scholarly journals A combination antioxidant therapy to inhibit NOX2 and activate Nrf2 decreases secondary brain damage and improves functional recovery after traumatic brain injury

2017 ◽  
Vol 38 (10) ◽  
pp. 1818-1827 ◽  
Author(s):  
Raghavendar Chandran ◽  
TaeHee Kim ◽  
Suresh L Mehta ◽  
Eshwar Udho ◽  
Vishal Chanana ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Motor Function ◽  
Neurological Dysfunction ◽  
Vehicle Group ◽  
Lesion Volume ◽  
Post Injury ◽  
Cortical Contusion ◽  
Nrf2 Activator

Uncontrolled oxidative stress contributes to the secondary neuronal death that promotes long-term neurological dysfunction following traumatic brain injury (TBI). Surprisingly, both NADPH oxidase 2 (NOX2) that increases and transcription factor Nrf2 that decreases reactive oxygen species (ROS) are induced after TBI. As the post-injury functional outcome depends on the balance of these opposing molecular pathways, we evaluated the effect of TBI on the motor and cognitive deficits and cortical contusion volume in NOX2 and Nrf2 knockout mice. Genetic deletion of NOX2 improved, while Nrf2 worsened the post-TBI motor function recovery and lesion volume indicating that decreasing ROS levels might be beneficial after TBI. Treatment with either apocynin (NOX2 inhibitor) or TBHQ (Nrf2 activator) alone significantly improved the motor function after TBI, but had no effect on the lesion volume, compared to vehicle control. Whereas, the combo therapy (apocynin + TBHQ) given at either 5 min/24 h or 2 h/24 h improved motor and cognitive function and decreased cortical contusion volume compared to vehicle group. Thus, both the generation and disposal of ROS are important modulators of oxidative stress, and a combo therapy that prevents ROS formation and potentiates ROS disposal concurrently is efficacious after TBI.

scholarly journals Administration of a 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor Improves Outcome in a Rat Model of Pediatric Traumatic Brain Injury

2019 ◽  
Vol 41 (3-4) ◽  
pp. 166-176 ◽  
Author(s):  
Shiyu Shu ◽  
Zhi Zhang ◽  
Dawn Spicer ◽  
Ewa Kulikowicz ◽  
Ke Hu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Ischemia Reperfusion ◽  
Memory Task ◽  
Male Rats ◽  
Lesion Volume ◽  
Hydroxyeicosatetraenoic Acid ◽  
Post Injury ◽  
Synthesis Inhibitor ◽  
Tnf Α

The arachidonic acid pathway metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemia/reperfusion brain injury. Inhibition of 20-HETE formation can protect the developing brain from global ischemia. Here, we examined whether treatment with the 20-HETE synthesis inhibitor N-hydroxy-N-4-butyl-2-methylphenylformamidine (HET0016) can protect the immature brain from traumatic brain injury (TBI). Male rats at postnatal day 9–10 underwent controlled cortical impact followed by intraperitoneal injection with vehicle or HET0016 (1 mg/kg, 5 min and 3 h post-injury). HET0016 decreased the lesion volume by over 50% at 3 days of recovery, and this effect persisted at 30 days as the brain matured. HET0016 decreased peri-lesion gene expression of proinflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β]) at 1 day and increased reparative cytokine (IL-4, IL-10) expression at 3 days. It also partially preserved microglial ramified processes, consistent with less activation. HET0016 decreased contralateral hindlimb foot faults and improved outcome on the novel object recognition memory task 30 days after TBI. In cultured BV2 microglia, HET0016 attenuated the lipopolysaccharide-evoked increase in release of TNF-α. Our data show that HET0016 improves acute and long-term histologic and functional outcomes, in association with an attenuated neuroinflammatory response after contusion of an immature rat brain.

scholarly journals Comparative Neuroprotective Effects of Cyclosporin a and NIM811, a Nonimmunosuppressive Cyclosporin a Analog, following Traumatic Brain Injury

2008 ◽  
Vol 29 (1) ◽  
pp. 87-97 ◽  
Author(s):  
Lamin Han Mbye ◽  
Indrapal N Singh ◽  
Kimberly M Carrico ◽  
Kathryn E Saatman ◽  
Edward D Hall
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cyclosporin A ◽  
Mitochondrial Dysfunction ◽  
Motor Function ◽  
Neurological Dysfunction ◽  
Neuroprotective Effects ◽  
Function Impairment ◽  
Calcineurin Inhibition ◽  
Experimental Traumatic Brain Injury

