Involvement of Inflammation, Degradation, and Apoptosis in a Mouse Model of Glaucoma

Zhou, Xin; Li, Feng; Kong, Li; Tomita, Hiroshi; Li, Chao; Cao, Wei

doi:10.1074/jbc.m502641200

Cited by 132 publications

(123 citation statements)

References 58 publications

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“…We started from two crucial members of the family, chosen as indicators of pro-apoptotic and/or pro-survival pathway implication, respectively p38 MAPK and ERK1/2 [22][23][24][25]28,[32][33][34]. In our murine model, we confirmed that retinal level of activated p38 MAPK increased in concomitance with IOP raise, and reached elevated and growing levels at 10 and 18 months of age.…”

Section: Discussionsupporting

confidence: 62%

Changes in BDNF and MAPK Signaling Pathways in Experimental Glaucoma

Fabiani¹,

Cerri²

2016

J Clin Exp Ophthalmol

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Glaucoma is currently recognized to be a multifactorial, progressive, neurodegenerative disorder. It is characterized by the retinal ganglion cells (RGCs) loss of axons as well as optic nerve atrophy, progressive degeneration of RGCs till cell death. In this work, we used DBA/2J mice as a model of spontaneous glaucoma and we investigated the involvement of BDNF and Mitogen-Activated Protein Kinases (MAPK) pathways in correlation with IOP elevation and progression of neurodegenerative processes in the retina of DBA/2J mice. In particular, we performed western blot analysis to study retinal levels of the BDNF and its receptor, TrkB, and to better understand possible modulation of p38 MAPK and ERK1/2 activation at different stages of retinal degeneration in DBA/2J mice. We showed that BDNF starts to decrease already at an early stage in correspondence to IOP elevation (7 months of age). MAPKs, in particular p38 MAPK and ERK1/2, appeared maximally affected at more advanced stages of neurodegeneration (10-12 and 18 months of age) characterized by RGC degeneration and death, optic nerve atrophy. Thus, BDNF signaling and MAPKs are differentially activated at different stages of retinal degeneration in DBA/2J mice, a murine model of glaucoma.

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Section: Discussionsupporting

confidence: 62%

Changes in BDNF and MAPK Signaling Pathways in Experimental Glaucoma

Fabiani¹,

Cerri²

2016

J Clin Exp Ophthalmol

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“…aqueous humor. Environmental factors such as hypoxia or an acute increase in induced hydrostatic pressure lead to inflammation processes and alterations in apoptotic signaling components, triggering cell death in anterior chamber structures (Zhou et al, 2005). This could be why melatonin and analogs are unable to fully return IOP to prepathology values in such advanced stages of glaucomatous disease.…”

mentioning

confidence: 99%

Effect of Melatonin and 5-Methoxycarbonylamino-N-Acetyltryptamine on the Intraocular Pressure of Normal and Glaucomatous Mice

Martínez-Águila

Fonseca

Lara

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Melatonin is a neurohormone that is produced not only by the pineal gland but also by several ocular structures. One of the main physiologic roles of melatonin is the reduction of intraocular pressure (IOP). Using both control C57BL/6J and glaucomatous DBA/2J mice as well as TonoLab tonometry, this study evaluated the effect of melatonin and 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) when glaucomatous pathology was fully established and compared pharmacological behavior in treated mice versus control mice. In addition, 5-MCA-NAT was tested to determine its effects on ameliorating increased IOP in a glaucoma model. The results demonstrate that melatonin and 5-MCA-NAT can reduce IOP in a concentration-dependent manner. The EC 50 values for melatonin in control and glaucomatous animals were 34 mM and 50 mM, respectively. Interestingly, melatonin decreased IOP in 19.4% 6 3.7% and 32.6% 6 6.0% of control and glaucomatous mice, respectively, when the animals were studied at age 12 months. 5-MCA-NAT reduced IOP in the same manner and was able to stop IOP progression in glaucomatous mice. Use of melatonin receptor antagonists showed that hypotensive effects were blocked by the MT 2 receptor antagonists luzindole and 4-phenyl-2-propionamidotetralin in the case of melatonin and by only 4-phenyl-2-propionamidotetralin in the case of 5-MCA-NAT. In conclusion, melatonin and 5-MCA-NAT can effectively reduce IOP in a glaucoma model, and their hypotensive effects are more profound in the glaucoma model than in control animals.

