scholarly journals SS-31 Provides Neuroprotection by Reversing Mitochondrial Dysfunction after Traumatic Brain Injury

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Yihao Zhu ◽  
Handong Wang ◽  
Jiang Fang ◽  
Wei Dai ◽  
Jiang Zhou ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mitochondrial Dysfunction ◽  
Nuclear Translocation ◽  
Neurological Diseases ◽  
Neurological Deficits ◽  
Secondary Brain Injury ◽  
Neuroprotective Effects ◽  
Weight Drop ◽  
Ros Scavenger

SS-31, a novel mitochondria-targeted peptide, has been proven to provide neuroprotection in a variety of neurological diseases. Its role as a mitochondrial reactive oxygen species (ROS) scavenger and the underlying pathophysiological mechanisms in traumatic brain injury (TBI) are still not well understood. The aim of the designed study was to investigate the potential neuroprotective effects of SS-31 and fulfill our understanding of the process of the mitochondrial change in the modified Marmarou weight-drop model of TBI. Mice were randomly divided into sham, TBI, TBI + vehicle, and TBI + SS-31 groups in this study. Peptide SS-31 (5 mg/kg) or vehicle was intraperitoneally administrated 30 min after TBI with brain samples harvested 24 h later for further analysis. SS-31 treatment significantly reversed mitochondrial dysfunction and ameliorated secondary brain injury caused by TBI. SS-31 can directly decrease the ROS content, restore the activity of superoxide dismutase (SOD), and decrease the level of malondialdehyde (MDA) and the release of cytochrome c, thus attenuating neurological deficits, brain water content, DNA damage, and neural apoptosis. Moreover, SS-31 restored the expression of SIRT1 and upregulated the nuclear translocation of PGC-1α, which were proved by Western blot and immunohistochemistry. Taken together, these data demonstrate that SS-31 improves the mitochondrial function and provides neuroprotection in mice after TBI potentially through enhanced mitochondrial rebiogenesis. The present study gives us an implication for further clinical research.

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 Neuroprotective Effects of Tempol, a Catalytic Scavenger of Peroxynitrite-Derived Free Radicals, in a Mouse Traumatic Brain Injury Model

2008 ◽  
Vol 28 (6) ◽  
pp. 1114-1126 ◽  
Author(s):  
Ying Deng-Bryant ◽  
Indrapal N Singh ◽  
Kimberly M Carrico ◽  
Edward D Hall
Keyword(s):  
Traumatic Brain Injury ◽  
Free Radicals ◽  
Brain Injury ◽  
Oxidative Damage ◽  
Mitochondrial Dysfunction ◽  
Neuroprotective Effect ◽  
Complete Suppression ◽  
Post Injury ◽  
Multiple Dosing ◽  
Neuroprotective Effects

We examined the ability of tempol, a catalytic scavenger of peroxynitrite (PN)-derived free radicals, to reduce cortical oxidative damage, mitochondrial dysfunction, calpain-mediated cytoskeletal (α-spectrin) degradation, and neurodegeneration, and to improve behavioral recovery after a severe (depth 1.0 mm), unilateral controlled cortical impact traumatic brain injury (CCI-TBI) in male CF-1 mice. Administration of a single 300 mg/kg intraperitoneal dose of tempol 15 mins after TBI produced a complete suppression of PN-mediated oxidative damage (3-nitrotyrosine, 3NT) in injured cortical tissue at 1 h after injury. Identical tempol dosing maintained respiratory function and attenuated 3NT in isolated cortical mitochondria at 12 h after injury, the peak of mitochondrial dysfunction. Multiple dosing with tempol (300 mg/kg intraperitoneally at 15 mins, 3, 6, 9, and 12 h) also suppressed α-spectrin degradation by 45% at its 24 h post-injury peak. The same dosing regimen improved 48 h motor function and produced a significant, but limited (17.4%, P<0.05), decrease in hemispheric neurodegeneration at 7 days. These results are consistent with a mechanistic link between PN-mediated oxidative damage to brain mitochondria, calpain-mediated proteolytic damage, and neurodegeneration. However, the modest neuroprotective effect of tempol suggests that multitarget combination strategies may be needed to interfere with posttraumatic secondary injury to a degree worthy of clinical translation.

