Induction Of Traumatic Brain Injury Research Articles

Bone marrow stromal cells promote neuromotor functional recovery, via upregulation of neurotrophic factors and synapse proteins following traumatic brain injury in rats.

It has previously been demonstrated that bone marrow stromal cells (BMSCs) exhibit great therapeutic potential in neuronal injuries; however, there is limited understanding of the precise underlying mechanisms that contribute to functional improvement following brain injury. The aim of the present study was to assess the effect of BMSC treatment on traumatic brain injury (TBI) in rats, and investigate if they migrate to injured areas and promote neuromotor functional recovery via upregulation of neurotrophic factors and synaptic proteins. BMSCs were cultured in vitro from female Sprague Dawley (SD) rat bone marrow and were subsequently infused into male adult SD rats via the tail vein, following induction of TBI. The results demonstrated that treatment with BMSCs significantly reduced TBI-induced neuromotor impairment and neuronal loss, as assessed by rota rod testing, western blot analysis, modified neurological severity score and immunohistochemistry. The distribution of transplanted BMSCs was tracked by monitoring the expression of sex determining region Y (SRY) in rats. The number of cells double-positive for SRY/neuronal nuclear antigen or SRY/glial fibrillary acidic protein was increased in the BMSC group, which demonstrated that BMSCs migrated to injured areas and differentiated into neurons and astrocytes, following TBI. Furthermore, administration of BMSCs increased expression of vascular endothelial growth factor and brain derived neurotrophic factor. Protein expression levels of synaptophysin were downregulated following TBI and this was reversed in part by treatment with BMSCs. These findings uncovered some underlying mechanisms of action of BMSCs, and may lead to their potential use as a future effective therapeutic agent for the treatment of TBI.

The Effects of Chunghyul-Dan, an Agent of Korean Medicine, on a Mouse Model of Traumatic Brain Injury.

Chunghyul-Dan (CHD) is the first choice agent for the prevention and treatment of stroke at the Kyung Hee Medical Hospital. To date, CHD has been reported to have beneficial effects on brain disease in animals and humans, along with antioxidative and anti-inflammatory effects. The aim of this study was to evaluate the pharmacological effects of CHD on a traumatic brain injury (TBI) mouse model to explore the possibility of CHD use in patients with TBI. The TBI mouse model was induced using the controlled cortical impact method. CHD was orally administered twice a day for 5 d after TBI induction; mice were assessed for brain damage, brain edema, blood-brain barrier (BBB) damage, motor deficits, and cognitive impairment. Treatment with CHD reduced brain damage seen on histological examination and improved motor and cognitive functions. However, CHD did not reduce brain edema and BBB damage. In conclusion, CHD could be a candidate agent in the treatment of patients with TBI. Further studies are needed to assess the exact mechanisms of the effects during the acute-subacute phase and pharmacological activity during the chronic-convalescent phase of TBI.

Neuroprotective effects of miR-27a against traumatic brain injury via suppressing FoxO3a-mediated neuronal autophagy

MicroRNA-27a (miR-27a) has been reported to be a brain-specific miRNA and aberrantly expressed in the brain suffered from traumatic brain injury (TBI). The present study is designed to investigate the potential role and molecular mechanism of miR-27a in the pathogenesis of TBI. The level of miR-27a in brain was manipulated by intracerebroventricular injection of lentiviral-encoding miR-27a before TBI induction. Real-time PCR was used to detected miR-27a and Forkhead box O3a (FoxO3a) levels in the hippocampus. Then, we evaluated the impact of miR-27a overexpression on neurological function, brain edema, lesion volume and neuronal autophagy after TBI. The blinding of miR-27a to the 3′UTR of FoxO3a mRNA and its effects on FoxO3a translation were analyzed by luciferase reporter assay and Western blot. The downregulation of miR-27a and the increase in FoxO3a level were observed in the hippocampus post-TBI. Overexpression of miR-27a significantly attenuated neurological deficits and brain injury, especially suppressed autophagic activation after TBI. Furthermore, we identified that miR-27a directly targeted the FoxO3a 3′UTR region to reduced FoxO3a protein expression. Knockdown of FoxO3a significantly reversed high levels of autophagy-related genes induced by TBI. Taken together, Overexpression of miR-27a may protect against brain injury via suppressing FoxO3a-mediated neuronal autophagy following TBI.

