From DNA damage to functional changes of the trabecular meshwork in aging and glaucoma

Saccà, Sergio Claudio; Gandolfi, Stefano; Bagnis, Alessandro; Manni, Gianluca; Damonte, Gianluca; Traverso, Carlo Enrico; Izzotti, Alberto

doi:10.1016/j.arr.2016.05.012

Cited by 118 publications

(113 citation statements)

References 244 publications

(254 reference statements)

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“…39,40 Recently, free radicals have been investigated as an emerging therapeutic target for the treatment of neurological disorders including Alzheimer's disease and ALS, 41 as well as ocular diseases such as glaucoma, diabetic retinopathy, and age-related macular degeneration. [42][43][44] Thus, VPA, as well as edaravone, seems to be a suitable candidate for drug repurposing for neurotrauma. We also showed that administration of edaravone was effective even after ONI, strongly suggesting the possibility that edaravone is a potential drug for treatment of optic neuropathy.…”

Section: Discussionmentioning

confidence: 99%

Edaravone Prevents Retinal Degeneration in Adult Mice Following Optic Nerve Injury

Akiyama

Azuchi

Guo

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To assess the therapeutic potential of edaravone, a free radical scavenger that is used for the treatment of acute brain infarction and amyotrophic lateral sclerosis, in a mouse model of optic nerve injury (ONI).METHODS. Two microliters of edaravone (7.2 mM) or vehicle were injected intraocularly 3 minutes after ONI. Optical coherence tomography, retrograde labeling of retinal ganglion cells (RGCs), histopathology, and immunohistochemical analyses of phosphorylated apoptosis signal-regulating kinase-1 (ASK1) and p38 mitogen-activated protein kinase (MAPK) in the retina were performed after ONI. Reactive oxygen species (ROS) levels were assessed with a CellROX Green Reagent.RESULTS. Edaravone ameliorated ONI-induced ROS production, RGC death, and inner retinal degeneration. Also, activation of the ASK1-p38 MAPK pathway that induces RGC death following ONI was suppressed with edaravone treatment. CONCLUSIONS.The results of this study suggest that intraocular administration of edaravone may be a useful treatment for posttraumatic complications.Keywords: edaravone, oxidative stress, neuroprotection, ASK1, retinal ganglion cell T raumatic optic neuropathy is a common clinical problem that occurs in 0.5% to 5% of patients with closed head injury.1 Damage to the optic nerve induces secondary swelling within the optic canal, accompanied by subsequent retinal ganglion cell (RGC) loss and optic nerve atrophy.2 Although no large natural history or randomized controlled trials have been published, corticosteroid therapy and optic canal decompression surgery are not considered to be effective for patients with traumatic optic neuropathy.3 Research into finding therapeutic targets for treatment of traumatic optic neuropathy indicated that neuroprotection might be an effective strategy and studies using an optic nerve injury (ONI) model in rodents have provided useful information. For example, neurotrophins, such as brain-derived neurotrophic factor and ciliary neurotrophic factor, protect retinal RGCs in an ONI model. [4][5][6] Also, inhibitors of glutamate receptors, tumor necrosis factor receptors, and nitric oxide synthase may be effective for RGC protection. 7-11The ONI model mimics some aspects of glaucoma, including RGC death induced by oxidative stress, and therefore, it is also a useful animal model for glaucoma.Edaravone is a free radical scavenger that has been used clinically to treat acute brain infarction and amyotrophic lateral sclerosis (ALS). Edaravone quenches hydroxyl radicals ( Á OH) and inhibits lipid peroxidation dependent and independent of Á OH. 12,13 In an in vitro cell culture study using the RGC-5 to study the neurobiology of RGCs, edaravone scavenged the intracellular Á OH, superoxide anion (O 2 ÀÁ ), and hydrogen peroxide (H 2 O 2 ) while demonstrating the strongest scavenging activity against14 Recent studies have shown that oxidative stress plays an important role in many ocular diseases including glaucoma. [15][16][17][18] Interestingly, edaravone attenuates retinal ischemia/reperfusion ...

