scholarly journals Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits

2019 ◽  
Author(s):  
Rebecca J. Henry ◽  
Rodney M. Ritzel ◽  
James P. Barrett ◽  
Sarah J. Doran ◽  
Yun Jiao ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Chronic Phase ◽  
Neurological Dysfunction ◽  
Neurological Deficits ◽  
Cortical Lesion ◽  
Translational Study ◽  
Chronic Neuroinflammation

AbstractChronic neuroinflammation with sustained microglial activation occurs following moderate-to-severe traumatic brain injury (TBI) and is believed to contribute to subsequent neurodegeneration and neurological deficits. Microglia, the primary innate immune cells in brain, are dependent on colony stimulating factor 1 receptor (CSF1R) signaling for their survival. In this translational study, we examined the effects of delayed depletion and subsequent repopulation of microglia on chronic neurodegeneration and functional recovery up to three months posttrauma. A CSF1R inhibitor, PLX5622, was administered to injured adult male C57Bl/6 mice at one month after controlled cortical impact to remove chronically activated microglia, and the inihibitor was withdrawn 1 week later to allow microglial repopulation. Following TBI, the repopulated microglia displayed a ramified morphology, similar to that of sham control uninjured animals, whereas microglia in untreated injured animals showed the typical chronic posttraumatic hypertrophic morphology. PLX5622 treatment limited TBI-associated neuropathological changes at 3 months posttrauma; these included a smaller cortical lesion, reduced neuronal cell death in the injured cortex and ipsilateral hippocampus, and decreased NOX2-dependent reactive microgliosis. Furthermore, delayed depletion of microglia led to widespread changes in the cortical transcriptome, including alterations in gene pathways involved in neuroinflammation, oxidative stress, and neuroplasticity. PLX5622 treated animals showed significantly improved neurological recovery using a variety of complementary neurobehavioral evaluations. These included beam walk and rotorod tests for sensori-motor function, as well as Y-maze, novel object recognition, and Morris water maze tests to evaluate cognitive function. Together, our findings show that chronic phase removal of neurotoxic microglia using CSF1R inhibitors after experimental TBI can markedly reduce chronic neuroinflammation and neurodegeneration, as well as related long-term motor and cognitive deficits. Thus, CSF1R inhibition may provide a clinically feasible approach to limit posttraumatic neurodegeneration and neurological dysfunction following head injury.

scholarly journals Deficiency in interleukin-18 ameliorated glial activation and neuroinflammation after traumatic brain injury in mice

2020 ◽  
Author(s):  
Wenwen Dong ◽  
Linlin Wang ◽  
Ziyuan Chen ◽  
Xiangshen Guo ◽  
Pengfei Wang ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Glial Activation ◽  
Neurological Deficits ◽  
Secondary Injury ◽  
Gm Csf ◽  
Tnf Α

Abstract Background: Neuroinflammation is recognized as one of the main pathological mechanisms of secondary injury caused by traumatic brain injury (TBI). It has been reported that interleukin (IL)-18 is expressed in glial cells and involved in the regulation of neuroinflammation. Further studies have revealed that IL-18 expression is upregulated and may contribute to pathogenesis in the later phases of TBI; however, the mechanism underlying the effect of IL-18 on TBI remains unclear. Our present study assessed the roles of IL-18 in inflammatory and neurodegenerative pathology in mice subjected to TBI.Methods: A controlled cortical impact (CCI) injury model was conducted to mimic TBI, and brains were collected at 3 and 7 days post TBI (dpi). The levels of IL-18 were detected by qRT-PCR and immunofluorescence staining. In addition, neurological severity score (NSS) was used to assess neurological deficits after TBI. Furthermore, neuronal cell death, glial activation, and inflammatory cytokine and chemokine secretion were evaluated in wild-type ( WT ) and Il18-knockout ( Il18 -KO) mice to explore the role of IL-18 in TBI.Results: IL-18 levels were upregulated post TBI, accompanied by reactive glial activation. Il-18 deficiency significantly ameliorated glial activation and improved neuronal cell death and neurological deficits. In addition, Il-18 deficiency reduced the TBI-induced M1-like microglia frequency. Interestingly, the levels of all pro- and anti-inflammatory cytokines, including IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL17A, G-CSF, GM-CSF, IFN-γ, and TNF-α, were downregulated in Il18 -KO mice. The deletion of Il-18 attenuated the levels of most chemokines induced by TBI, including CCL2, CCL3, CCL4, CCL5, CCL7, CCL12, CCL20, CXCL1, CXCL2, CXCL10, CXCL12, CXCL13, and CXCL16.Conclusions: These data demonstrated that IL-18 is involved in TBI induced neuroinflammation, which suggests that IL-18 is important for the development of secondary injury induced by TBI.