scholarly journals Vitamin D Receptor Activation Influences NADPH Oxidase (NOX2) Activity and Protects against Neurological Deficits and Apoptosis in a Rat Model of Traumatic Brain Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Changmeng Cui ◽  
Sixin Song ◽  
Jianzhong Cui ◽  
Yan Feng ◽  
Junling Gao ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Vitamin D ◽  
Brain Injury ◽  
Nadph Oxidase ◽  
Neurological Diseases ◽  
Receptor Activation ◽  
Neurological Deficits ◽  
Protective Effects ◽  
Ca1 Region ◽  
Neurobehavioral Deficits

Traumatic brain injury (TBI) is a worldwide phenomenon which results in significant neurological and cognitive deficits in humans. Vitamin D (VD) is implicated as a therapeutic strategy for various neurological diseases now. Recently, inhibition of the NADPH oxidase (NOX2) was reported to protect against oxidative stress (ROS) production. However, whether alterations in NOX2expression and NOX activity are associated with calcitriol (active metabolite of VD) treatment following TBI remains unclear. In the present study, rats were randomly assigned to the sham, TBI, and calcitriol-treated groups. Calcitriol was administered intraperitoneally (2 μg/kg) at 30 min, 24 h, and 48 h after TBI insult. We observed that calcitriol treatment alleviated neurobehavioral deficits and brain edema following TBI. At the molecular levels, administration of calcitriol activated the expression of VDR and downregulated NOX2as well as suppressed apoptosis cell rate in the hippocampus CA1 region of TBI rats. In conclusion, our findings indicate that the protective effects of calcitriol may be related to the modulation of NADPH oxidase and thereby ultimately inhibited the progression of apoptosis. Calcitriol may be promising as a protective intervention following TBI, and more study is warranted for its clinical testing in the future.

scholarly journals Adenosine A3 receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Susan A. Farr ◽  
Salvatore Cuzzocrea ◽  
Emanuela Esposito ◽  
Michela Campolo ◽  
Michael L. Niehoff ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Tissue Injury ◽  
Pathological Condition ◽  
Brain Infarction ◽  
Inflammasome Activation ◽  
Secondary Brain Injury ◽  
Male Mice ◽  
Neuroprotective Effects ◽  
Secondary Tissue

Abstract Background Traumatic brain injury (TBI) is a common pathological condition that presently lacks a specific pharmacological treatment. Adenosine levels rise following TBI, which is thought to be neuroprotective against secondary brain injury. Evidence from stroke and inflammatory disease models suggests that adenosine signaling through the G protein-coupled A3 adenosine receptor (A3AR) can provide antiinflammatory and neuroprotective effects. However, the role of A3AR in TBI has not been investigated. Methods Using the selective A3AR agonist, MRS5980, we evaluated the effects of A3AR activation on the pathological outcomes and cognitive function in CD1 male mouse models of TBI. Results When measured 24 h after controlled cortical impact (CCI) TBI, male mice treated with intraperitoneal injections of MRS5980 (1 mg/kg) had reduced secondary tissue injury and brain infarction than vehicle-treated mice with TBI. These effects were associated with attenuated neuroinflammation marked by reduced activation of nuclear factor of kappa light polypeptide gene enhancer in B cells (NFκB) and MAPK (p38 and extracellular signal-regulated kinase (ERK)) pathways and downstream NOD-like receptor pyrin domain-containing 3 inflammasome activation. MRS5980 also attenuated TBI-induced CD4+ and CD8+ T cell influx. Moreover, when measured 4–5 weeks after closed head weight-drop TBI, male mice treated with MRS5980 (1 mg/kg) performed significantly better in novel object-placement retention tests (NOPRT) and T maze trials than untreated mice with TBI without altered locomotor activity or increased anxiety. Conclusion Our results provide support for the beneficial effects of small molecule A3AR agonists to mitigate secondary tissue injury and cognitive impairment following TBI.