Neuroprotective Effects of Bone Marrow Stromal Cell Transplantation in Combination With Treadmill Exercise Following Traumatic Brain Injury.

Purpose:Traumatic brain injury (TBI) causes cognitive impairments, motor deficits, and neuropsychiatric/behavioral deficits problems. Transplantation of bone marrow stromal cells (BMSCs) facilitates functional recovery from brain insults. Treadmill exercise increases neurogenesis and inhibits apoptosis. In this study, we investigated the effects of BMSC transplantation in combination with treadmill exercise on memory function, by evaluating its effect on neurogenesis and apoptosis in the hippocampus following TBI.Methods:TBI was induced using an electromagnetic-controlled cortical impact device. BMSCs were transplanted into both sides of traumatic scar region 1 week after TBI induction. One week after transplantation of BMSCs, the rats in the exercise groups were trained to run on a treadmill for 30 minutes once daily for 28 days. Step-down avoidance task and radial 8-arm maze test were conducted. Levels of 5-bromo-2ʹ-deoxyuridine and caspase-3 were evaluated using immunohistochemistry. Western blot was used to evaluate the expression of brain-derived neurotrophic factor (BDNF), tyrosine kinase B (TrkB), total-extracellular signal-regulated kinase 1 and 2 (t-ERK1/2), phosphorylated-ERK1/2 (p-ERK1/2), Bcl-2, and Bax.Results:TBI deteriorated memory function, suppressed neurogenesis, and accelerated apoptosis in the hippocampus. Treadmill exercise and BMSC transplantation independently improved memory function by increasing neurogenesis with suppression of apoptosis through the BDNF-ERK pathway in the TBI-induced rats. Combination of BMSC transplantation with treadmill exercise showed additional enhancement of neurogenesis and suppression of apoptosis in the hippocampus.Conclusions:The present study shows that treadmill exercise may aid the therapeutic effect of BMSC transplantation on TBI in rats.

Chromatographically isolated CD63+CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI

Extracellular vesicles (EVs) secreted by cells present an attractive strategy for developing new therapies, but progress in the field is limited by several issues: The quality of the EVs varies with the type and physiological status of the producer cells; protocols used to isolate the EVs are difficult to scale up; and assays for efficacy are difficult to develop. In the present report, we have addressed these issues by using human mesenchymal stem/stromal cells (MSCs) that produce EVs when incubated in a protein-free medium, preselecting the preparations of MSCs with a biomarker for their potency in modulating inflammation, incubating the cells in a chemically defined protein-free medium that provided a stable environment, isolating the EVs with a scalable chromatographic procedure, and developing an in vivo assay for efficacy of the cells in suppressing neuroinflammation after traumatic brain injury (TBI) in mice. In addition, we demonstrate that i.v. infusion of the isolated EVs shortly after induction of TBI rescued pattern separation and spatial learning impairments 1 mo later.

Gallic acid improved behavior, brain electrophysiology, and inflammation in a rat model of traumatic brain injury.

Traumatic brain injury (TBI) is one of the main causes of intellectual and cognitive disabilities. In the clinic it is essential to limit the development of cognitive impairment after TBI. In this study, the effects of gallic acid (GA; 100 mg/kg, per oral, from 7 days before to 2 days after TBI induction) on neurological score, passive avoidance memory, long-term potentiation (LTP) deficits, and levels of proinflammatory cytokines including interleukin-1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) in the brain have been evaluated. Brain injury was induced following Marmarou's method. Data were analyzed by one-way and repeated measures ANOVA followed by Tukey's post-hoc test. The results indicated that memory was significantly impaired (p < 0.001) in the group treated with TBI + vehicle, together with deterioration of the hippocampal LTP and increased brain tissue levels of IL-1β, IL-6, and TNF-α. GA treatment significantly improved memory and LTP in the TBI rats. The brain tissue levels of IL-1β, IL-6, and TNF-α were significantly reduced (p < 0.001) in the group treated with GA. The results suggest that GA has neuroprotective properties against TBI-induced behavioral, electrophysiological, and inflammatory disorders, probably via the decrease of cerebral proinflammatory cytokines.