Earlier experiments have shown that cyclosporin A (CsA) and its non-calcineurin inhibitory analog NIM811 attenuate mitochondrial dysfunction after experimental traumatic brain injury (TBI). Presently, we compared the neuroprotective effects of previously determined mitochondrial protective doses of CsA (20 mg/kg intraperitoneally) and NIM811 (10 mg/kg intraperitoneally) when administered at 15 mins postinjury in preventing cytoskeletal (α-spectrin) degradation, neuro-degeneration, and neurological dysfunction after severe (1.0 mm) controlled cortical impact (CCI) TBI in mice. In a first set of experiments, we analyzed calpain-mediated α-spectrin proteolysis at 24 h postinjury. Both NIM811 and CsA significantly attenuated the increased α-spectrin breakdown products observed in vehicle-treated animals ( P < 0.005). In a second set of experiments, treatment of animals with either NIM811 or CsA at 15 mins and again at 24 h postinjury attenuated motor function impairment at 48 h and 7 days ( P < 0.005) and neurodegeneration at 7 days postinjury ( P < 0.0001). Delayed administration of NIM811 out to 12 h was still able to significantly reduce α-spectrin degradation. These results show that the neuroprotective mechanism of CsA involves maintenance of mitochondrial integrity and that calcineurin inhibition plays little or no role because the non-calcineurin inhibitory analog, NIM811, is as effective as CsA.

scholarly journals Effects of α‑tocopherol and ascorbic acid in the severity and management of traumatic brain injury in albino rats

2013 ◽  
Vol 04 (03) ◽  
pp. 292-297 ◽  
Author(s):  
Gaafar M Ishaq ◽  
Yusuf Saidu ◽  
Lawal S Bilbis ◽  
Suleiman A Muhammad ◽  
Nasir Jinjir ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Ascorbic Acid ◽  
Superoxide Dismutase ◽  
Brain Injury ◽  
Brain Tissue ◽  
Closed Head Injury ◽  
Albino Rats ◽  
Post Injury ◽  
Chain Reactions

ABSTRACT Background: Traumatic brain injury (TBI) is accompanied by substantial accumulation of biomarkers of oxidative stress and depletion of antioxidants reserve which initiate chain reactions that damage brain cells. The present study investigated the role of ascorbic acid and α-tocopherol on the severity and management of TBI in rats. Materials and Methods: Wistar rats were subjected to closed head injury using an accelerated impact device. Rats were administered 45 mg/kg and 60 mg/kg body weight of ascorbic acid, α-tocopherol or a combination of the two vitamins for 2 weeks pre- and post injury. Blood and brain tissue homogenates were analyzed for vitamin C, vitamin E, malondialdehyde, superoxide dismutase, and creatine kinase activities. Results: The results indicated that TBI caused significant (P < 0.05) decreased in vitamins C and E levels in the blood and brain tissue of TBI-untreated rats. The activities of superoxide dismutase in TBI rats were markedly reduced when compared with non traumatized control and showed a tendency to increased following supplementation with vitamins C and E. Supplementation of the vitamins significantly (P < 0.05) reduced malondialdehyde in the treatment groups compared with the TBI-untreated group. Conclusion: The study indicated that pre and post treatment with ascorbic acid and α-tocopherol reduced oxidative stress induced by brain injury and effectively reduced mortality rate in rats.

scholarly journals N-arachidonoyl-L-serine (AraS) Possesses Proneurogenic Properties in Vitro and in Vivo after Traumatic Brain Injury

2013 ◽  
Vol 33 (8) ◽  
pp. 1242-1250 ◽  
Author(s):  
Ayelet Cohen-Yeshurun ◽  
Dafna Willner ◽  
Victoria Trembovler ◽  
Alexander Alexandrovich ◽  
Raphael Mechoulam ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cannabinoid Receptor ◽  
Fold Increase ◽  
Lesion Volume ◽  
Post Injury ◽  
Neuroprotective Effects ◽  
Neurobehavioral Function

N-arachidonoyl-L-serine (AraS) is a novel neuroprotective endocannabinoid. We aimed to test the effects of exogenous AraS on neurogenesis after traumatic brain injury (TBI). The effects of AraS on neural progenitor cells (NPC) proliferation, survival, and differentiation were examined in vitro. Next, mice underwent TBI and were treated with AraS or vehicle. Lesion volumes and clinical outcome were evaluated and the effects on neurogenesis were tested using immunohistochemistry. Treatment with AraS led to a dose-dependent increase in neurosphere size without affecting cell survival. These effects were partially reversed by CB1, CB2, or TRPV1 antagonists. AraS significantly reduced the differentiation of NPC in vitro to astrocytes or neurons and led to a 2.5-fold increase in expression of the NPC marker nestin. Similar effects were observed in vivo in mice treated with AraS 7 days after TBI. These effects were accompanied by a reduction in lesion volume and an improvement in neurobehavioral function compared with controls. AraS increases proliferation of NPCs in vitro in cannabinoid-receptor-mediated mechanisms and maintains NPC in an undifferentiated state in vitro and in vivo. Moreover, although given at 7 days post injury, these effects are associated with significant neuroprotective effects leading to an improvement in neurobehavioral functions.

