Neuroprotective Effect of Hypothermia on Neuronal Injury in Diffuse Traumatic Brain Injury Coupled With Hypoxia and Hypotension

Traumatic brain injury (TBI) is a major health concern worldwide and is classified based on severity into mild, moderate, and severe. The mechanical injury in TBI leads to a metabolic and ionic imbalance, which eventually leads to excessive production of reactive oxygen species (ROS) and a state of oxidative stress. To date, no drug has been approved by the food and drug administration (FDA) for the treatment of TBI. Nevertheless, it is thought that targeting the pathology mechanisms would alleviate the consequences of TBI. For that purpose, antioxidants have been considered as treatment options in TBI and were shown to have a neuroprotective effect. In this review, we will discuss oxidative stress in TBI, the history of antioxidant utilization in the treatment of TBI, and we will focus on two novel antioxidants, mitoquinone (MitoQ) and edaravone. MitoQ can cross the blood brain barrier and cellular membranes to accumulate in the mitochondria and is thought to activate the Nrf2/ARE pathway leading to an increase in the expression of antioxidant enzymes. Edaravone is a free radical scavenger that leads to the mitigation of damage resulting from oxidative stress with a possible association to the activation of the Nrf2/ARE pathway as well.

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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 ◽

10.1186/s13054-020-03373-9 ◽

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.

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Reduction of Traumatic Brain Damage by Tspo Ligand Etifoxine

International Journal of Molecular Sciences ◽

10.3390/ijms20112639 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2639 ◽

Cited By ~ 6

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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0416 Poor Sleep Quality Predicts Serum Markers of Neurodegeneration and Cognitive Deficits in Warriors with Mild Traumatic Brain Injury

SLEEP ◽

10.1093/sleep/zsaa056.413 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A159-A159

Author(s):

K Werner ◽

P Shahim ◽

J Gill ◽

R Nakase-Richardson ◽

K Kenney

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Sleep Quality ◽

Sleep Disorders ◽

Cognitive Deficits ◽

Neuronal Injury ◽

Small Sample ◽

Cross Sectional ◽

Sleep Dysfunction ◽

Obstructive Sleep

Abstract Introduction Increasing evidence links neurodegeneration to traumatic brain injury (TBI), and a separate body of literature links neurodegeneration to sleep dysfunction, implicating increased toxin production and decreased glymphatic clearance. Sleep disorders affect 50% of TBI patients, yet the sleep-neurodegeneration connection in these patients remains unexplored. We hypothesized that warfighters with TBI and sleep dysfunction would have increased neuronal injury, revealing potential mechanistic underpinnings for TBI outcomes. We measured plasma biomarkers, cognitive function and sleep surveys for correlation analysis. Methods In a retrospective cross-sectional study of warfighters (n=113 chronic mild TBI patients), the Pittsburgh sleep quality index (PSQI) was compared with amyloid β42 (Aβ42), neurofilament light (NFL), tau, and phospho-tau (threonine 181) isolated from plasma and exosomes. Executive function was tested with the categorical fluency test. Exosomes were precipitated from plasma. Proteins were measured with the Single Molecule Array (Quanterix). Linear models were adjusted for age, ApoE, and number of TBIs. Results Poor sleepers with TBI (PSQI>8) had elevated NFL compared to good sleepers in plasma (p=0.007) and exosomes (p=0.00017), and PSQI directly correlated with NFL (plasma: Beta=0.23, p=0.0079; exosomes: Beta=2.19, p=0.0013) stronger than any other marker of neurodegeneration. Poor sleepers also showed higher obstructive sleep apnea (OSA) risk compared to good sleepers by STOP-BANG scores (3.6, SD=1.6 vs 2.8, SD=1.74; p=0.0014) as well as decreased categorical fluency (20.7, SD=4.1) (18.3, SD=4.6, p=.0067). Plasma tau and Aβ42 also correlated with PSQI (Beta=0.64, p=0.028, and Beta=0.40, p=0.049 respectively). Conclusion This is the first reported data correlating markers of neuronal injury and cognitive deficits with sleep complaints and OSA risk in patients with TBI - possibly identifying treatable pathophysiological mediators of TBI neurodegeneration. Limitations include a small sample size, lack of objective sleep measures, and inability to establish directionality due to cross-sectional design. Prospective trials will be required to further explore our proposed hypothesis. If confirmed, these findings would call for targeting sleep disorders in the TBI population to mitigate risk of neurodegeneration. Support This work was supported by grant funding from: Department of Defense, Chronic Effects of Neurotrauma Consortium (CENC) Award W81XWH-13-2-0095 and Department of Veterans Affairs CENC Award I01 CX001135.

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