs) on behavioral changes, brain edema, gliosis, and inflammatory responses in a rat model of TBI. After TBI, hNS/PCs were transplanted within the injury site and CM-NPs were orally administered for 10 days. Finally, the effect of combination therapy was compared to several control groups. Our results indicated a significant improvement of general locomotor activity in the hNS/PCs + CM-NPs treatment group compared to the control groups. We also observed a significant improvement in brain edema in the hNS/PCs + CM-NPs treatment group compared to the other groups. Furthermore, a significant decrease in astrogliosis was seen in the combined treatment group. Moreover, TLR4-, NF-κB-, and TNF-α- positive cells were significantly decreased in hNS/PCs + CM-NPs group compared to the control groups. Taken together, this study indicated that combination therapy of stem cells with CM-NPs can be an effective therapy for TBI.

Does access to acute intensive trauma rehabilitation (AITR) programs affect the disposition of brain injury patients?

Early incorporation of rehabilitation services for severe traumatic brain injury (TBI) patients is expected to improve outcomes and quality of life. This study aimed to compare the outcomes regarding the discharge destination and length of hospital stay of selected TBI patients before and after launching an acute intensive trauma rehabilitation (AITR) program at King Saud Medical City. It was a retrospective observational before-and-after study of TBI patients who were selected and received AITR between December 2018 and December 2019. Participants' demographics, mechanisms of injury, baseline characteristics, and outcomes were compared with TBI patients who were selected for rehabilitation care in the pre-AITR period between August 2017 and November 2018. A total of 108 and 111 patients were managed before and after the introduction of the AITR program, respectively. In the pre-AITR period, 63 (58.3%) patients were discharged home, compared to 87 (78.4%) patients after AITR (p = 0.001, chi-squared 10.2). The pre-AITR group's time to discharge from hospital was 52.4 (SD 30.4) days, which improved to 38.7 (SD 23.2) days in the AITR (p < 0.001; 95% CI 6.6-20.9) group. The early integration of AITR significantly reduced the percentage of patients referred to another rehabilitation or long-term facility. We also emphasize the importance of physical medicine and rehabilitation (PM&R) specialists as the coordinators of structured, comprehensive, and holistic rehabilitation programs delivered by the multi-professional team working in an interdisciplinary way. The leadership and coordination of the PM&R physicians are likely to be effective, especially for those with severe disabilities after brain injury.

Reorganization of Thalamic Inputs to Lesioned Cortex Following Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) disrupts thalamic and cortical integrity. The effect of post-injury reorganization and plasticity in thalamocortical pathways on the functional outcome remains unclear. We evaluated whether TBI causes structural changes in the thalamocortical axonal projection terminals in the primary somatosensory cortex (S1) that lead to hyperexcitability. TBI was induced in adult male Sprague Dawley rats with lateral fluid-percussion injury. A virus carrying the fluorescent-tagged opsin channel rhodopsin 2 transgene was injected into the ventroposterior thalamus. We then traced the thalamocortical pathways and analyzed the reorganization of their axonal terminals in S1. Next, we optogenetically stimulated the thalamocortical relays from the ventral posterior lateral and medial nuclei to assess the post-TBI functionality of the pathway. Immunohistochemical analysis revealed that TBI did not alter the spatial distribution or lamina-specific targeting of projection terminals in S1. TBI reduced the axon terminal density in the motor cortex by 44% and in S1 by 30%. A nematic tensor-based analysis revealed that in control rats, the axon terminals in layer V were orientated perpendicular to the pial surface (60.3°). In TBI rats their orientation was more parallel to the pial surface (5.43°, difference between the groups p < 0.05). Moreover, the level of anisotropy of the axon terminals was high in controls (0.063) compared with TBI rats (0.045, p < 0.05). Optical stimulation of the sensory thalamus increased alpha activity in electroencephalography by 312% in controls (p > 0.05) and 237% (p > 0.05) in TBI rats compared with the baseline. However, only TBI rats showed increased beta activity (33%) with harmonics at 5 Hz. Our findings indicate that TBI induces reorganization of thalamocortical axonal terminals in the perilesional cortex, which alters responses to thalamic stimulation.

Naringenin attenuates endoplasmic reticulum stress, reduces apoptosis, and improves functional recovery in experimental traumatic brain injury.