Traumatic brain injury opens blood–brain barrier to stealth liposomes via an enhanced permeability and retention (EPR)-like effect

The opening of the tight junctions in the blood–brain barrier (BBB) following traumatic brain injury (TBI) is hypothesized to be sufficient to enable accumulation of large drug carriers, such as stealth liposomes, in a similar manner to the extravasation seen in tumor tissue via the enhanced permeability and retention (EPR) effect. The controlled cortical impact model of TBI was used to evaluate liposome accumulation in mice. Dual-radiolabeled PEGylated liposomes were administered either immediately after induction of TBI or at increasing times post-TBI to mimic the likely clinical scenario. The accumulation of radiolabel in the brain tissue ipsilateral and contralateral to the site of trauma, as well as in other organs, was evaluated. Selective influx of liposomes occurred at 0–8 h after injury, while the barrier closed between 8 and 24 hr after injury, consistent with reports on albumin infiltration. Significantly enhanced accumulation of liposomes occurred in mice subjected to TBI compared to anaesthetized controls, and accumulation was greater in the injured versus the contralateral side of the brain. Thus, stealth liposomes show potential to enhance drug delivery to the site of brain injury with a wide range of encapsulated therapeutic candidates.

Effects of Modifications of the Functional State of the Central Cholinergic System on Neurological Deficiency Related to Experimental Traumatic Brain Injury

Using a 100-point Todd scale, we examined the level of neurological deficiency in male albino rats subjected to dosed experimental traumatic brain injury (TBI). In one of the three experimental groups with TBI, animals were not subjected to additional influences; in another group, the central cholinergic system (CChS) was activated by introduction of a central-action cholinomimetic, choline alfoscerate (Gliatilin); in the third group, the activity of the above system was suppressed by a cholinoblocker, biperiden (Akineton). In rats with TBI, the level of neurological deficiency progressively increased; in this group, the estimates at 3 and 72 h after TBI induction corresponded to 474 and 950% of the respective values in intact animals. Blocking of the cholinergic system additionally aggravated manifestations of neurological deficiency, especially within earlier time intervals after TBI (3 and 24 h). Pharmacological activation of the CChS significantly smoothed manifestations of neurological disorders (several times, as compared with those in the TBI group with no additional influences).

The effect of traumatic brain injury on bone healing: an experimental study in a novel in vivo animal model

IntroductionAmong many factors determining the outcome of complex fractures in polytrauma patients, the role of traumatic brain injury (TBI) remains only partly understood. The aim of the present study was to examine the effect of traumatic brain injury on bone healing through the establishment of a novel standardised animal model that sequentially combines traumatic brain injury (TBI) with a long bone injury. Materials and methodsThirty-six female twelve-week old C57/BL6 mice were randomised in two groups (fracture (Fx)-group and combined-trauma (Fx/TBI) group). The methods of the Control Cortical Impact Injury for induction of TBI and of the femoral osteotomy, fixed with an external fixator for the simulation of the long bone fracture, were combined. No TBI was induced in the Fx-group. Bone healing was examined using in vivo micro-CT measurements over a period of three weeks. ResultsThe severity of the TBI was sufficient to stimulate a significantly increased callus formation in the Fx/TBI-group with an acceptable mortality rate. The micro-CT analysis of fracture healing displayed a significantly increased callus volume in the Fx/TBI-group already from the second postoperative week. This difference remained significant throughout the entire study period. DiscussionThe successful and standardised combination of TBI and fracture in a mouse model allows systematic and quantitative in vivo analysis of underlying pathways that trigger the mutual interaction between musculoskeletal trauma and brain injury, as well as, corresponding differences in fracture healing using micro-CT methods. ConclusionThe present study offers three new aspects: a standardised model for combined injury of TBI and femoral osteotomy; direct and serial in vivo imaging and quantification of fracture healing response using micro-CT; testing of potentially beneficial therapeutic regimens for fracture treatment in presence of TBI. Thus this model provides a valuable basic approach for the study of the amplifying effect of TBI on callus formation seen in patients with craniocerebral injury and concomitant skeletal trauma.