scholarly journals Vitamin D confers neuroprotective effects in traumatic brain injury by activating Nrf2 signaling through an autophagy-mediated mechanism

2021 ◽  
Author(s):  
Changmeng Cui ◽  
Changshui Wang ◽  
Feng Jin ◽  
Mengqi Yang ◽  
Lingsheng Kong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Vitamin D ◽  
Brain Injury ◽  
Neurological Deficits ◽  
Autophagic Flux ◽  
Related Factor ◽  
Neuroprotective Effects ◽  
Nrf2 Activation ◽  
Autophagic Process

Abstract Background: Traumatic brain injury (TBI) initiates an oxidative cascade that contributes to the delayed progressive damage, whereas autophagy is critical in maintaining homeostasis during stressful challenge. We previously demonstrated that vitamin D (VitD) shows strong neuroprotective and anti-oxidative properties in the animal models of TBI. Therefore, the present study aimed to further explore the potential interrelationship between oxidative stress and autophagy in the progression of TBI and therapeutic mechanism of VitD. Methods: Neuroprotective effects of calcitriol, the active form of VitD, were examined following TBI. We further evaluated the impacts of TBI and VitD treatment on autophagic process and nuclear factor E2-related factor 2 (Nrf2) signaling. To confirm the mechanism, chloroquine (CQ) treatment and Nrf2−/− mice were used to block autophagy and Nrf2 pathway, respectively. Results: We found that treatment of calcitriol markedly ameliorated the neurological deficits and histopathological changes following TBI. The brain damage impaired autophagic flux and impeded Nrf2 signaling, the major regulator in antioxidant response, consequently leading to uncontrolled and excessive oxidative stress. Meanwhile, calcitriol promoted autophagic process and activated Nrf2 signaling as evidenced by the reduced Keap1 expression and enhanced Nrf2 translocation, thereby mitigating TBI-induced oxidative damage. To further confirm whether autophagy was responsible for Keap1 degradation and Nrf2 activation, the lysosomal inhibitor, CQ, was used to block autophagy. Our data suggested that CQ treatment abrogated calcitriol-induced autophagy and compromised Nrf2 activation with increased Keap1 accumulation and reduced expression of Nrf2-targeted genes. Additionally, both CQ treatment and Nrf2 genetic knockout abolished the protective effects of VitD against both TBI-induced neurological deficits and neuronal apoptosis. Conclusions: Therefore, our work demonstrated a neuroprotective role of VitD in TBI by triggering Nrf2 activation, which might be mediated by autophagy.

scholarly journals Effects of Alpha-2 Adrenergic Agonist Mafedine on Brain Electrical Activity in Rats after Traumatic Brain Injury

2021 ◽  
Vol 11 (8) ◽  
pp. 981
Author(s):  
Yuriy I. Sysoev ◽  
Veronika A. Prikhodko ◽  
Roman T. Chernyakov ◽  
Ruslan D. Idiyatullin ◽  
Pavel E. Musienko ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Electrical Activity ◽  
Drug Efficacy ◽  
Brain Regions ◽  
Neurological Deficits ◽  
Efficacy Evaluation ◽  
Vascular Events ◽  
Neuroprotective Effects ◽  
Somatosensory Stimulation

The search for and development of new neuroprotective (or cerebroprotective) drugs, as well as suitable methods for their preclinical efficacy evaluation, are priorities for current biomedical research. Alpha-2 adrenergic agonists, such as mafedine and dexmedetomidine, are a highly appealing group of drugs capable of reducing neurological deficits which result from brain trauma and vascular events in both experimental animals and human patients. Thus, our aim was to assess the effects of mafedine and dexmedetomidine on the brain’s electrical activity in a controlled cortical-impact model of traumatic brain injury (TBI) in rats. The functional status of the animals was assessed by electrocorticography (ECoG), using ECoG electrodes which were chronically implanted in different cortical regions. The administration of intraperitoneal mafedine sodium at 2.5 mg∙kg−1 at 1 h after TBI induction, and daily for the following 6 days, restored interhemispheric connectivity in remote brain regions and intrahemispheric connections within the unaffected hemisphere at post-TBI day 7. Animals that had received mafedine sodium also demonstrated an improvement in cortical responses to photic and somatosensory stimulation. Dexmedetomidine at 25 μg∙kg−1 did not affect the brain’s electrical activity in brain-injured rats. Our results confirm the previously described neuroprotective effects of mafedine sodium and suggest that ECoG registration and analysis are a viable method evaluating drug efficacy in experimental animal models of TBI.