Traumatic brain injury (TBI) is a significant cause of disability and death worldwide. Accumulating evidence suggests that endoplasmic reticulum (ER) stress would be an important component in the pathogenesis of TBI. Although the neuroprotective effects of naringenin, a natural flavonoid isolated from citrus plants, have been confirmed in several neurological diseases, its mechanism of action in TBI needs further investigation. In ICR mice, we found that TBI induced elevated expression of ER stress marker proteins, including 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) in the perilesional cortex, which peaked at 7 days and 3 days after TBI, respectively. The induction of ER stress-related proteins partly coincided with ER architectural changes at 3 days post-TBI, indicating ER stress activation in our TBI model. Our results also revealed that continuous naringenin administration ameliorated neurological dysfunction, cerebral edema, plasmalemma permeability, and neuron cell loss at day 3 after TBI. Further, Naringenin suppressed TBI-induced activation of the ER stress pathway (p-eIF2α, ATF4, and CHOP), oxidative stress and apoptosis on day 3 after TBI. In summary, our data suggest that naringenin could ameliorate TBI-induced secondary brain injury by pleiotropic effects, including ER stress attenuation.

Human platelet lysate biotherapy for traumatic brain injury: preclinical assessment.

Traumatic brain injury (TBI) leads to major brain anatomopathological damages underlined by neuroinflammation, oxidative stress and progressive neurodegeneration, ultimately leading to motor and cognitive deterioration. The multiple pathological events resulting from TBI can be addressed not by a single therapeutic approach, but rather by a synergistic biotherapy capable of activating a complementary set of signalling pathways and providing synergistic neuroprotective, anti-inflammatory, antioxidative, and neurorestorative activities. Human platelet lysate might fulfil these requirements as it is composed of a plethora of biomolecules readily accessible as a TBI biotherapy. In the present study, we tested the therapeutic potential of human platelet lysate using in vitro and in vivo models of TBI. We first prepared and characterized platelet lysate from clinical-grade human platelet concentrates. Platelets were pelletized, lysed by three freeze-thaw cycles, and centrifuged. The supernatant was purified by 56°C 30 min heat treatment and spun to obtain the heat-treated platelet pellet lysate that was characterized by ELISA and proteomic analyses. Two mouse models were used to investigate platelet lysate neuroprotective potential. The injury was induced by an in-house manual controlled scratching of the animals' cortex or by controlled cortical impact injury. The platelet lysate treatment was performed by topical application of 60 µl in the lesioned area, followed by daily 60 µl intranasal administration from Day 1 to 6 post-injury. Platelet lysate proteomics identified over 1000 proteins including growth factors, neurotrophins, and antioxidants. ELISA detected several neurotrophic and angiogenic factors at ∼1-50 ng/ml levels. We demonstrate, using two mouse models of TBI, that topical application and intranasal platelet lysate consistently improved mouse motor function in the beam and rotarod tests, mitigated cortical neuroinflammation, and oxidative stress in the injury area, as revealed by downregulation of pro-inflammatory genes and the reduction in reactive oxygen species levels. Moreover, platelet lysate treatment reduced the loss of cortical synaptic proteins. Unbiased proteomic analyses revealed that heat-treated platelet pellet lysate reversed several pathways promoted by both controlled cortical impact and cortical brain scratch and related to transport, postsynaptic density, mitochondria or lipid metabolism. The present data strongly support, for the first time, that human platelet lysate is a reliable and effective therapeutic source of neurorestorative factors. Therefore, brain administration of platelet lysate is a therapeutical strategy that deserves serious and urgent consideration for universal brain trauma treatment.

Inhibition of ASC enhances the protective role of salvianolic acid A in traumatic brain injury via inhibition of inflammation and recovery of mitochondrial function.

