Nitroxides affect neurological deficits and lesion size induced by a rat model of traumatic brain injury

Inflammation which accompanies traumatic brain injury (TBI) can exacerbate neurological deficits. Thus, anti-inflammatory treatments have the potential to improve outcome. Angiotensin II receptor type 1 (ART1) mediates vasoconstriction, and its inhibition has been widely used to treat hypertension. However, recent work has suggested that it may also modulate apoptosis, and neuroinflammation. Thus, treatment with already available ART1 blockers may have additional neuroprotective value. We explore the contribution of ART1 to neuroprotection and brain hemorrhage in a model of TBI. Male, wildtype (Wt) and ART1 knockout (Ko) mice were subjected to TBI using controlled cortical impact (CCI). This model leads to reproducible traumatic brain injury with disruption of motor function and hemorrhage into the area of injury. Sensorimotor function (adhesive removal & elevated body swing tests), brain hemorrhage and lesion size were assessed at 3, 7 and 14 days. To explore the clinical relevance of ART1 in brain injury, we also gave Wt mice an ATR1 inhibitor (candesartan, 0.1mg/kg IP). We found that ATR1 deficient mice were protected from CCI as evidenced by decreased lesion and hemorrhage volumes (decreases of ∼40% in lesion size amongst Ko mice, n=6/group, p<0.05), improved neurobehavioral outcomes (n=6/group, p<0.05) and fewer activated microglia in Ko mice (p<0.05). This was also associated with decreased cytokine expression relative to Wt. Candesartan similarly protected against brain injury and improved neurological outcome out to 14 days post CCI (n=6/group, p<0.05). These data are consistent with the notion that ART1 contributes negatively to traumatic brain injury, and its inhibition or deficiency leads to improved outcomes and decreased immune responses. Considering the clinical availability of ART1 inhibitors, this approach may be a promising novel therapeutic target against TBI and related conditions including stroke.

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

10.1101/2021.06.01.446662 ◽

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.

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Inhibition of Epac2 Attenuates Neural Cell Apoptosis and Improves Neurological Deficits in a Rat Model of Traumatic Brain Injury

Frontiers in Neuroscience ◽

10.3389/fnins.2018.00263 ◽

2018 ◽

Vol 12 ◽

Cited By ~ 6

Author(s):

Ling Zhang ◽

Li Zhang ◽

Huixiang Liu ◽

Feng Jiang ◽

Huanjing Wang ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Rat Model ◽

Cell Apoptosis ◽

Neural Cell ◽

Neurological Deficits

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Study of the Inhibitory Effect of Antibodies Against C3 Complement Component in a Rat Model of Traumatic Brain Injury

Российский иммунологический журнал ◽

10.31857/s102872210002623-0 ◽

2018 ◽

pp. 641-643

Author(s):

N. Gorbunov ◽

A. Ischenko ◽

A. Zhakhov ◽

A. Trofimov ◽

E. Denisenko ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Rat Model ◽

Inhibitory Effect ◽

Complement Component

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Ulinastatin alleviates traumatic brain injury by reducing endothelin-1

Translational Neuroscience ◽

10.1515/tnsci-2021-0001 ◽

2020 ◽

Vol 12 (1) ◽

pp. 001-008

Author(s):

Ting Liu ◽

Xing-Zhi Liao ◽

Mai-Tao Zhou

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Western Blot ◽

Water Content ◽

Brain Edema ◽

Rat Model ◽

Neurosurgical Procedures ◽

Brain Water Content ◽

The Brain ◽

Brain Water

Abstract Background Brain edema is one of the major causes of fatality and disability associated with injury and neurosurgical procedures. The goal of this study was to evaluate the effect of ulinastatin (UTI), a protease inhibitor, on astrocytes in a rat model of traumatic brain injury (TBI). Methodology A rat model of TBI was established. Animals were randomly divided into 2 groups – one group was treated with normal saline and the second group was treated with UTI (50,000 U/kg). The brain water content and permeability of the blood–brain barrier were assessed in the two groups along with a sham group (no TBI). Expression of the glial fibrillary acidic protein, endthelin-1 (ET-1), vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) were measured by immunohistochemistry and western blot. Effect of UTI on ERK and PI3K/AKT signaling pathways was measured by western blot. Results UTI significantly decreased the brain water content and extravasation of the Evans blue dye. This attenuation was associated with decreased activation of the astrocytes and ET-1. UTI treatment decreased ERK and Akt activation and inhibited the expression of pro-inflammatory VEGF and MMP-9. Conclusion UTI can alleviate brain edema resulting from TBI by inhibiting astrocyte activation and ET-1 production.

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