scholarly journals Pioglitazone treatment prior to transplantation improves the efficacy of human mesenchymal stem cells after traumatic brain injury in rats

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Mahasweta Das ◽  
Karthick Mayilsamy ◽  
Xiaolan Tang ◽  
Jung Yeon Han ◽  
Elspeth Foran ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Combination Treatment ◽  
Brain Lesion ◽  
Human Mesenchymal Stem Cells ◽  
Human Mesenchymal Stem Cell ◽  
Lesion Volume ◽  
Inflammatory Microenvironment ◽  
Fluid Percussion Injury ◽  
Inflammatory Chemokines

Abstract Traumatic brain injury is a leading cause of death and disability around the world. So far, drugs are not available to repair brain damage. Human mesenchymal stem cell (hMSC) transplantation therapy is a promising approach, although the inflammatory microenvironment of the injured brain affects the efficacy of transplanted hMSCs. We hypothesize that reducing the inflammation in the cerebral microenvironment by reducing pro-inflammatory chemokines prior to hMSC administration will improve the efficacy of hMSC therapy. In a rat model of lateral fluid percussion injury, combined pioglitazone (PG) and hMSC (combination) treatment showed less anxiety-like behavior and improved sensorimotor responses to a noxious cold stimulus. Significant reduction in brain lesion volume, neurodegeneration, microgliosis and astrogliosis were observed after combination treatment. TBI induced expression of inflammatory chemokine CCL20 and IL1-β were significantly decreased in the combination treatment group. Combination treatment significantly increased brain-derived neurotrophic factor (BDNF) level and subventricular zone (SVZ) neurogenesis. Taken together, reducing proinflammatory cytokine expression in the cerebral tissues after TBI by PG administration and prior to hMSC therapy improves the outcome of the therapy in which BDNF could have a role.

scholarly journals Modeling traumatic brain injury combined with hemorrhagic shock in rats: Neurological assessment and PET imaging with 18F-fluorodeoxyglucaric acid

2021 ◽  
Author(s):  
Hibah O Awwad ◽  
Andria Hedrick ◽  
Alex Mdzinarishvili ◽  
Hailey Houson ◽  
Kelly Standifer ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Hemorrhagic Shock ◽  
Tissue Injury ◽  
Brain Lesion ◽  
Lesion Size ◽  
Neurological Deficits ◽  
Lesion Volume ◽  
Sprague Dawley ◽  
The Impact

Traumatic brain injury (TBI)is a major cause of death and disability worldwide. Hemorrhagic shock (HS) aggravates tissue injury and complicates TBI recovery. We studied the combined insult of mild TBI and HS and investigated the impact of varying loss of blood volume on neurologic deficit and brain lesion volume. A novel positron emission tomography (PET) technique was employed to monitor tissue injury. Male Sprague Dawley rats received mTBI by controlled cortical impact (CCI) followed by withdrawal of 0%, 30-40%, 45%, or 50% of blood (mTBI, mTBI+HS≤40%, mTBI+HS45%, and mTBI+HS50%, respectively). Neurological deficit (mNSS= 5.6, 7.6, and 12.3) and mortality (2/12, 2/6, and 7/12) were higher in mTBI+HS≤40%, mTBI+HS45%, and mTBI+HS50%, than in mTBI alone rats (no death; mNSS=3.3). Histologic lesion size increased 3.5-fold in mTBI+HS50% compared to mTBI alone and the infarct-avid PET agent 18F-fluorodeoxyglucaric acid (FGA) proportionately detected tissue necrosis in mTBI+HS50% rats. Based on these results, we conclude that HS aggravates mTBI-induced neurological deficits, tissue injury and mortality. PET using 18F-FGA as an imaging marker can detect the extent of injury in a non-invasive manner.

scholarly journals Disrupting nNOS–PSD95 Interaction Improves Neurological and Cognitive Recoveries after Traumatic Brain Injury

2020 ◽  
Vol 30 (7) ◽  
pp. 3859-3871 ◽  
Author(s):  
Wenrui Qu ◽  
Nai-Kui Liu ◽  
Xiangbing Wu ◽  
Ying Wang ◽  
Yongzhi Xia ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
P38 Mapk ◽  
Brain Lesion ◽  
Mapk Signaling ◽  
Motor Deficits ◽  
Neuronal Cultures ◽  
Normal Brain ◽  
Lesion Volume ◽  
Oxide Synthase