More than 50 million people are affected by traumatic brain injury (TBI) each year around the world, and nearly half of the population worldwide will have one or more TBI(s) in their lifetime. And in 2017, more than 1.39 billion people in China suffered from TBI, representing nearly 18% of the world population; these were mainly caused by road traffic incidents. Salvianolic acid A is a compound obtained from Salvia miltiorrhiza Bunge, which is one of the active components of many traditional Chinese medicines for the treatment of cardiovascular and cerebrovascular disease, with the effect of inhibition of inflammatory response. ASC is a critical factor in the activation of inflammation response process via promoting the maturation of caspase-1, and activation of NLPR3 under bacterial infection promotes the necrosis of cells in an ASC-dependent manner. However, few studies focus on the effect of ASC in a TBI model. In this study, we found that inhibition of ASC reduced the expression of inflammatory cytokines, and the concentration of calcium and ROS, while it increased the expression of mitochondrial function-related proteins. We further noticed that these effects were regulated by DLK2/MLK3/JNK signalling pathway and might contribute to the treatment of TBI.

Cannabidiol and Other Cannabinoids in Demyelinating Diseases.

A growing body of preclinical evidence indicates that certain cannabinoids, including cannabidiol (CBD) and synthetic derivatives, may play a role in the myelinating processes and are promising small molecules to be developed as drug candidates for management of demyelinating diseases such as multiple sclerosis (MS), stroke and traumatic brain injury (TBI), which are three of the most prevalent demyelinating disorders. Thanks to the properties described for CBD and its interesting profile in humans, both the phytocannabinoid and derivatives could be considered as potential candidates for clinical use. In this review we will summarize current advances in the use of CBD and other cannabinoids as future potential treatments. While new research is accelerating the process for the generation of novel drug candidates and identification of druggable targets, the collaboration of key players such as basic researchers, clinicians and pharmaceutical companies is required to bring novel therapies to the patients.

Panax notoginseng protects the rat brain function from traumatic brain injury by inhibiting autophagy via mammalian targeting of rapamycin.

Traumatic brain injury (TBI) remains one of the leading causes of death and disability worldwide. Our previous studies have found that traditional Chinese medicine, Panax notoginseng (P. notoginseng) can reduce cerebral hemorrhage in rats with TBI. Yet, the exact mechanism still remains unclear. According to the random number table, 36 SD rats were randomly divided into six groups: Sham group (negative control group), Model group, PIK inhibitor group (positive group), P. notoginseng group (experimental group), Rapamycin group, and Panax notoginseng+Rapamycin group (experimental group). In the Model group (M group, the group showing signs of TBI without any treatment), the neural function defect score was significantly decreased, while sequestosome 1 (P62), Beclin 1, and microtubule-associated protein 1 light chain 3 (LC3-II) were significantly increased. The brain tissue was significantly damaged, and many autophagosomes were observed in the cytoplasm. Compared with the Model group and the Rapamycin group (M+Rapa group, the group showing signs of TBI with Rapamycin treatment), P62, Beclin 1, and LC3-II were significantly decreased, the score of neural function defect was significantly improved, and the brain tissue damage was significantly reduced in the PIK (phosphatidylinositol 3-kinase) inhibitor group (M+LY group, the group showing signs of TBI with PIK inhibitor treatment). Compared with the Model group, mTOR was decreased and LC3-II was increased; however, there were no significant changes in neural function defect score, HE staining, Nissl staining, and transmission electron microscopy in the Rapamycin group. Compared with the Model group, the neural function defect score at 72h was significantly improved, mTOR was significantly increased, P62, Beclin 1, and LC3-II significantly decreased, brain tissue damage was reduced in HE staining and Nissl staining, autophagosomes were reduced in cytoplasm by transmission electron microscopy in the P. notoginseng group (M+PN group, the group showing signs of TBI with P. notoginseng treatment). Also, there was no significant difference between P. notoginseng group and P. notoginseng+Rapamycin group (M+PN+Rapa group, the group showing signs of TBI with P. notoginseng+Rapamycin treatment). P. notoginseng protects the rat brain function from TBI by inhibiting autophagy through the mTOR signaling pathway and other autophagy pathways.

Androgen is responsible for enhanced susceptibility of melatonin against traumatic brain injury in females.