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“…These include reduced levels of neurotrophic factors, deprivation of cytokines to neurons, altered intracellular calcium levels, presence of reactive oxygen species, and excitotoxicity due to raised extracellular levels of certain neurotransmitters and neuromodulators [95][96]. The mitochondria-and caspase -dependent cell death pathway are known to be associated with neuronal cell death in diabetic retinas [59].…”

Section: Anti-apoptotic Agentsmentioning

confidence: 99%

Diabetes Mellitus and Retinal Vein Occlusion as Risk Factors for Open Angle Glaucoma and Neuroprotective Therapies for Retinal Ganglion Cell Neuropathy

Bikbova¹,

Oshitari²,

Yamamoto³

2011

J Clin Exp Ophthalmol

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of glaucoma (NTG), and the prevalence of NTG is 3.6% in patients >40-years-of-age in Japan [10]. The average intraocular pressure (IOP) in patients with POAG is 15.4 ± 2.8 mmHg, which is significantly higher than that of normal subjects (14.5 ± 2.5 mmHg) [1][2][3][4][5][6][7][8][9][10] even though the average difference in the IOP is only 0.9 mmHg. Thus, a reduction of the IOP the standard therapy for glaucoma may not be sufficient for the complete management of the patients with glaucoma in Japan. Other therapeutic modalities, such as neuroprotection, should be considered for a complete therapeutic regimen for glaucoma patients.RGC death and axonal degeneration are most likely involved in the progression of DR, RVO, and glaucoma. Many neuroprotective therapies that prevent RGC death and axonal degeneration have been and are being investigated, and some of these neuroprotective factors may be used clinically in the near future. To establish neuroprotective therapies for DR, RVO and glaucoma, a determination of the exact mechanism that leads to a progression of RGC neuropathy to death and axonal degeneration is required [11]. However, the pathogenesis of the onset and progression of RGC neuropathy has still not been definitively determined. Identification of the risk factors for the onset and the progression of disease would help in determining the Abstract Glaucoma, diabetic retinopathy (DR), and retinal vein occlusion (RVO) are major diseases that can lead to blindness and affect mainly the elderly population worldwide. The results of recent investigations have demonstrated that the death of retinal ganglion cells (RGCs) and their axons is the common pathological change in these three disease processes. The exact mechanism that is responsible for the onset and progression of RGC death and axonal degeneration in patients with glaucoma, DR and RVO has not been definitively determined. Thus, identifying the risk factors for the onset and the progression of RGC neuropathy can help in deciding not only the specific treatments but also whether the treatments should be initiated, withheld, or augmented in individuals with glaucoma, DR, and RVO. This review describes the major risk factors for the onset of glaucoma, and the factors associated with the progression of glaucoma that have been obtained from large population-based prevalence and incidence studies. In addition, the potential risk factors for glaucoma, diabetes mellitus, and RVO are discussed in terms of the results obtained by both clinical and laboratory studies. This review introduces potential neuroprotective therapies for damaged RGC in eyes with RGC neuropathy, and the factors that should be considered for a complete therapy for the RGC neuropathy involved in glaucoma, DR and RVO. Neuroprotective therapies combined with a reduction of the IOP should be considered for the complete management of RGC neuropathy involved in glaucoma,

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Involvement of Inflammation, Degradation, and Apoptosis in a Mouse Model of Glaucoma

Cited by 132 publications

References 58 publications

Changes in BDNF and MAPK Signaling Pathways in Experimental Glaucoma

Changes in BDNF and MAPK Signaling Pathways in Experimental Glaucoma

Effect of Melatonin and 5-Methoxycarbonylamino-N-Acetyltryptamine on the Intraocular Pressure of Normal and Glaucomatous Mice

Diabetes Mellitus and Retinal Vein Occlusion as Risk Factors for Open Angle Glaucoma and Neuroprotective Therapies for Retinal Ganglion Cell Neuropathy

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