The acute phase of mild traumatic brain injury is characterized by a distance-dependent neuronal hypoactivity.

The consequences of mild traumatic brain injury (TBI) on neuronal functionality are only now being elucidated. We have now examined the changes in sensory encoding in the whisker-recipient barrel cortex and the brain tissue damage in the acute phase (24 h) after induction of TBI (n=9), with sham controls receiving surgery only (n=5). Injury was induced using the lateral fluid percussion injury method, which causes a mixture of focal and diffuse brain injury. Both population and single cell neuronal responses evoked by both simple and complex whisker stimuli revealed a suppression of activity that decreased with distance from the locus of injury both within a hemisphere and across hemispheres, with a greater extent of hypoactivity in ipsilateral barrel cortex compared with contralateral cortex. This was coupled with an increase in spontaneous output in Layer 5a, but only ipsilateral to the injury site. There was also disruption of axonal integrity in various regions in the ipsilateral but not contralateral hemisphere. These results complement our previous findings after mild diffuse-only TBI induced by the weight-drop impact acceleration method where, in the same acute post-injury phase, we found a similar depth-dependent hypoactivity in sensory cortex. This suggests a common sequelae of events in both diffuse TBI and mixed focal/diffuse TBI in the immediate post-injury period that then evolve over time to produce different long-term functional outcomes.

Ulinastatin attenuates brain edema after traumatic brain injury in rats.

Traumatic brain injury (TBI) remains the leading cause of injury-related death and disability. Brain edema, one of the most major complications of TBI, contributes to elevated intracranial pressure, and poor prognosis following TBI. The objective of this study was to evaluate whether Ulinastatin (UTI), a serine protease inhibitor, attenuates brain edema following TBI. Our results showed that treatment with UTI at a dose of 50,000 U/kg attenuated the brain edema, as assayed by water content 24 h after TBI induction. This attenuation was associated with a significant decrease of the expression level of aquaporin-4. In addition, we showed that UTI treatment also markedly inhibited the expression of pro-inflammatory cytokines including IL-1β and TNF-α as well as activity of NF-κB. Collectively, our findings suggested that UTI may be a promising strategy to treat brain edema following TBI.

The effects of cyclooxygenase inhibitors on the gastric emptying and small intestine transit in the male rats following traumatic brain injury.

This study was carried out to investigate the effects of COX-2 selective inhibitor (Celecoxib) or non-selective COX inhibitor (Ibuprofen) on gastrointestinal motility. THE RATS WERE RANDOMLY DIVIDED INTO FIVE GROUPS INCLUDING: intact, sham, traumatic brain injury (TBI) group (intact rats under TBI), Celecoxib group (10 mg/kg), Ibuprofen group (10 mg/kg). Rats of the treatment groups received gavages at 1 hr before the TBI induction. The TBI was moderate and diffused using the Marmarou method. The gastric emptying and small intestine transit were measured by phenol red method. The gastric emptying didn't change following TBI induction compared to intact group. The consumption of ibuprofen or celecoxib didn't have any effect on gastric emptying compared to sham group. TBI induction didn't have any effect on the intestinal transit. Also, there was no significant difference between ibuprofen or celecoxib consumption vs. sham group (P>0.05). The COX-2 selective inhibitor (celecoxib) or non-selective COX inhibitor (ibuprofen) have no effects on gastric or small bowel transit. Further work is necessary to investigate the effects of non-selective COX inhibitors and their impact on gastrointestinal motility disorders.

Neuroprotection induced by N-acetylcysteine and selenium against traumatic brain injury-induced apoptosis and calcium entry in hippocampus of rat.