BACKGROUND: Numerous publications have demonstrated that melatonin administration is associated with mortality reduction and improvement in neurological outcomes after traumatic brain injury (TBI). However, there are significant sex differences in several diseases associated with melatonin. We aimed to determine whether androgen was responsible for enhanced susceptibility of melatonin against TBI in females, as well as potential molecular mechanisms. METHODS: Weight-drop was used to establish a rodent model of TBI. Melatonin (10 mg/kg) and testosterone (1 mg/kg) were administered three times every day for three days after TBI using subcutaneous injection, respectively. Seven days after TBI, an open field assay was used to evaluate locomotor and exploratory activities. Neuronal amount, neuronal apoptosis, and expression of phosphorylated extracellularly regulated protein kinases 1/2 (ERK1/2), c-jun N-terminal kinase 1/2 (JNK1/2), and p38 mitogen-activated protein kinase (p38MAPK) in neurons were assessed using immunofluorescence assay seven days after TBI. The expression of caspase-3, Bax, and Bcl-2 in the frontal cortex was detected using western blot. RESULTS: Compared with female rats, melatonin administration exhibited more neuroprotective effects (including improved locomotor and exploratory activities, elevated neuronal amount, and reduced neuronal apoptosis) in male rats exposed to TBI. Moreover, testosterone significantly improved locomotor and exploratory activities, elevated neuronal amount, decreased neuronal apoptosis, downregulated phosphorylation of JNK1/2- and p38MAPK-positive neurons, but upregulated phosphorylation of ERK1/2-positive neurons in the frontal cortex, and reduced the expressions of cleaved caspase-3, Bax, but increased Bcl-2 expressions in female rats exposed to TBI. CONCLUSIONS: Androgen was responsible for the enhanced susceptibility to TBI under melatonin supplementation in females through a mechanism that may be associated with MAPK pathway regulation.

Dietary manipulation of vulnerability to traumatic brain injury-induced neuronal plasma membrane permeability.

Traumatic brain injury (TBI) can produce physical disruptions in the plasma membranes of neurons, referred to as mechanoporation, which lead to increased cell permeability. We suspect that such trauma-induced membrane disruptions may be influenced by the physical properties of the plasma membrane, such as elasticity or rigidity. These membrane properties are influenced by lipid composition, which can be modulated via diet, leading to the intriguing possibility of prophylactically altering diet to confer resiliency to this mechanism of acute neuronal damage in TBI. In this proof-of-concept study, we used three different diets-one high in polyunsaturated fatty acids suggested to increase elasticity (Fish Oil), one high in saturated fatty acids and cholesterol suggested to increase rigidity (High Fat), and one standard rat chow (Control)-to alter brain plasma membrane lipid composition before subjecting rats to lateral fluid percussion injury (FPI). Lipid analysis (n = 12 rats) confirmed that diets altered brain fatty acid composition after 4 weeks of feeding, with the Fish Oil diet increasing unsaturated fatty acids, and interestingly, the High Fat diet increasing omega-6 docosapentaenoic acid. One cohort of animals (n = 34 rats) was assessed immediately after FPI or sham injury for acute changes in neuronal membrane permeability in the injury-adjacent cortex. Surprisingly, sham animals fed Fish Oil had increased membrane permeability, suggesting altered passive membrane properties. In contrast, injured animals fed the High Fat diet displayed less intense uptake of permeability marker, suggesting a reduced extent of injury-induced plasma membrane disruption, although the density of affected cells matched the other diet groups. In a separate cohort survived for 7 days after FPI (n = 48 rats), animals fed the High Fat diet exhibited a reduced lesion area. At both time points there were no statistically significant differences in inflammation. Unexpectedly, these results indicate that the High Fat diet, as opposed to the Fish Oil diet, beneficially modulated acute plasma membrane permeability and resulted in a smaller lesion size at 7 days post-injury. Additional studies are necessary to determine the impact of these various diets on behavioral outcomes post-TBI. Further investigation is also needed to understand the physical properties in neuronal plasma membranes that may underlie increased resiliency to trauma-induced disruptions and, importantly, to understand how these properties may be influenced by targeted dietary modifications for vulnerable populations.

Antioxidant Combo Therapy Protects White Matter After Traumatic Brain Injury.