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Section: Discussionmentioning

confidence: 99%

Edaravone Prevents Retinal Degeneration in Adult Mice Following Optic Nerve Injury

Akiyama

Azuchi

Guo

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…Compared to nuclear DNA, mtDNA is highly susceptible to oxidative damage due to lacking of protective histones and limited capacity of DNA repair . Oxidative stress and mitochondrial injury have been postulated as the possible mechanism in the pathogenesis of hepatitis and subsequent development of cirrhosis and HCC .…”

Section: Discussionmentioning

confidence: 99%

Association between mitochondrial DNA content and baseline serum levels of HBsAg in chronic hepatitis B infection

et al. 2017

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Recent studies have demonstrated a potential link between mitochondrial DNA (mtDNA) content and cirrhosis or hepatocellular carcinoma (HCC). However, there are few studies evaluating mtDNA content as a noninvasive marker of chronic hepatitis B infection (CHB). In this study, we conducted a case-control study to determine mtDNA content in peripheral blood leukocyte (PBL) samples from 76 CHB cases naïve to antivirus therapy and 96 healthy controls, and then evaluated the association between mtDNA content and baseline serum concentration of HBV markers. Consequently, CHB cases had significantly higher mtDNA content than healthy controls (1052.85 vs 618.98, P < 0.001). Pearson's correlation analysis revealed that mtDNA content was negatively correlated with the baseline levels of hepatitis B surface antigen (HBsAg) (r = -0.291, P = 0.011) in CHB patients. In a trend analysis, a statistically significant association was detected between lower mtDNA content and increasing levels of HBsAg (P = 0.015). In conclusion, our study provides the first epidemiological evidence that mtDNA content of CHB cases naive to antivirus therapy is significantly higher than healthy controls and the levels of mtDNA content is negatively associated with HBsAg. mtDNA content may serve as a potential noninvasive biomarker of CHB which may need more researches to validate.

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“… The inflammatory microenvironment, through the action of tumor necrosis factor‐alpha (TNF‐α) and other signaling molecules, activates inactive cytosolic NF‐κΒ and induces its translocation into the nucleus and binding to the iNOS gene promoter, thus resulting in its activation and transcription Activated NF‐κB enters the nucleus to induce transcription of genes that mediate various cellular events, including immunity, inflammation, proliferation, apoptosis, and cellular senescence NF‐κB activation is a frequent pathological pathway in several disorders characterized by inflammation, including glaucoma …”

Section: No's Double‐edged Sword: a Cause Of Ocular Pathologymentioning

confidence: 99%

“…Glaucoma, a neurodegenerative disease, is characterized by progressive retinal ganglion cell (RGC) apoptotic death. This results in cupping of the optic disk and blindness . Ocular physiology sustains a perpetual and indestructible cycle of aqueous humor (AH) production by the ciliary body—the anterior portion of the uveal tract located between the iris and the choroid—and a passage from the posterior into the anterior chamber through the pupil.…”

Section: Introductionmentioning

confidence: 99%

Impact of nitric oxide's bidirectional role on glaucoma: focus onHelicobacter pylori–related nitrosative stress

Papaefthymiou

Doulberis

Katsinelos

et al. 2019

Annals of the New York Academy of Sciences

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Nitric oxide (NO), a small molecule generated ubiquitously, targets a plethora of tissues to regulate both physiological and pathophysiological functions. NO overproduction, stimulated by microenvironmental conditions, is the main component that dysregulates the tight balance between its beneficial and damaging roles in ocular homeostasis. Considering the protective functions of NO against glaucoma, its endogenous release facilitates aqueous humor drainage and regulates ocular blood flow, maintaining a normal intraocular pressure. NO overproduction generates free radicals, such as peroxynitrite, which induce a vicious circle of vascular disharmony and dysregulation, transient ischemia, nitrosative stress, neuronal degeneration, and permanent glaucomatic injury. Helicobacter pylori (Hp) is considered a burdening factor of glaucoma. NO overproduction and possible systematic dispersion in Hp infection (Hp‐I) could suggest a potential pathophysiological bridge between these conditions. In this review, we aim to elucidate the role of NO in glaucoma with respect to Hp‐I, with the aim to stimulate further studies.

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From DNA damage to functional changes of the trabecular meshwork in aging and glaucoma

Cited by 118 publications

References 244 publications

Edaravone Prevents Retinal Degeneration in Adult Mice Following Optic Nerve Injury

Edaravone Prevents Retinal Degeneration in Adult Mice Following Optic Nerve Injury

Association between mitochondrial DNA content and baseline serum levels of HBsAg in chronic hepatitis B infection

Impact of nitric oxide's bidirectional role on glaucoma: focus onHelicobacter pylori–related nitrosative stress

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