scholarly journals Transcriptomic Analysis of Mouse Brain After Traumatic Brain Injury Reveals That the Angiotensin Receptor Blocker Candesartan Acts Through Novel Pathways

2021 ◽  
Vol 15 ◽  
Author(s):  
Peter J. Attilio ◽  
Dustin M. Snapper ◽  
Milan Rusnak ◽  
Akira Isaac ◽  
Anthony R. Soltis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Region ◽  
Molecular Mechanisms ◽  
Angiotensin Receptor Blockers ◽  
Differentially Expressed ◽  
Lesion Volume ◽  
Angiotensin Receptor ◽  
Post Injury

Traumatic brain injury (TBI) results in complex pathological reactions, where the initial lesion is followed by secondary inflammation and edema. Our laboratory and others have reported that angiotensin receptor blockers (ARBs) have efficacy in improving recovery from traumatic brain injury in mice. Treatment of mice with a subhypotensive dose of the ARB candesartan results in improved functional recovery, and reduced pathology (lesion volume, inflammation and gliosis). In order to gain a better understanding of the molecular mechanisms through which candesartan improves recovery after controlled cortical impact injury (CCI), we performed transcriptomic profiling on brain regions after injury and drug treatment. We examined RNA expression in the ipsilateral hippocampus, thalamus and hypothalamus at 3 or 29 days post injury (dpi) treated with either candesartan (0.1 mg/kg) or vehicle. RNA was isolated and analyzed by bulk mRNA-seq. Gene expression in injured and/or candesartan treated brain region was compared to that in sham vehicle treated mice in the same brain region to identify genes that were differentially expressed (DEGs) between groups. The most DEGs were expressed in the hippocampus at 3 dpi, and the number of DEGs reduced with distance and time from the lesion. Among pathways that were differentially expressed at 3 dpi after CCI, candesartan treatment altered genes involved in angiogenesis, interferon signaling, extracellular matrix regulation including integrins and chromosome maintenance and DNA replication. At 29 dpi, candesartan treatment reduced the expression of genes involved in the inflammatory response. Some changes in gene expression were confirmed in a separate cohort of animals by qPCR. Fewer DEGs were found in the thalamus, and only one in the hypothalamus at 3 dpi. Additionally, in the hippocampi of sham injured mice, 3 days of candesartan treatment led to the differential expression of 384 genes showing that candesartan in the absence of injury had a powerful impact on gene expression specifically in the hippocampus. Our results suggest that candesartan has broad actions in the brain after injury and affects different processes at acute and chronic times after injury. These data should assist in elucidating the beneficial effect of candesartan on recovery from TBI.

scholarly journals Effect of melatonin on regeneration of cortical neurons in rats with traumatic brain injury

2020 ◽  
Vol 43 (4) ◽  
pp. E8-16
Author(s):  
Jianbin Ge ◽  
Dandan Chen ◽  
Jingjing Ben ◽  
Xinjian Song ◽  
Linqing Zou ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Brain Injury ◽  
Cognitive Function ◽  
Cortical Neurons ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Vehicle Group ◽  
Post Injury ◽  
Doppler Flowmetry

Purpose: To investigate the effect of melatonin on regeneration of cortical neurons in rats with traumatic brain injury (TBI). Methods: Sprague-Dawley rats (n=36) were randomly divided into sham, TBI+vehicle and TBI+melatonin groups. Cerebral blood flow and cognitive function were observed via laser Doppler flowmetry and by Morris water maze testing, respectively. The serum malondialdehyde (MDA) and superoxide dismutase (SOD) levels were used to assess oxidative stress. Immunofluorescence and terminal deoxynucleotidyl transferase dUTP nick end labelling assay was used to observe the newborn neurons and apoptotic cells. Results: Cerebral blood flow in the TBI+melatonin group was higher than that of the TBI+vehicle group at one, 12, 24 and 48 h post-injury, but the difference was not statistically significant (P>0.05). The cognitive function of the rats was better in the TBI+melatonin group than the TBI+vehicle group (P

scholarly journals Small Interference RNA Targeting Connexin-43 Improves Motor Function and Limits Astrogliosis After Juvenile Traumatic Brain Injury