Following traumatic brain injury (TBI), increased production of reactive oxygen species (ROS) and the ensuing oxidative stress promotes the secondary brain damage that encompasses both grey matter and white matter. As this contributes to the long-term neurological deficits, decreasing oxidative stress during the acute period of TBI is beneficial. While NADPH oxidase (NOX2) is the major producer of ROS, transcription factor Nrf2 that induces antioxidant enzymes promotes efficient ROS disposal. We recently showed that treatment with an antioxidant drug combo of apocynin (NOX2 inhibitor) and TBHQ (Nrf2 activator) protects the grey matter in adult mice subjected to TBI. We currently show that this antioxidant combo therapy given at 2 h and 24 h after TBI also protects white matter in mouse brain. Thus, the better functional outcomes after TBI in the combo therapy treated mice might be due to a combination of sparing both grey matter and white matter. Hence, the antioxidant combo we tested is a potent therapeutic option for translation in future.

Orally Administered Cinnamon Extract Attenuates Cognitive and Neuronal Deficits Following Traumatic Brain Injury.

The present paper shows how cinnamon extract (CE) consumption mitigates neuronal loss and memory impairment following traumatic brain injury (TBI), one of the world's most common neurodegenerative diseases. TBI patients suffer short- and long-term behavioral, cognitive, and emotional impairments, including difficulties in concentration, memory loss, and depression. Research shows that CE application can mitigate cognitive and behavioral impairments in animal models for Alzheimer's and Parkinson's disease, whose pathophysiology is similar to that of TBI. This study builds on prior research by showing similar results in TBI mice models. After drinking CE for a week, mice were injured using our 70-g weight drop TBI device. For 2 weeks thereafter, the mice continued drinking CE alongside standard lab nutrition. Subsequently, the mice underwent behavioral tests to assess their memory, motor activity, and anxiety. The mice brains were harvested for immunohistochemistry staining to evaluate overall neuronal survival. Our results show that CE consumption almost completely mitigates memory impairment and decreases neuronal loss after TBI. Mice that did not consume CE demonstrated impaired memory. Our results also show that CE consumption attenuated neuronal loss in the temporal cortex and the dentate gyrus. Mice that did not consume CE suffered a significant neuronal loss. There were no significant differences in anxiety levels and motor activity between all groups. These findings show a new therapeutic approach to improve cognitive function and decrease memory loss after TBI.

Effects of Nimodipine and Nigella sativa on Oxidative Stress and Apoptosis in Serum and Brain Tissue of Rats with Experimental Head Trauma.

AIM: To investigate whether Nimodipine (N) and Nigella sativa (NS) oil have protective, antioxidant effects in brain injury caused by experimental head trauma. MATERIAL AND METHODS: Fifty albino Wistar rats were randomly divided into 5 groups that underwent experimental head trauma. Oxidative parameters were compared in the serum and brain tissue of the different groups. In addition, apoptosis and caspase-3 immunoreactivity were evaluated by histopathological examination. RESULTS: Serum total antioxidant status (TAS) levels were significantly increased in N and N+NS groups when compared with controls (p=0.001, p < 0.01). Tissue TAS levels were significantly higher in the NS and N+NS groups compared to controls (p=0.001, p < 0.01). Total oxidant status levels in the brain tissue were significantly higher in the NS group than in the control group (p=0.021). CONCLUSION: N and NS were shown to significantly reduce the occurrence of oxidative stress in secondary brain injury due to head trauma. We also found that apoptosis levels decreased in response to N, NS and N+NS treatments after head trauma.

Corticosteroid receptor rebalancing alleviates critical illness-related corticosteroid insufficiency after traumatic brain injury by promoting paraventricular nuclear cell survival via Akt/CREB/BDNF signaling.