Abstract Excessive activation of N-methyl-D-aspartate receptors (NMDARs) and the resulting neuronal nitric oxide synthase (nNOS) activation plays a crucial role in the pathogenesis of traumatic brain injury (TBI). However, directly inhibiting NMDARs or nNOS produces adverse side effects because they play key physiological roles in the normal brain. Since interaction of nNOS–PSD95 is a key step in NMDAR-mediated excitotoxicity, we investigated whether disrupting nNOS–PSD95 interaction with ZL006, an inhibitor of nNOS–PSD95 interaction, attenuates NMDAR-mediated excitotoxicity. In cortical neuronal cultures, ZL006 treatment significantly reduced glutamate-induced neuronal death. In a mouse model of controlled cortical impact (CCI), administration of ZL006 (10 mg/kg, i.p.) at 30 min postinjury significantly inhibited nNOS–PSD95 interaction, reduced TUNEL- and phospho-p38-positive neurons in the motor cortex. ZL006 treatment also significantly reduced CCI-induced cortical expression of apoptotic markers active caspase-3, PARP-1, ratio of Bcl-2/Bax, and phosphorylated p38 MAPK (p-p38). Functionally, ZL006 treatment significantly improved neuroscores and sensorimotor performance, reduced somatosensory and motor deficits, reversed CCI-induced memory deficits, and attenuated cognitive impairment. Histologically, ZL006 treatment significantly reduced the brain lesion volume. These findings collectively suggest that blocking nNOS–PSD95 interaction represents an attractive strategy for ameliorating consequences of TBI and that its action is mediated via inhibiting neuronal apoptosis and p38 MAPK signaling.

scholarly journals Inhaled Nitric Oxide Reduces Secondary Brain Damage after Traumatic Brain Injury in Mice

2012 ◽  
Vol 33 (2) ◽  
pp. 311-318 ◽  
Author(s):  
Nicole A Terpolilli ◽  
Seong-Woong Kim ◽  
Serge C Thal ◽  
Wolfgang M Kuebler ◽  
Nikolaus Plesnila
Keyword(s):  
Nitric Oxide ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Damage ◽  
Brain Regions ◽  
Lesion Volume ◽  
Effective Treatment Option ◽  
Secondary Brain Damage ◽  
Edema Formation ◽  
Regional Ischemia

Ischemia, especially pericontusional ischemia, is one of the leading causes of secondary brain damage after traumatic brain injury (TBI). So far efforts to improve cerebral blood flow (CBF) after TBI were not successful because of various reasons. We previously showed that nitric oxide (NO) applied by inhalation after experimental ischemic stroke is transported to the brain and induces vasodilatation in hypoxic brain regions, thus improving regional ischemia, thereby improving brain damage and neurological outcome. As regional ischemia in the traumatic penumbra is a key mechanism determining secondary posttraumatic brain damage, the aim of the current study was to evaluate the effect of NO inhalation after experimental TBI. NO inhalation significantly improved CBF and reduced intracranial pressure after TBI in male C57 Bl/6 mice. Long-term application (24 hours NO inhalation) resulted in reduced lesion volume, reduced brain edema formation and less blood–brain barrier disruption, as well as improved neurological function. No adverse effects, e.g., on cerebral auto-regulation, systemic blood pressure, or oxidative damage were observed. NO inhalation might therefore be a safe and effective treatment option for TBI patients.

scholarly journals Rapid Accumulation of Endogenous Tau Oligomers in a Rat Model of Traumatic Brain Injury

2013 ◽  
Vol 288 (23) ◽  
pp. 17042-17050 ◽  
Author(s):  
Bridget E. Hawkins ◽  
Shashirekha Krishnamurthy ◽  
Diana L. Castillo-Carranza ◽  
Urmi Sengupta ◽  
Donald S. Prough ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
The United States ◽  
Tau Proteins ◽  
Diagnostic Tools ◽  
Phosphorylated Tau ◽  
Fluid Percussion Injury ◽  
Rapid Accumulation ◽  
Severe Tbi ◽  
Effective Treatments

Traumatic brain injury (TBI) is a serious problem that affects millions of people in the United States alone. Multiple concussions or even a single moderate to severe TBI can also predispose individuals to develop a pathologically distinct form of tauopathy-related dementia at an early age. No effective treatments are currently available for TBI or TBI-related dementia; moreover, only recently has insight been gained regarding the mechanisms behind their connection. Here, we used antibodies to detect oligomeric and phosphorylated Tau proteins in a non-transgenic rodent model of parasagittal fluid percussion injury. Oligomeric and phosphorylated Tau proteins were detected 4 and 24 h and 2 weeks post-TBI in injured, but not sham control rats. These findings suggest that diagnostic tools and therapeutics that target only toxic forms of Tau may provide earlier detection and safe, more effective treatments for tauopathies associated with repetitive neurotrauma.