Neurodegeneration associated with acute central nervous system injuries and diseases such as spinal cord injury and traumatic brain injury (TBI) are reported to be mediated by the regulation of apoptosis and oxidative stress through Ca(2+) influx. The thiol redox system antioxidants, such as N-acetylcysteine (NAC) and selenium (Se), display neuroprotective activities mediated at least in part by their antioxidant and anti-inflammatory properties. However, there are no reports on hippocampal apoptosis, cytosolic reactive oxygen species (ROS), or Ca(2+) values in rats with an induced TBI. Therefore, we tested the effects of Se and NAC administration on apoptosis, oxidative stress, and Ca(2+) influx through TRPV1 channel activations in the hippocampus of TBI-induced rats. The 32 rats were divided into four groups: control, TBI, TBI + NAC, and TBI + Se groups. Intraperitoneal administrations of NAC and Se were performed at 1, 24, 48, and 72 h after TBI induction. After 3 days, the hippocampal neurons were freshly isolated from the rats. In cytosolic-free Ca(2+) analyses, the neurons were stimulated with the TRPV1 channel agonist capsaicin, a pungent compound found in hot chili peppers. Cytosolic-free Ca(2+), apoptosis, cytosolic ROS levels, and caspase-3 and -9 activities were higher in the TBI group than control. The values in the hippocampus were decreased by Se and NAC administrations. In conclusion, we observed that NAC and Se have protective effects on oxidative stress, apoptosis, and Ca(2+) entry via TRPV1 channel activation in the hippocampus of this TBI model, but the effect of NAC appears to be much greater than that of Se. They are both interesting candidates for studying the amelioration of TBIs.

N-Acetylcysteine and Selenium Modulate Oxidative Stress, Antioxidant Vitamin and Cytokine Values in Traumatic Brain Injury-Induced Rats

It has been suggested that oxidative stress plays an important role in the pathophysiology of traumatic brain injury (TBI). N-acetylcysteine (NAC) and selenium (Se) display neuroprotective activities mediated at least in part by their antioxidant and anti-inflammatory properties although there is no report on oxidative stress, antioxidant vitamin, interleukin-1 beta (IL)-1β and IL-4 levels in brain and blood of TBI-induced rats. We investigated effects of NAC and Se administration on physical injury-induced brain toxicity in rats. Thirty-six male Sprague-Dawley rats were equally divided into four groups. First and second groups were used as control and TBI groups, respectively. NAC and Se were administrated to rats constituting third and forth groups at 1, 24, 48 and 72h after TBI induction, respectively. At the end of 72h, plasma, erythrocytes and brain cortex samples were taken. TBI resulted in significant increase in brain cortex, erythrocytes and plasma lipid peroxidation, total oxidant status (TOS) in brain cortex, and plasma IL-1β values although brain cortex vitamin A, β-carotene, vitamin C, vitamin E, reduced glutathione (GSH) and total antioxidant status (TAS) values, and plasma vitamin E concentrations, plasma IL-4 level and brain cortex and erythrocyte glutathione peroxidase (GSH-Px) activities decreased by TBI. The lipid peroxidation and IL-1β values were decreased by NAC and Se treatments. Plasma IL-4, brain cortex GSH, TAS, vitamin C and vitamin E values were increased by NAC and Se treatments although the brain cortex vitamin A and erythrocyte GSH-Px values were increased through NAC only. In conclusion, NAC and Se caused protective effects on the TBI-induced oxidative brain injury and interleukin production by inhibiting free radical production, regulation of cytokine-dependent processes and supporting antioxidant redox system.

Does the Neuroprotective Role of Anandamide Display Diurnal Variations?