ASN NEURO ◽  
2019 ◽  
Vol 11 ◽  
pp. 175909141984709 ◽  
Author(s):  
Aleksandra Ichkova ◽  
Andrew M. Fukuda ◽  
Nina Nishiyama ◽  
Germaine Paris ◽  
Andre Obenaus ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Gap Junctions ◽  
Motor Function ◽  
Connexin 43 ◽  
Post Injury ◽  
Edema Formation ◽  
Small Interference Rna ◽  
Interference Rna

Juvenile traumatic brain injury (jTBI) is the leading cause of death and disability for children and adolescents worldwide, but there are no pharmacological treatments available. Aquaporin 4 (AQP4), an astrocytic perivascular protein, is increased after jTBI, and inhibition of its expression with small interference RNA mitigates edema formation and reduces the number of reactive astrocytes after jTBI. Due to the physical proximity of AQP4 and gap junctions, coregulation of AQP4 and connexin 43 (Cx43) expressions, and the possibility of water diffusion via gap junctions, we decided to address the potential role of astrocytic gap junctions in jTBI pathophysiology. We evaluated the role of Cx43 in the spread of the secondary injuries via the astrocyte network, such as edema formation associated with blood–brain barrier dysfunctions, astrogliosis, and behavioral outcome. We observed that Cx43 was altered after jTBI with increased expression in the perilesional cortex and in the hippocampus at several days post injury. In a second set of experiments, cortical injection of small interference RNA against Cx43 decreased Cx43 protein expression, improved motor function recovery, and decreased astrogliosis but did not result in differences in edema formation as measured via T2-weighted imaging or diffusion-weighted imaging at 1 day or 3 days. Based on our findings, we can speculate that while decreasing Cx43 has beneficial roles, it likely does not contribute to the spread of edema early after jTBI.

scholarly journals Hypobaria-Induced Oxidative Stress Facilitates Homocysteine Transsulfuration and Promotes Glutathione Oxidation in Rats with Mild Traumatic Brain Injury

2021 ◽  
Vol 13 ◽  
pp. 117957352098819
Author(s):  
Flaubert Tchantchou ◽  
Catriona Miller ◽  
Molly Goodfellow ◽  
Adam Puche ◽  
Gary Fiskum
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Glutathione Metabolism ◽  
Compensatory Mechanism ◽  
Oxidative Stress Markers ◽  
Sprague Dawley ◽  
Post Injury ◽  
Stress Markers ◽  
Glutathione Oxidation

Background: United States service members injured in combat theatre are often aeromedically evacuated within a few days to regional military hospitals. Animal and epidemiological research indicates that early exposure to flight hypobaria may worsen brain and other injuries. The mechanisms by which secondary exposure to hypobaria worsen trauma outcomes are not well elucidated. This study tested the hypothesis that hypobaria-induced oxidative stress and associated changes in homocysteine levels play a role in traumatic brain injury (TBI) pathological progression caused by hypobaria. Methods: Male Sprague Dawley rats were exposed to a 6 h hypobaria 24 h after mild TBI by the controlled cortical impact. Plasma and brain tissues were assessed for homocysteine levels, oxidative stress markers or glutathione metabolism, and behavioral deficits post-injury in the absence and presence of hypobaria exposure. Results: We found that hypobaria after TBI increased oxidative stress markers, altered homocysteine metabolism, and promoted glutathione oxidation. Increased glutathione metabolism was driven by differential upregulation of glutathione metabolizing genes. These changes correlated with increased anxiety-like behavior. Conclusion: These data provide evidence that hypobaria exposure after TBI increases oxidative stress and alters homocysteine elimination likely through enhanced glutathione metabolism. This pathway may represent a compensatory mechanism to attenuate free radical formation. Thus, hypobaria-induced enhancement of glutathione metabolism represents a potential therapeutic target for TBI management.

scholarly journals Treatment of traumatic brain injury in rats with N-acetyl-seryl-aspartyl-lysyl-proline

2017 ◽  
Vol 126 (3) ◽  
pp. 782-795 ◽  
Author(s):  
Yanlu Zhang ◽  
Zheng Gang Zhang ◽  
Michael Chopp ◽  
Yuling Meng ◽  
Li Zhang ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Spatial Learning ◽  
Functional Recovery ◽  
Transforming Growth Factor ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Therapeutic Window ◽  
Vehicle Group ◽  
Lesion Volume