scholarly journals Downregulation of phosphoglycerate mutase 5 improves microglial inflammasome activation after traumatic brain injury

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yuhua Chen ◽  
Kai Gong ◽  
Limin Guo ◽  
Bingchang Zhang ◽  
Sifang Chen ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Physiological Mechanism ◽  
Neurological Deficits ◽  
Phosphoglycerate Mutase ◽  
Inflammasome Activation ◽  
Secondary Brain Injury

AbstractTraumatic brain injury (TBI) is considered as the most common cause of disability and death, and therefore an effective intervention of cascade pathology of secondary brain injury promptly can be a potential therapeutic direction for TBI prognosis. Further study of the physiological mechanism of TBI is urgent and important. Phosphoglycerate mutase 5 (Pgam5), a mitochondrial protein, mediate mitochondrial homeostasis, cellular senescence, and necroptosis. This study evaluated the effects of Pgam5 on neurological deficits and neuroinflammation of controlled cortical impact-induced TBI mouse model in vivo and LPS + ATP-induced microglia model in vitro. Pgam5 was overexpressed post-TBI. Pgam5 depletion reduced pyroptosis-related molecules and improved microglia activation, neuron damage, tissue lesion, and neurological dysfunctions in TBI mice. RNA-seq analysis and molecular biology experiments demonstrated that Pgam5 might regulate inflammatory responses by affecting the post-translational modification and protein expression of related genes, including Nlrp3, caspase1, Gsdmd, and Il-1β. In microglia, Pgam5-sh abrogated LPS + ATP-induced Il-1β secretion through Asc oligomerization-mediated caspase-1 activation, which was independent of Rip3. The data demonstrate the critical role Pgam5 plays in nerve injury in the progression of TBI, which regulates Asc polymerization and subsequently caspase1 activation, and thus reveals a fundamental mechanism linking microglial inflammasome activation to Asc/caspase1-generated Il-1β-mediated neuroinflammation. Thus, our data indicate Pgam5 worsens physiological and neurological outcomes post-TBI, which may be a potential therapeutic target to improve neuroinflammation after TBI.

scholarly journals C1q/CTRP1 exerts neuroprotective effects in TBI rats by regulating inflammation and autophagy

2020 ◽  
Author(s):  
Ming Pei ◽  
Chaoqun Wang ◽  
Zhengdong Li ◽  
Jianhua Zhang ◽  
Ping Huang ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Underlying Mechanism ◽  
Inflammatory Factors ◽  
Vehicle Group ◽  
Secondary Brain Injury ◽  
Neuroprotective Effects ◽  
Cerebral Ischemia Reperfusion Injury

AbstractObjectiveC1q/CTRP1 is a newly discovered adiponectin protein, which is highly expressed in adipose and heart tissues. Recent studies have revealed that C1q/CTRP1 can regulate metabolism and inhibit inflammation. CTRP1 is also expressed in brain tissues and vascular cells of human and rat, and research on cerebral hemorrhage and cerebral ischemia-reperfusion injury demonstrates that the CTRP family can attenuate secondary brain injury and exert neuroprotective effects. Thus, this study was designed to explore the role of CTRP1 in traumatic brain injury (TBI) and the underlying mechanism.Main methodsRats were assigned into rCTRP1 group, vehicle group, and sham group. Modified Feeney’s method was used to establish a closed traumatic brain injury model. Morris water maze was used for directional navigation, reverse searching and space exploration tests in rats. In addition, Golgi-Cox staining was utilized to visualize neurons, dendrites and dendritic spines. ELISA was conducted to detect the levels of inflammatory factors (IL-6 and TNF-α). Finally, Western blot was adopted to detect the relative expression of p-mTOR and autophagy-related proteins (Beclin-1 and LC3-II).ResultsCTRP1 improved the behavioral and histopathological outcomes, inhibited the inflammatory response, activated mTOR and decreased autophagy-associated protein synthesis in TBI rats.ConclusionCTRP1 exerts neuroprotective effects in TBI rats by regulating inflammation and autophagy and has potential therapeutic properties after TBI.

