Blast Preconditioning Protects Retinal Ganglion Cells and Reveals Targets for Prevention of Neurodegeneration Following Blast-Mediated Traumatic Brian Injury

Harper, Matthew M.; Woll, Addison W.; Evans, Lucy; Delcau, Michael; Akurathi, Abhigna; Hedberg-Buenz, Adam; Soukup, Dana A.; Boehme, Nickolas; Hefti, Marco M.; Dutca, Laura M.; Anderson, Michael G.; Bassuk, Alexander G.

doi:10.1167/iovs.19-27565

Cited by 22 publications

(29 citation statements)

References 92 publications

(110 reference statements)

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“…Whether these metabolites in the KP affect RGCs was less studied. During our study, a study by Harper et al [25] showed that systemic inhibition of KMO protects RGCs in an experimental mouse model for traumatic brain injury, supporting the idea that KP metabolites play a role in RGC health. We found that the absence of KMO led to higher levels of KYN, KYNA and AA in the serum and retina, coincident with a protection against retinal I/R injury.…”

Section: Discussionsupporting

confidence: 83%

“…High levels of QUIN and 3OHKYN and reduced levels of KYNA have been observed in the brains of Huntington's disease patients [21][22][23]. It has been found that traumatic brain injury activates the KP resulting in elevated QUIN [24], and another study showed that KMO plays an important role in RGC death in mice subjected to traumatic brain injury [25]. Previous studies have shown that the absence of KMO activity resulted in beneficial effects by reducing inflammation and a reduction in peripheral lipopolysaccharide-induced depressive-like behaviors in mice [26].…”

Section: Introductionmentioning

confidence: 99%

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Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

Nahomi

Nam

Rankenberg

et al. 2020

IJMS

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Background: Glaucoma is an optic neuropathy and involves the progressive degeneration of retinal ganglion cells (RGCs), which leads to blindness in patients. We investigated the role of the neuroprotective kynurenic acid (KYNA) in RGC death against retinal ischemia/reperfusion (I/R) injury. Methods: We injected KYNA intravenously or intravitreally to mice. We generated a knockout mouse strain of kynurenine 3-monooxygenase (KMO), an enzyme in the kynurenine pathway that produces neurotoxic 3-hydroxykynurenine. To test the effect of mild hyperglycemia on RGC protection, we used streptozotocin (STZ) induced diabetic mice. Retinal I/R injury was induced by increasing intraocular pressure for 60 min followed by reperfusion and RGC numbers were counted in the retinal flat mounts. Results: Intravenous or intravitreal administration of KYNA protected RGCs against I/R injury. The I/R injury caused a greater loss of RGCs in wild type than in KMO knockout mice. KMO knockout mice had mildly higher levels of fasting blood glucose than wild type mice. Diabetic mice showed significantly lower loss of RGCs when compared with non-diabetic mice subjected to I/R injury. Conclusion: Together, our study suggests that the absence of KMO protects RGCs against I/R injury, through mechanisms that likely involve higher levels of KYNA and glucose.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

Nahomi

Nam

Rankenberg

et al. 2020

IJMS

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“…We followed a well-established protocol to identify RGCs via BRN3A immunohistochemistry, as previously described. 32 After euthanasia, mice were transcardially perfused with 0.01-M PBS followed by 4% paraformaldehyde in 0.01-M PBS. Ipsilateral whole eyes were enucleated and posterior cups were dissected and fixed for 4 hours at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Sex Does Not Influence Visual Outcomes After Blast-Mediated Traumatic Brain Injury but IL-1 Pathway Mutations Confer Partial Rescue

Evans

Boehme

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose In a mouse model of blast-mediated traumatic brain injury (bTBI), interleukin-1 (IL-1)-pathway components were tested as potential therapeutic targets for bTBI-mediated retinal ganglion cell (RGC) dysfunction. Sex was also evaluated as a variable for RGC outcomes post-bTBI. Methods Male and female mice with null mutations in genes encoding IL-1α, IL-1β, or IL-1RI were compared to C57BL/6J wild-type (WT) mice after exposure to three 20-psi blast waves given at an interblast interval of 1 hour or to mice receiving sham injury. To determine if genetic blockade of IL-1α, IL-1β, or IL-1RI could prevent damage to RGCs, the function and structure of these cells were evaluated by pattern electroretinogram and optical coherence tomography, respectively, 5 weeks following blast or sham exposure. RGC survival was also quantitatively assessed via immunohistochemical staining of BRN3A at the completion of the study. Results Our results showed that male and female WT mice had a similar response to blast-induced retinal injury. Generally, constitutive deletion of IL-1α, IL-1β, or IL-1RI did not provide full protection from the effects of bTBI on visual outcomes; however, injured WT mice had significantly worse visual outcomes compared to the injured genetic knockout mice. Conclusions Sex does not affect RGC outcomes after bTBI. The genetic studies suggest that deletion of these IL-1 pathway components confers some protection, but global deletion from birth did not result in a complete rescue.

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“…It should be noted that the method of inducing blastmediated TBI that was used in this study results in uniform damage among mice exposed to blast. Previously published transcriptomic studies using this model demonstrates very little intra-animal variability in gene expression changes [87].…”

Section: Discussionmentioning

confidence: 85%

Identification of chronic brain protein changes and protein targets of serum auto-antibodies after blast-mediated traumatic brain injury

Harper

Rudd²,

Meyer

et al. 2020

Heliyon

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In addition to needing acute emergency management, blast-mediated traumatic brain injury (TBI) is also a chronic disorder with delayed-onset symptoms that manifest and progress over time. While the immediate consequences of acute blast injuries are readily apparent, chronic sequelae are harder to recognize. Indeed, the identification of individuals with mild-TBI or TBI-induced symptoms is greatly impaired in large part due to the lack of objective and robust biomarkers. The purpose of this study was to address these need by identifying candidates for serumbased biomarkers of blast TBI, and also to identify unique or differentially regulated protein expression in the thalamus in C57BL/6J mice exposed to blast using high throughput qualitative screens of protein expression. To identify thalamic proteins differentially or uniquely associated with blast exposure, we utilized an antibody-based affinity-capture strategy (referred to as "proteomics-based analysis of depletomes"; PAD) to deplete thalamic lysates from blast-treated mice of endogenous thalamic proteins also found in control mice. Analysis of this "depletome" detected 75 unique proteins, many with associations to the myelin sheath. To identify blastassociated proteins eliciting production of circulating autoantibodies, serum antibodies of blast-treated mice were immobilized, and their immunogens subsequently identified by proteomic analysis of proteins specifically captured following incubation with thalamic lysates (a variant of a strategy referred to as "proteomics-based expression library screening"; PELS). This analysis identified 46 blast-associated immunogenic proteins, including 6 shared in common with the PAD analysis (ALDOA, PHKB, HBA-A1, DPYSL2, SYN1, and CKB). These proteins and their autoantibodies are appropriate for further consideration as biomarkers of blast-mediated TBI.

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Blast Preconditioning Protects Retinal Ganglion Cells and Reveals Targets for Prevention of Neurodegeneration Following Blast-Mediated Traumatic Brian Injury

Abstract: Blast preconditioning protects retinal ganglion cells and reveals targets for prevention of neurodegeneration following blast-mediated traumatic brain injury.

Cited by 22 publications

References 92 publications

Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

Sex Does Not Influence Visual Outcomes After Blast-Mediated Traumatic Brain Injury but IL-1 Pathway Mutations Confer Partial Rescue

Identification of chronic brain protein changes and protein targets of serum auto-antibodies after blast-mediated traumatic brain injury

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