Oxidative Stress: Major Threat in Traumatic Brain Injury

2018 ◽  
Vol 17 (9) ◽  
pp. 689-695 ◽  
Author(s):  
Nidhi Khatri ◽  
Manisha Thakur ◽  
Vikas Pareek ◽  
Sandeep Kumar ◽  
Sunil Sharma ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mitochondrial Dysfunction ◽  
Calcium Influx ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Physical Assault ◽  
Mortality And Morbidity ◽  
Primary Injury

Background & Objective: Traumatic Brain Injury (TBI) is one of the major causes of mortality and morbidity worldwide. It represents mild, moderate and severe effects of physical assault to brain which may cause sequential, primary or secondary ramifications. Primary injury can be due to the first physical hit, blow or jolt to one of the brain compartments. The primary injury is then followed by secondary injury which leads to biochemical, cellular, and physiological changes like blood brain barrier disruption, inflammation, excitotoxicity, necrosis, apoptosis, mitochondrial dysfunction and generation of oxidative stress. Apart from this, there is also an immediate increase in glutamate at the synapses following severe TBI. Excessive glutamate at synapses in turn activates corresponding NMDA and AMPA receptors that facilitate excessive calcium influx into the neuronal cells. This leads to the generation of oxidative stress which further leads to mitochondrial dysfunction, lipid peroxidation and oxidation of proteins and DNA. As a consequence, neuronal cell death takes place and ultimately people start facing some serious disabilies. Conclusion: In the present review we provide extensive overview of the role of reactive oxygen species (ROS)-induced oxidative stress and its fatal effects on brain after TBI.

scholarly journals Effects of Transient Receptor Potential Cation 5 (TRPC5) Inhibitor, NU6027, on Hippocampal Neuronal Death after Traumatic Brain Injury

2020 ◽  
Vol 21 (21) ◽  
pp. 8256 ◽  
Author(s):  
Min Kyu Park ◽  
Bo Young Choi ◽  
A Ra Kho ◽  
Song Hee Lee ◽  
Dae Ki Hong ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Death ◽  
Transient Receptor Potential ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Treated Group ◽  
Therapeutic Window ◽  
Permanent Disability ◽  
Fluoro Jade B

Traumatic brain injury (TBI) can cause physical, cognitive, social, and behavioral changes that can lead to permanent disability or death. After primary brain injury, translocated free zinc can accumulate in neurons and lead to secondary events such as oxidative stress, inflammation, edema, swelling, and cognitive impairment. Under pathological conditions, such as ischemia and TBI, excessive zinc release, and accumulation occurs in neurons. Based on previous research, it hypothesized that calcium as well as zinc would be influx into the TRPC5 channel. Therefore, we hypothesized that the suppression of TRPC5 would prevent neuronal cell death by reducing the influx of zinc and calcium. To test our hypothesis, we used a TBI animal model. After the TBI, we immediately injected NU6027 (1 mg/kg, intraperitoneal), TRPC5 inhibitor, and then sacrificed animals 24 h later. We conducted Fluoro-Jade B (FJB) staining to confirm the presence of degenerating neurons in the hippocampal cornus ammonis 3 (CA3). After the TBI, the degenerating neuronal cell count was decreased in the NU6027-treated group compared with the vehicle-treated group. Our findings suggest that the suppression of TRPC5 can open a new therapeutic window for a reduction of the neuronal death that may occur after TBI.

scholarly journals Safety and Efficacy of Erythropoietin in Traumatic Brain Injury Patients: A Pilot Randomized Trial

2010 ◽  
Vol 2010 ◽  
pp. 1-5 ◽  
Author(s):  
R. Nirula ◽  
R. Diaz-Arrastia ◽  
K. Brasel ◽  
J. A. Weigelt ◽  
K. Waxman
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Randomized Trial ◽  
Treatment Effect ◽  
Neuronal Cell Death ◽  
Neuron Specific Enolase ◽  
Neuronal Cell ◽  
Trauma Patients ◽  
Stroke Patients ◽  
Rule Out