OBJECTIVE The authors' previous studies have suggested that thymosin beta 4 (Tβ4), a major actin-sequestering protein, improves functional recovery after neural injury. N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an active peptide fragment of Tβ4. Its effect as a treatment of traumatic brain injury (TBI) has not been investigated. Thus, this study was designed to determine whether AcSDKP treatment improves functional recovery in rats after TBI. METHODS Young adult male Wistar rats were randomly divided into the following groups: 1) sham group (no injury); 2) TBI + vehicle group (0.01 N acetic acid); and 3) TBI + AcSDKP (0.8 mg/kg/day). TBI was induced by controlled cortical impact over the left parietal cortex. AcSDKP or vehicle was administered subcutaneously starting 1 hour postinjury and continuously for 3 days using an osmotic minipump. Sensorimotor function and spatial learning were assessed using a modified Neurological Severity Score and Morris water maze tests, respectively. Some of the animals were euthanized 1 day after injury, and their brains were processed for measurement of fibrin accumulation and neuroinflammation signaling pathways. The remaining animals were euthanized 35 days after injury, and brain sections were processed for measurement of lesion volume, hippocampal cell loss, angiogenesis, neurogenesis, and dendritic spine remodeling. RESULTS Compared with vehicle treatment, AcSDKP treatment initiated 1 hour postinjury significantly improved sensorimotor functional recovery (Days 7–35, p < 0.05) and spatial learning (Days 33–35, p < 0.05), reduced cortical lesion volume, and hippocampal neuronal cell loss, reduced fibrin accumulation and activation of microglia/macrophages, enhanced angiogenesis and neurogenesis, and increased the number of dendritic spines in the injured brain (p < 0.05). AcSDKP treatment also significantly inhibited the transforming growth factor–β1/nuclear factor–κB signaling pathway. CONCLUSIONS AcSDKP treatment initiated 1 hour postinjury provides neuroprotection and neurorestoration after TBI, indicating that this small tetrapeptide has promising therapeutic potential for treatment of TBI. Further investigation of the optimal dose and therapeutic window of AcSDKP treatment for TBI and the associated underlying mechanisms is therefore warranted.

scholarly journals The CNS lymphatic system modulates the adaptive neuro-immune response in the perilesional cortex in a mouse model of traumatic brain injury

2019 ◽  
Author(s):  
Wojciechowski Sara ◽  
Vihma Maria ◽  
Galbardi Barbara ◽  
Virenque Anaïs ◽  
Meike H. Keuters ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Immune Response ◽  
T Cells ◽  
Brain Injury ◽  
Lymphatic Vessels ◽  
Lesion Size ◽  
Lesion Volume ◽  
Post Injury ◽  
Circulating T Cells ◽  
The Brain

AbstractRationaleThe recently discovered meningeal lymphatic vessels (mLVs) have been proposed to be the missing link between the immune and the central nervous systems. The role of mLVs in modulating the neuro-immune response following a brain injury, however, has not been analyzed. Parenchymal T lymphocyte infiltration has been previously reported as part of secondary events after traumatic brain injury (TBI), suggestive of an adaptive neuro-immune response. The phenotype of these cells has remained mostly uncharacterized. In this study, we identified the subpopulations of T cells infiltrating the perilesional areas 30 days post-injury (an early-chronic time point). Furthermore, we analyzed how the lack of mLVs affects the magnitude and the type of immune response in the brain after TBI.MethodsTBI was induced in K14-VEGFR3-Ig transgenic (TG) mice or in their littermate controls (WT; wild type), applying a controlled cortical impact (CCI). One month after TBI, T cells were isolated from cortical areas ipsilateral or contralateral to the trauma and from the spleen, then characterized by flow cytometry. Lesion size in each animal was evaluated by MRI.ResultsIn both WT and TG-CCI mice, we found a prominent T cell infiltration in the brain confined to the perilesional cortex and hippocampus. The majority of infiltrating T cells were cytotoxic CD8+ expressing a CD44hiCD69+ phenotype, suggesting that these are effector resident memory T cells. K14-VEGFR3-Ig mice showed a significant reduction of infiltrating CD4+ T lymphocytes, implying that mLVs are important in establishing a proper neuro-immune response. Extension of the lesion (measured as lesion volume from MRI) did not differ between the genotypes. Finally, TBI did not relate with alterations in peripheral circulating T cells, as assessed one month after injury induction.ConclusionsOur data support the hypothesis that mLVs are pivotal for a proper and specific neuro-immune response after TBI, which is principally mediated by the resident memory CD8+ T cells.

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