BACKGROUND: We previously found that high-dose methylprednisolone increased the incidence of critical illness-related corticosteroid insufficiency (CIRCI) and mortality in rats with traumatic brain injury (TBI), whereas low-dose hydrocortisone but not methylprednisolone exerted protective effects. However, the receptor-mediated mechanism remains unclear. This study investigated the receptor-mediated mechanism of the opposite effects of different glucocorticoids on the survival of paraventricular nucleus (PVN) cells and the incidence of CIRCI after TBI. METHODS: Based on controlled cortical impact (CCI) and treatments, male SD rats (n = 300) were randomly divided into the sham, CCI, CCI + GCs (methylprednisolone 1 or 30 mg/kg/day; corticosterone 1 mg/kg/day), CCI + methylprednisolone+RU486 (RU486 50 mg/kg/day), and CCI + corticosterone+spironolactone (spironolactone 50 mg/kg/day) groups. Blood samples were collected 7 days before and after CCI. Brain tissues were collected on postinjury day 7 and processed for histology and western blot analysis. RESULTS: We examined the incidence of CIRCI, mortality, apoptosis in the PVN, the receptor-mediated mechanism, and downstream signaling pathways on postinjury day 7. We found that methylprednisolone and corticosterone exerted opposite effects on the survival of PVN cells and the incidence of CIRCI by activating different receptors. High-dose methylprednisolone increased the nuclear glucocorticoid receptor (GR) level and subsequently increased cell loss in the PVN and the incidence of CIRCI. In contrast, low-dose corticosterone but not methylprednisolone played a protective role by upregulating mineralocorticoid receptor (MR) activation. The possible downstream receptor signaling mechanism involved the differential effects of GR and MR on the activity of the Akt/CREB/BDNF pathway. CONCLUSION: The excessive activation of GR by high-dose methylprednisolone exacerbated apoptosis in the PVN and increased CIRCI. In contrast, refilling of MR by corticosterone protects PVN neurons and reduces the incidence of CIRCI by promoting GR/MR rebalancing after TBI.

Valproic acid treatment rescues injured tissues after traumatic brain injury.

BACKGROUND: No agents that are specifically neuroprotective are currently approved to emergently treat patients with traumatic brain injury (TBI). The histone deacetylase inhibitor, high-dose valproic acid (VPA) has been shown to have cytoprotective potential in models of combined TBI and hemorrhagic shock, but it has not been tested in an isolated TBI model. We hypothesized that VPA, administered after isolated TBI, will penetrate the injured brain, attenuate the lesion size, and activate prosurvival pathways. METHODS: Yorkshire swine were subjected to severe TBI by cortical impact. One hour later, animals were randomized to VPA treatment (150 mg/kg delivered intravenously for 1 hour; n = 4) or control (saline vehicle; n = 4) groups. Seven hours after injury, animals were sacrificed, and brain lesion size was measured. Mass spectrometry imaging was used to visualize and quantitate brain tissue distribution of VPA. Sequential serum samples were assayed for key biomarkers and subjected to proteomic and pathway analysis. RESULTS: Brain lesion size was 50% smaller (p = 0.01) in the VPA-treated animals (3,837 ± 948 mm) compared with the controls (1,900 ± 614 mm). Endothelial regions had eightfold higher VPA concentrations than perivascular regions by mass spectrometry imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared with the control animals (p < 0.05). More than 500 proteins were differentially expressed in the brain, and pathway analysis revealed that VPA affected critical modulators of TBI response including calcium signaling pathways, mitochondria metabolism, and biosynthetic machinery. CONCLUSION: Valproic acid penetrates injured brain tissues and exerts neuroprotective and prosurvival effects that resulted in a significant reduction in brain lesion size after isolated TBI. Levels of serum biomarkers reflect these changes, which could be useful for monitoring the response of TBI patients during clinical studies.

Circulating GFAP and Iba-1 levels are associated with pathophysiological sequelae in the thalamus in a pig model of mild TBI.

Serum biomarkers are promising tools for evaluating patients following traumatic brain injury (TBI). However, their relationship with diffuse histopathology remains unclear. Additionally, translatability is a focus of neurotrauma research, however, studies using translational animal models are limited. Here, we evaluated associations between circulating biomarkers and acute thalamic histopathology in a translational micro pig model of mTBI. Serum samples were collected pre-injury, and 1 min-6 h following mTBI. Markers of neuronal injury (Ubiquitin Carboxy-terminal Hydrolase L1 [UCH-L1]), microglial/macrophage activation (Ionized calcium binding adaptor molecule-1 [Iba-1]) and interleukin-6 [IL-6]) and astrogliosis/astrocyte damage (glial fibrillary acidic protein [GFAP]) were measured. Axonal injury and histological features of neurons and glia were also investigated using immunofluorescent labeling and correlated to serum levels of the associated biomarkers. Consistent with prior experimental and human studies, GFAP, was highest at 6 h post-injury, while no substantial changes were observed in UCH-L1, Iba-1 or IL-6 over 6 h. This study also found promising associations between thalamic glial histological signatures and ensuing release of Iba-1 and GFAP into the circulation. Our findings suggest that in diffuse injury, monitoring serum Iba-1 and GFAP levels can provide clinically relevant insight into the underlying acute pathophysiology and biomarker release kinetics following mTBI, providing previously underappreciated diagnostic capability.