Background. Erythropoietin (EPO) is a neuroprotective agent utilized in stroke patients. This pilot study represents the first randomized trial of EPO in traumatic brain injury (TBI) patients.Methods. Adult, blunt trauma patients with evidence of TBI were randomized to EPO or placebo within 6 hours of injury. Baseline and daily serum S-100B and Neuron Specific Enolase (NSE) levels were measured.Results. TBI was worse in the EPO (n=11) group compared to placebo patients (n=5). The use of EPO did not impact NSE (P=.89) or S100 B (P=.53) levels compared to placebo.Conclusions. At the dose used, EPO did not reduce neuronal cell death compared to placebo; however, TBI severity was worse in the EPO group while levels of NSE and S100-B were similar to the less injured placebo group making it difficult to rule out a treatment effect. A larger, balanced study is necessary to confirm a potential treatment effect.

scholarly journals Peroxisome Proliferator-Activated Receptors: “Key” Regulators of Neuroinflammation after Traumatic Brain Injury

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-7 ◽  
Author(s):  
Philip F. Stahel ◽  
Wade R. Smith ◽  
Jay Bruchis ◽  
Craig H. Rabb
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Cell Death ◽  
Synthetic Cannabinoids ◽  
Experimental Studies ◽  
Neuronal Cell ◽  
Peroxisome Proliferator ◽  
Therapeutic Concept ◽  
Anti Inflammatory ◽  
Peroxisome Proliferator Activated Receptors

Traumatic brain injury is characterized by neuroinflammatory pathological sequelae which contribute to brain edema and delayed neuronal cell death. Until present, no specific pharmacological compound has been found, which attenuates these pathophysiological events and improves the outcome after head injury. Recent experimental studies suggest that targeting peroxisome proliferator-activated receptors (PPARs) may represent a new anti-inflammatory therapeutic concept for traumatic brain injury. PPARs are “key” transcription factors which inhibit NFκBactivity and downstream transcription products, such as proinflammatory and proapoptotic cytokines. The present review outlines our current understanding of PPAR-mediated neuroprotective mechanisms in the injured brain and discusses potential future anti-inflammatory strategies for head-injured patients, with an emphasis on the putative beneficial combination therapy of synthetic cannabinoids (e.g., dexanabinol) with PPARαagonists (e.g., fenofibrate).

scholarly journals Disruption of Bax Protein Prevents Neuronal Cell Death but Produces Cognitive Impairment in Mice following Traumatic Brain Injury

2008 ◽  
Vol 25 (7) ◽  
pp. 755-767 ◽  
Author(s):  
Roya Tehranian ◽  
Marie E. Rose ◽  
Vincent Vagni ◽  
Alicia M. Pickrell ◽  
Raymond P. Griffith ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Cognitive Impairment ◽  
Brain Injury ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Bax Protein

scholarly journals Therapeutic Time Window for Edaravone Treatment of Traumatic Brain Injury in Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Kazuyuki Miyamoto ◽  
Hirokazu Ohtaki ◽  
Kenji Dohi ◽  
Tomomi Tsumuraya ◽  
Dandan Song ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Death ◽  
Time Window ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Therapeutic Time Window

Traumatic brain injury (TBI) is a major cause of death and disability in young people. No effective therapy is available to ameliorate its damaging effects. Our aim was to investigate the optimal therapeutic time window of edaravone, a free radical scavenger which is currently used in Japan. We also determined the temporal profile of reactive oxygen species (ROS) production, oxidative stress, and neuronal death. Male C57Bl/6 mice were subjected to a controlled cortical impact (CCI). Edaravone (3.0 mg/kg), or vehicle, was administered intravenously at 0, 3, or 6 hours following CCI. The production of superoxide radicals (O2∙-) as a marker of ROS, of nitrotyrosine (NT) as an indicator of oxidative stress, and neuronal death were measured for 24 hours following CCI. Superoxide radical production was clearly evident 3 hours after CCI, with oxidative stress and neuronal cell death becoming apparent after 6 hours. Edaravone administration after CCI resulted in a significant reduction in the injury volume and oxidative stress, particularly at the 3-hour time point. Moreover, the greatest decrease inO2∙-levels was observed when edaravone was administered 3 hours following CCI. These findings suggest that edaravone could prove clinically useful to ameliorate the devastating effects of TBI.

scholarly journals Cognitive Impairments Accompanying Rodent Mild Traumatic Brain Injury Involve p53-Dependent Neuronal Cell Death and Are Ameliorated by the Tetrahydrobenzothiazole PFT-α

PLoS ONE ◽  
2013 ◽  
Vol 8 (11) ◽  
pp. e79837 ◽  
Author(s):  
Lital Rachmany ◽  
David Tweedie ◽  
Vardit Rubovitch ◽  
Qian-Sheng Yu ◽  
Yazhou Li ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Cognitive Impairments ◽  
Neuronal Cell Death ◽  
Neuronal Cell
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