The endocannabinoid system is a component of the neuroprotective mechanisms that an organism displays after traumatic brain injury (TBI). A diurnal variation in several components of this system has been reported. This variation may influence the recovery and survival rate after TBI. We have previously reported that the recovery and survival rate of rats is higher if TBI occurs at 1:00 than at 13:00. This could be explained by a diurnal variation of the endocannabinoid system. Here, we describe the effects of anandamide administration in rats prior to the induction of TBI at two different times of the day: 1:00 and 13:00. We found that anandamide reduced the neurological damage at both times. Nevertheless, its effects on bleeding, survival, food intake, and body weight were dependent on the time of TBI. In addition, we analyzed the diurnal variation of the expression of the cannabinoid receptors CB1R and CB2R in the cerebral cortex of both control rats and rats subjected to TBI. We found that CB1R protein was expressed more during the day, whereas its mRNA level was higher during the night. We did not find a diurnal variation for the CB2R. In addition, we also found that TBI increased CB1R and CB2R in the contralateral hemisphere and disrupted the CB1R diurnal cycle.

Survivin, a key component of the Wnt/β-catenin signaling pathway, contributes to traumatic brain injury-induced adult neurogenesis in the mouse dentate gyrus

The enhancement of endogenous neurogenesis has been suggested in the treatment of traumatic brain injury (TBI); however, the factors that trigger the process of adult neurogenesis following TBI remain elusive. In the adult mammalian central nervous system, there are 2 neurogenic regions: the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles, both of which maintain relatively quiescent states in a stable microenvironment. However, once stimulated by intrinsic and extrinsic events, relevant signals are activated in these 2 regions. In this study, in order to explore the mechanisms behind endogenous neurogenesis following TBI, we investigated potential factors regulating this process. We observed that the expression of survivin, an anti-apoptotic protein, increased in a time-dependent manner in the hippocampus in a mouse model of TBI. In addition, the number of survivin (+) cells, as well as that of BrdU (+) cells increased in the SGZ of the dentate gyrus (DG) in the hippocampus following TBI, as shown by immunofluorescence double staining; the co-localization of survivin and BrdU was shown in the merged images. The expression of survivin was also significantly increased in the doublecortin (DCX) (+) immature neurons in the DG of the hippocampus soon after the induction of TBI. Taken together, these data confirm the connection between the expression of survivin and adult neurogenesis following TBI; our data also suggest the therapeutic potential of upregulating survivin expression as a novel strategy for the effective treatment of TBI.

Contribution of estrogen receptors alpha and beta in the brain response to traumatic brain injury

Although there is evidence that estradiol has neuroprotective effects after traumatic brain injury (TBI) in female rats, it is unclear which estrogen receptor (ER) subtype, ERα or ERβ, mediates this effect. The authors therefore examined the roles of the different ERs in this effect. Here the authors used the ERα selective agonist propyl pyrazole triol (PPT) and the ERβ selective agonist diarylpropionitrile (DPN) alone and in combination in female rats to investigate this question. Before the ovariectomized animals were injured using the Marmarou TBI technique, they were randomly divided into the following 9 groups: control, sham, TBI, vehicle, E1 (physiological dose of 17-β estradiol), E2 (pharmacological dose of 17-β estradiol), PPT, DPN, and PPT+DPN. Levels of blood-brain barrier (BBB) disruption (5 hours) and water content (24 hours) were evaluated after TBI. In groups receiving drugs or vehicle, treatment was administered as a single dose intraperitoneally 30 minutes after induction of TBI. Results showed that brain edema or brain water content after TBI was lower (p < 0.001) in the E2, PPT, DPN, and PPT+DPN groups than it was in the vehicle group. After trauma, the Evans blue dye content or BBB permeability was significantly higher in the TBI and vehicle groups (p < 0.001) than in the E2, PPT, DPN, and PPT+DPN groups. The inhibitory effects of PPT+DPN on brain water content, neurological scores, and Evans blue dye content were the highest for all groups. Although both PPT and DPN increased neurological scores after TBI, PPT appears to be more effective in increasing neurological scores. Neuroprotective effects of estradiol on brain edema, BBB permeability, and neurological scores are mediated through both ERα and ERβ. This may suggest a therapeutic potential in the brain trauma for ER-specific agonists.

