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1.
J Neuroinflammation ; 18(1): 157, 2021 Jul 17.
Article in English | MEDLINE | ID: mdl-34273979

ABSTRACT

BACKGROUND: Repetitive mild traumatic brain injury (mTBI) can result in chronic visual dysfunction. G-protein receptor 110 (GPR110, ADGRF1) is the target receptor of N-docosahexaenoylethanolamine (synaptamide) mediating the anti-neuroinflammatory function of synaptamide. In this study, we evaluated the effect of an endogenous and a synthetic ligand of GPR110, synaptamide and (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-hydroxy-2-methylpropyl) docosa-4,7,10,13,16,19-hexaenamide (dimethylsynaptamide, A8), on the mTBI-induced long-term optic tract histopathology and visual dysfunction using Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA), a clinically relevant model of mTBI. METHODS: The brain injury in wild-type (WT) and GPR110 knockout (KO) mice was induced by CHIMERA applied daily for 3 days, and GPR110 ligands were intraperitoneally injected immediately following each impact. The expression of GPR110 and proinflammatory mediator tumor necrosis factor (TNF) in the brain was measured by using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) in an acute phase. Chronic inflammatory responses in the optic tract and visual dysfunction were assessed by immunostaining for Iba-1 and GFAP and visual evoked potential (VEP), respectively. The effect of GPR110 ligands in vitro was evaluated by the cyclic adenosine monophosphate (cAMP) production in primary microglia isolated from adult WT or KO mouse brains. RESULTS: CHIMERA injury acutely upregulated the GPR110 and TNF gene level in mouse brain. Repetitive CHIMERA (rCHIMERA) increased the GFAP and Iba-1 immunostaining of glia cells and silver staining of degenerating axons in the optic tract with significant reduction of N1 amplitude of visual evoked potential at up to 3.5 months after injury. Both GPR110 ligands dose- and GPR110-dependently increased cAMP in cultured primary microglia with A8, a ligand with improved stability, being more effective than synaptamide. Intraperitoneal injection of A8 at 1 mg/kg or synaptamide at 5 mg/kg significantly reduced the acute expression of TNF mRNA in the brain and ameliorated chronic optic tract microgliosis, astrogliosis, and axonal degeneration as well as visual deficit caused by injury in WT but not in GPR110 KO mice. CONCLUSION: Our data demonstrate that ligand-induced activation of the GPR110/cAMP system upregulated after injury ameliorates the long-term optic tract histopathology and visual impairment caused by rCHIMERA. Based on the anti-inflammatory nature of GPR110 activation, we suggest that GPR110 ligands may have therapeutic potential for chronic visual dysfunction associated with mTBI.


Subject(s)
Brain Concussion/complications , Ethanolamines/metabolism , Ethanolamines/pharmacology , Gliosis/drug therapy , Gliosis/metabolism , Optic Tract/drug effects , Optic Tract/pathology , Receptors, G-Protein-Coupled/metabolism , Animals , Brain/metabolism , Brain/pathology , Brain Concussion/pathology , Cell Culture Techniques , Cyclic AMP/metabolism , Disease Models, Animal , Electroretinography , Evoked Potentials, Visual , Gliosis/complications , Inflammation , Ligands , Mice , Mice, Inbred C57BL , Mice, Knockout , Microglia/metabolism , Optic Tract/injuries , Tumor Necrosis Factor-alpha/metabolism , Vision, Ocular
2.
J Neurosci Res ; 98(11): 2232-2244, 2020 11.
Article in English | MEDLINE | ID: mdl-32840025

ABSTRACT

Previous studies suggest that long-term supplementation and dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) may have neuroprotective effects following brain injury. The objective of this study was to investigate potential neuroprotective effects of omega-3 PUFAs on white matter following closed-head trauma. The closed-head injury model of engineered rotational acceleration (CHIMERA) produces a reproducible injury in the optic tract and brachium of the superior colliculus in mice. Damage is detectable using diffusion tensor imaging (DTI) metrics, particularly fractional anisotropy (FA), with sensitivity comparable to histology. We acquired in vivo (n = 38) and ex vivo (n = 41) DTI data in mice divided into sham and CHIMERA groups with two dietary groups: one deficient in omega-3 PUFAs and one adequate in omega-3 PUFAs. We examined injury effects (reduction in FA) and neuroprotection (FA reduction modulated by diet) in the optic tract and brachium. We verified that diet did not affect FA in sham animals. In injured animals, we found significantly reduced FA in the optic tract and brachium (~10% reduction, p < 0.001), and Bayes factor analysis showed strong evidence to reject the null hypothesis. However, Bayes factor analysis showed substantial evidence to accept the null hypothesis of no diet-related FA differences in injured animals in the in vivo and ex vivo samples. Our results indicate no neuroprotective effect from adequate dietary omega-3 PUFA intake on white matter damage following traumatic brain injury. Since damage from CHIMERA mainly affects white matter, our results do not necessarily contradict previous findings showing omega-3 PUFA-mediated neuroprotection in gray matter.