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 Treatment of traumatic brain injury with thymosin β4 in rats

2011 ◽  
Vol 114 (1) ◽  
pp. 102-115 ◽  
Author(s):  
Ye Xiong ◽  
Asim Mahmood ◽  
Yuling Meng ◽  
Yanlu Zhang ◽  
Zheng Gang Zhang ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Sham Group ◽  
Therapeutic Potential ◽  
Cell Loss ◽  
Saline Group ◽  
Lesion Volume ◽  
Male Wistar Rats ◽  
Left Parietal Cortex ◽  
First Time

Object This study was designed to investigate the efficacy of delayed thymosin β4 (Tβ4) treatment of traumatic brain injury (TBI) in rats. Methods Young adult male Wistar rats were divided into the following groups: 1) sham group (6 rats); 2) TBI + saline group (9 rats); 3) and TBI + Tβ4 group (10 rats). Traumatic brain injury was induced by controlled cortical impact over the left parietal cortex. Thymosin β4 (6 mg/kg) or saline was administered intraperitoneally starting at Day 1 and then every 3 days for an additional 4 doses. Neurological function was assessed using a modified neurological severity score (mNSS), foot fault, and Morris water maze tests. Animals were killed 35 days after injury, and brain sections were stained for immunohistochemistry to assess angiogenesis, neurogenesis, and oligodendrogenesis after Tβ4 treatment. Results Compared with the saline treatment, delayed Tβ4 treatment did not affect lesion volume but significantly reduced hippocampal cell loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, increased oligodendrogenesis in the CA3 region, and significantly improved sensorimotor functional recovery and spatial learning. Conclusions These data for the first time demonstrate that delayed administration of Tβ4 significantly improves histological and functional outcomes in rats with TBI, indicating that Tβ4 has considerable therapeutic potential for patients with TBI.

scholarly journals Xenon treatment after severe traumatic brain injury improves locomotor outcome, reduces acute neuronal loss and enhances early beneficial neuroinflammation: a randomized, blinded, controlled animal study

Critical Care ◽  
2020 ◽  
Vol 24 (1) ◽  
Author(s):  
Rita Campos-Pires ◽  
Haldis Onggradito ◽  
Eszter Ujvari ◽  
Shughoofa Karimi ◽  
Flavia Valeo ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Functional Outcome ◽  
Neuroprotective Effect ◽  
Neuronal Loss ◽  
Brain Trauma ◽  
Lesion Volume ◽  
Oxygen Balance ◽  
Sprague Dawley ◽  
Locomotor Deficits

Abstract Background Traumatic brain injury (TBI) is a major cause of morbidity and mortality, but there are no clinically proven treatments that specifically target neuronal loss and secondary injury development following TBI. In this study, we evaluate the effect of xenon treatment on functional outcome, lesion volume, neuronal loss and neuroinflammation after severe TBI in rats. Methods Young adult male Sprague Dawley rats were subjected to controlled cortical impact (CCI) brain trauma or sham surgery followed by treatment with either 50% xenon:25% oxygen balance nitrogen, or control gas 75% nitrogen:25% oxygen. Locomotor function was assessed using Catwalk-XT automated gait analysis at baseline and 24 h after injury. Histological outcomes were assessed following perfusion fixation at 15 min or 24 h after injury or sham procedure. Results Xenon treatment reduced lesion volume, reduced early locomotor deficits, and attenuated neuronal loss in clinically relevant cortical and subcortical areas. Xenon treatment resulted in significant increases in Iba1-positive microglia and GFAP-positive reactive astrocytes that was associated with neuronal preservation. Conclusions Our findings demonstrate that xenon improves functional outcome and reduces neuronal loss after brain trauma in rats. Neuronal preservation was associated with a xenon-induced enhancement of microglial cell numbers and astrocyte activation, consistent with a role for early beneficial neuroinflammation in xenon’s neuroprotective effect. These findings suggest that xenon may be a first-line clinical treatment for brain trauma.

scholarly journals Reduction of Traumatic Brain Damage by Tspo Ligand Etifoxine

2019 ◽  
Vol 20 (11) ◽  
pp. 2639 ◽  
Author(s):  
Mona Shehadeh ◽  
Eilam Palzur ◽  
Liat Apel ◽  
Jean Francois Soustiel
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Damage ◽  
Neuroprotective Effect ◽  
Experimental Studies ◽  
Potential Effect ◽  
Translocator Protein ◽  
Male Rats ◽  
Lesion Volume ◽  
Sprague Dawley

Experimental studies have shown that ligands of the 18 kDa translocator protein can reduce neuronal damage induced by traumatic brain injury by protecting mitochondria and preventing metabolic crisis. Etifoxine, an anxiolytic drug and 18 kDa translocator protein ligand, has shown beneficial effects in the models of peripheral nerve neuropathy. The present study investigates the potential effect of etifoxine as a neuroprotective agent in traumatic brain injury (TBI). For this purpose, the effect of etifoxine on lesion volume and modified neurological severity score at 4 weeks was tested in Sprague–Dawley adult male rats submitted to cortical impact contusion. Effects of etifoxine treatment on neuronal survival and apoptosis were also assessed by immune stains in the perilesional area. Etifoxine induced a significant reduction in the lesion volume compared to nontreated animals in a dose-dependent fashion with a similar effect on neurological outcome at four weeks that correlated with enhanced neuron survival and reduced apoptotic activity. These results are consistent with the neuroprotective effect of etifoxine in TBI that may justify further translational research.

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