scholarly journals FGF2 Attenuates Neural Cell Death via Suppressing Autophagy after Rat Mild Traumatic Brain Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Chonghui Tang ◽  
Yudong Shan ◽  
Yilan Hu ◽  
Zhanjian Fang ◽  
Yun Tong ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Early Stage ◽  
Pharmacological Therapy ◽  
Tissue Loss ◽  
Neurological Deficits ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Mild Tbi ◽  
Beneficial Effects

Traumatic brain injury (TBI) can lead to physical and cognitive deficits, which are caused by the secondary injury process. Effective pharmacotherapies for TBI patients are still lacking. Fibroblast growth factor-2 (FGF2) is an important neurotrophic factor that can stimulate neurogenesis and angiogenesis and has been shown to have neuroprotective effects after brain insults. Previous studies indicated that FGF2’s neuroprotective effects might be related to its function of regulating autophagy. The present study investigated FGF2’s beneficial effects in the early stage of rat mild TBI and the underlying mechanisms. One hundred and forty-four rats were used for creating controlled cortical impact (CCI) models to simulate the pathological damage after TBI. Our results indicated that pretreatment of FGF2 played a neuroprotective role in the early stage of rat mild TBI through alleviating brain edema, reducing neurological deficits, preventing tissue loss, and increasing the number of surviving neurons in injured cortex and the ipsilateral hippocampus. FGF2 could also protect cells from various forms of death such as apoptosis or necrosis through inhibition of autophagy. Finally, autophagy activator rapamycin could abolish the protective effects of FGF2. This study extended our understanding of FGF2’s neuroprotective effects and shed lights on the pharmacological therapy after TBI.

scholarly journals Post-Injury Neuroprotective Effects of the Thalidomide Analog 3,6′-Dithiothalidomide on Traumatic Brain Injury

2019 ◽  
Vol 20 (3) ◽  
pp. 502 ◽  
Author(s):  
Buyandelger Batsaikhan ◽  
Jing-Ya Wang ◽  
Michael Scerba ◽  
David Tweedie ◽  
Nigel Greig ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cultured Cells ◽  
Therapeutic Potential ◽  
Neuronal Degeneration ◽  
Neurological Deficits ◽  
Post Injury ◽  
Neuroprotective Effects ◽  
Tnf Α

Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide. Long-term deficits after TBI arise not only from the direct effects of the injury but also from ongoing processes such as neuronal excitotoxicity, inflammation, oxidative stress and apoptosis. Tumor necrosis factor-α (TNF-α) is known to contribute to these processes. We have previously shown that 3,6′-dithiothalidomide (3,6′-DT), a thalidomide analog that is more potent than thalidomide with similar brain penetration, selectively inhibits the synthesis of TNF-α in cultured cells and reverses behavioral impairments induced by mild TBI in mice. In the present study, we further explored the therapeutic potential of 3,6′-DT in an animal model of moderate TBI using Sprague-Dawley rats subjected to controlled cortical impact. A single dose of 3,6′-DT (28 mg/kg, i.p.) at 5 h after TBI significantly reduced contusion volume, neuronal degeneration, neuronal apoptosis and neurological deficits at 24 h post-injury. Expression of pro-inflammatory cytokines in the contusion regions were also suppressed at the transcription and translation level by 3,6′-DT. Notably, neuronal oxidative stress was also suppressed by 3,6′-DT. We conclude that 3,6′-DT may represent a potential therapy to ameliorate TBI-induced functional deficits.

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