Subject(s)
Brain Injuries, Traumatic/diagnostic imaging , Diet , Fatty Acids, Omega-3/therapeutic use , Neuroprotective Agents/therapeutic use , White Matter/diagnostic imaging , White Matter/injuries , Animals , Bayes Theorem , Diffusion Tensor Imaging , Gray Matter/pathology , Head Injuries, Closed/diagnostic imaging , Male , Mice , Mice, Inbred C57BL , Optic Tract/diagnostic imaging , Optic Tract/injuries , Superior Colliculi/diagnostic imaging , Superior Colliculi/injuries
3.
World Neurosurg ; 138: e564-e578, 2020 06.
Article in English | MEDLINE | ID: mdl-32169622

ABSTRACT

OBJECTIVE: To comprehensively compare the vision improvement rate in patients with traumatic optic neuropathy with different surgical timing and other different preoperative conditions. METHODS: PubMed, Embase, and MEDLINE Ovid were searched to identify studies. We performed subgroup analyses for differences in the surgical timing, surgical approach, optic canal fractures, state of consciousness after trauma, time of visual loss development, incision of the optic nerve sheath, and treatment methods. RESULTS: A total of 74 studies involving 6084 patients were included in the final analysis. In the groups of patients with early (≤3 days), middle (4-7 days), and late (>7 days) surgical interventions, 58.4%, 53.2%, and 45.4% demonstrated visual improvements, respectively. The results of the statistical analysis revealed that patients with early surgical intervention had a higher improvement rate than patients with late surgical intervention (P = 0.00953). The improvement rate was significantly lower for patients who presented with no light perception before surgery than for patients whose vision was better than no light perception (relative risk, 0.498; 95% confidence interval [CI], 0.443-0.561; P = 0.001) and lower for patients with immediate visual loss after trauma than for those with secondary visual loss (relative risk, 0.639; 95% CI, 0.498-0.819; P = 0.001). CONCLUSIONS: We recommend that patients seek medical treatment as soon as possible after traumatic optic nerve injury, and patients with secondary injuries can have a good recovery effect while still living with light perception or more. The option of treatment and whether to incise the optic nerve sheath still remains controversial.


Subject(s)
Decompression, Surgical/methods , Ophthalmologic Surgical Procedures/methods , Optic Nerve Injuries/surgery , Humans , Optic Nerve Injuries/complications , Optic Tract/injuries , Optic Tract/surgery , Patient Selection , Prognosis , Time-to-Treatment , Treatment Outcome , Vision Disorders/etiology , Vision Disorders/prevention & control , Visual Acuity
4.
Cell Mol Neurobiol ; 39(7): 1051-1060, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31197745

ABSTRACT

Chronic cerebral hypoperfusion (CCH)-induced white matter lesions (WMLs) are region-specific with the optic tract (OT) displaying the most severe damages and leading to visual-based behavioral impairment. Previously we have demonstrated that anti-high-mobility group box 1 (HMGB1) neutralizing antibody (Ab) prevents CCH-induced hippocampal damages via inhibition of neuroinflammation. Here we tested the protective role of the Ab on CCH-induced OT injuries. Rats were treated with permanent occlusion of common carotid arteries (2-VO) or a sham surgery, and then administered with PBS, anti-HMGB1 Ab, or paired control Ab. Pupillary light reflex examination, visual water maze, and tapered beam-walking were performed 28 days post-surgery to investigate the behavioral deficits. Meanwhile, WMLs were measured by Klüver-Barrera (KB) and H&E staining, and glial activation was further assessed to evaluate inflammatory responses in OT. Results revealed that anti-HMGB1 Ab ameliorated the morphological damages (grade scores, vacuoles, and thickness) in OT area and preserved visual abilities. Additionally, the increased levels of inflammatory responses and expressions of TLR4 and NF-κB p65 and phosphorylated NF-κB p65 (p-p65) in OT area were partly down-regulated after anti-HMGB1 treatment. Taken together, these findings suggested that HMGB1 neutralization could ease OT injuries and visual-guided behavioral deficits via suppressing inflammatory responses.


Subject(s)
Down-Regulation , HMGB1 Protein/metabolism , Inflammation/pathology , Neutralization Tests , Optic Tract/blood supply , Optic Tract/injuries , White Matter/blood supply , White Matter/pathology , Animals , Antibodies/pharmacology , Behavior, Animal , Male , Maze Learning , NF-kappa B/metabolism , Neuroglia/metabolism , Optic Tract/pathology , Rats, Wistar , Signal Transduction , Toll-Like Receptor 4/metabolism
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