Curcumin alleviates neuroinflammation, enhances hippocampal neurogenesis, and improves spatial memory after traumatic brain injury.

Cognitive decline is one of the most obvious symptoms of traumatic brain injury (TBI). Previous studies have demonstrated that cognitive decline is related to substantially increased neuroinflammation and decreased neurogenesis in the hippocampus in a rat model of TBI. Using this model, we explored the role of curcumin (Cur) in ameliorating TBI-impaired spatial memory because Cur has been shown to exhibit anti-chronic-neuroinflammatory, neurogenesis-promoting, and memory-improving properties. Animals received daily Cur or vehicle treatment for 28 days after TBI and also received 50-bromodeoxyuridine(BrdU) for the first 7 days of the treatment for assaying neurogenesis. An optimal Cur dose of 30 mg/kg, selected from a range of 10-50 mg/kg, was used for the present study. Neuroinflammation was evaluated by astrocyte hypertrophy, activated microglia, and inflammatory factors in the hippocampus. Behavioral water-maze studies were conducted for 5 days, starting at 35-day post-TBI. The tropomyosin receptor kinase B (Trkb) inhibitor, ANA-12, was used to test the role of the brain-derived neurotrophic factor (BDNF)/ TrkB/Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in regulating inflammation and neurogenesis in the hippocampus. Treatment with Cur ameliorated the spatial memory of TBI rats, reduced TBI-induced chronic inflammation, typified by diminished astrocyte hypertrophy, reduction in activated microglia, declined inflammatory factors, and increased neurogenesis in the hippocampus. We also found that BDNF/Trkb/PI3K/Akt signaling was involved in the effects of Cur in TBI rats. Thus, Cur treatment can ameliorate the spatial memory in a murine model of TBI, which may be attributable to decreased chronic neuroinflammation, increased hippocampal neurogenesis, and/or BDNF/Trkb/PI3K/Akt signaling.

The Attenuation of Traumatic Brain Injury via Inhibition of Oxidative Stress and Apoptosis by Tanshinone IIA.

Traumatic brain injury (TBI) is a major source of mortality and long-term disability worldwide. The mechanisms associated with TBI development are poorly understood, and little progress has been made in the treatment of TBI. Tanshinone IIA is an effective agent to treat a variety of disorders; however, the mechanisms of Tanshinone IIA on TBI remain unclear. The aim of the present study was to investigate the therapeutic potential of Tanshinone IIA on TBI and its underlying molecular mechanisms. Changes in microvascular permeability were examined to determine the extent of TBI with Evans blue dye. Brain edema was assessed by measuring the wet weight to dry weight ratio. The expression levels of CD11, interleukin- (IL-) 1ß, and tumor necrosis factor- (TNF-) α mRNA were determined by reverse transcription-quantitative PCR. Aquaporin-4 (AQP4), glial fibrillary acidic protein (GFAP), and p47phox protein expression levels were detected by western blotting. Superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-PX) activities, and malondialdehyde (MDA) content were determined using commercial kits. Cell apoptosis was detected by western blotting and TUNEL staining. Tanshinone IIA (10 mg/kg/day, intraperitoneal administration) significantly reduced brain water content and vascular permeability at 12, 24, 48, and 72 h after TBI. Tanshinone IIA downregulated the mRNA expression levels of various factors induced by TBI, including CD11, IL-1ß, and TNF-α. Notably, CD11 mRNA downregulation suggested that Tanshinone IIA inhibited microglia activation. Further results showed that Tanshinone IIA treatment significantly downregulated AQP4 and GFAP expression. TBI-induced oxidative stress and apoptosis were markedly reversed by Tanshinone IIA, with an increase in SOD and GSH-PX activities and a decrease in the MDA content. Moreover, Tanshinone IIA decreased TBI-induced NADPH oxidase activation via the inhibition of p47phox. Tanshinone IIA attenuated TBI, and its mechanism of action may involve the inhibition of oxidative stress and apoptosis.