Resuscitation from experimental traumatic brain injury by magnolol therapy

BackgroundThe purpose of the present study was to determine whether magnolol, a free radical scavenger, mitigates the deleterious effects of traumatic brain injury (TBI). Material and methodsTraumatic brain injuries were induced in anesthetized male Sprague-Dawley rats using fluid percussion, and the rats were divided into groups treated with magnolol (2 mg/kg, intravenously) or vehicle. A group of rats that did not undergo TBI induction was also studied as controls. Biomarkers of TBI, including glycerol and 2,3-dihydroxybenzoic acid, were evaluated by microdialysis. Infraction volume, extent of neuronal apoptosis, and antiapoptosis factor transforming growth factor β1 (TGF-β1) were also measured. Functional outcomes were assessed by motor assays. ResultsCompared with the rats without TBI, the animals with TBI exhibited higher hippocampal glycerol and 2,3-dihydroxybenzoic acid. Relative to the vehicle-treated group, the magnolol-treated group showed decreased hippocampal levels of glycerol and hydroxyl radical levels. The magnolol-treated rats also exhibited decreased cerebral infarction volume and neuronal apoptosis and increased antiapoptosis-associated factor TGF-β1 expression. These effects were translated into improved motor function post TBI. ConclusionsOur results suggest that intravenous magnolol injection mitigates the deleterious effects of TBI in rats based on its potent free radical scavenging capability, and the mechanism of anti–neuronal apoptosis is partly due to an increase in TGF-β1 expression in the ischemic cortex.

Intranasal delivery of nerve growth factor attenuates aquaporins-4-induced edema following traumatic brain injury in rats

Traumatic brain injury (TBI) remains the leading cause of injury-related death and disability. Brain edema, one of the most major complications of TBI, contributes to elevated intracranial pressure, and poor prognosis following TBI. Nerve growth factor (NGF) appears to be a viable strategy to treat brain edema and TBI. Unfortunately, due to its poor blood-brain barrier (BBB) permeability, the clinical application of NGF has been greatly limited. We previously demonstrated that intranasal NGF could bypass the BBB and distribute throughout the brain. Here we further studied whether intranasal NGF could attenuate TBI-induced brain edema and its putative mechanisms. TBI was produced by a modified weight-drop model. We found that intranasal administration of NGF (5μg/d) attenuated the brain edema, as assayed by hemisphere water content, at 12h, 24h and 72h after TBI induction. This attenuation was associated with a prominent decrease of the content of aquaporin-4, which plays a pivotal role in the formation of brain edema. By the use of RT-PCR and ELISA, we showed that intranasal NGF markedly inhibited the transcription and expression of pro-inflammatory cytokines including IL-1β and TNF-α. An electrophoretic mobility shift assay (EMSA) displayed a significant activation of nuclear factor-κB following TBI, which was, however, much lowered in the NGF-treated rats. Furthermore, upon intranasal NGF supplementation, mitochondria-mediated apoptosis following TBI was minimized, as indicated by upregulation of Bcl-2 and downregulation of caspase-3. Collectively, our findings suggested that intranasal NGF may be a promising strategy to treat brain edema and TBI.

The effects of cyclooxygenase inhibitors on the brain inflammatory response following traumatic brain injury in rats.

Cytokines such as IL-1β are involved in inflammatory responses. This study evaluated the role of two different kinds of drugs (ibuprofen and celecoxib) on brain IL-10 and IL-1β after traumatic brain injury (TBI) in male rats. Rats were assigned into 6 groups: intact, sham, TBI, and treated rats with vehicle, celecoxib or iboprophen. Cytokine concentrations were quantified by ELISA kits. Groups showed no significant difference in brain IL-10 either after TBI induction or after treatment with ibuprofen or celecoxib. Serum IL-10 in vehicle or ibuprofen treated animals was lower than in sham groups (P< 0.01). Brain IL-1β decreased after treatment by ibuprofen or celecoxib (P< 0.001). There was no statistical difference in serum IL-1β in TBI and intact. Serum IL-1β significantly decreased in rats that received celecoxib compared to TBI group (P< 0.01). Based on our study IL-1β can decrease through both cyclooxygenase 1 (COX-1) and COX-2 pathway but serum IL-1β can decrease only by COX-2 pathway.