Apoptosis in retinal ganglion cell decrease in human glaucomatous eyes

doi:10.1016/S0021-5155(97)00013-0

Japanese Journal of Ophthalmology

Volume 41, Issue 2, March–April 1997, Pages 84-88

https://doi.org/10.1016/S0021-5155(97)00013-0 Get rights and content

Abstract

Hematoxylin-eosin staining, the TUNEL method for in situ detection of the intranuclear DNA fragmentation, which indicates apoptosis, and electron microscopy were used to study the morphologic changes in specimens from the eyes of 8 patients with secondary glaucoma and 2 normal control eyes to evaluate our hypothesis that apoptosis causes a decrease in retinal ganglion cells in human glaucomatous eyes. The TUNEL method permits identification of intranuclear DNA fragmentation. Apoptosis was found in the ganglion cells of 2 glaucomatous eyes with recent sight loss, and in the ganglion cells of a control eye from a 95-year-old subject, taken at autopsy. Results of our study indicate that a decrease in retinal ganglion cells in glaucomatous eyes is caused by apoptosis. In addition, apoptosis resulting from aging must be considered in order to understand the reduction of retinal ganglion cells in the glaucomatous eyes of elderly patients.

References (12)

L. Dandona et al.
Selective effects of experimental glaucoma on axonal transport by retinal ganglion cells to the dorsal lateral geniculate nucleus
Invest Ophthalmol Vis Sci
(1991)
H.A. Quigley et al.
Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis
Invest Ophthalmol Vis Sci
(1995)
G.M. Bray et al.
Neuronal and non-neuronal influences on retinal ganglion cell survival, axonal regrowth and connectivity after axotomy
Ann NY Acad Sci
(1991)
S. Thanos et al.
Treatment of the adult retina with microglial suppressing factors retards axotomy-induced neuronal degradation and changes axonal regeneration in vivo and in vitro
J Neurosci
(1993)
A. Batistatou et al.
Internucleosomal DNA cleavage and neuronal survival/death
J Cell Bio1
(1991)
E. Garcia-Valenzuela et al.
Programmed cell death of retinal ganglion cells during experimental glaucoma
Exp Eye Res
(1995)

There are more references available in the full text version of this article.

Cited by (90)

Potential role of P2X7 receptor in neurodegenerative processes in a murine model of glaucoma
2019, Brain Research Bulletin
Glaucoma is a common cause of visual impairment and blindness, characterized by retinal ganglion cell (RGC) death. The mechanisms that trigger the development of glaucoma remain unknown and have gained significant relevance in the study of this neurodegenerative disease. P2X7 purinergic receptors (P2X7R) could be involved in the regulation of the synaptic transmission and neuronal death in the retina through different pathways. The aim of this study was to characterize the molecular signals underlying glaucomatous retinal injury.
The time-course of functional, morphological, and molecular changes in the glaucomatous retina of the DBA/2J mice were investigated. The expression and localization of P2X7R was analysed in relation with retinal markers. Caspase-3, JNK, and p38 were evaluated in control and glaucomatous mice by immunohistochemical and western-blot analysis. Furthermore, electroretinogram recordings (ERG) were performed to assess inner retina dysfunction.
Glaucomatous mice exhibited changes in P2X7R expression as long as the pathology progressed. There was P2X7R overexpression in RGCs, the primary injured neurons, which correlated with the loss of function through ERG measurements. All analyzed MAPK and caspase-3 proteins were upregulated in the DBA/2J retinas suggesting a pro-apoptotic cell death.
The increase in P2X7Rs presence may contribute, together with other factors, to the changes in retinal functionality and the concomitant death of RGCs. These findings provide evidence of possible intracellular pathways responsible for apoptosis regulation during glaucomatous degeneration.
All roads lead to glaucoma: Induced retinal injury cascades contribute to a common neurodegenerative outcome
2019, Experimental Eye Research
Glaucoma describes a distinct optic neuropathy with complex etiology and a variety of associated risk factors, but with similar pathological endpoints. Risk factors such as age, increased intraocular pressure (IOP), low mean arterial pressure, and autoimmune disease, can all be associated with death of retinal ganglion cells (RGCs) and optic nerve head remodeling. Today, IOP management remains the standard of care, even though IOP elevation is not pathognomonic of glaucoma, and patients can continue to lose vision despite effective IOP control. A contemporary view of glaucoma as a complex, neurodegenerative disease has developed, along with the recognition of a need for new disease modifying retinal treatment strategies and improved outcomes. However, the distinction between risk factors triggering the disease process and retinal injury responses is not always clear. In this review, we attempt to distinguish between the various triggers, and their association with subsequent key RGC injury mechanisms. We propose that distinct glaucomatous risk factors result in similar retinal and optic nerve injury cascades, including oxidative and metabolic stress, glial reactivity, and altered inflammatory responses, which induce common molecular signals to induce RGC apoptosis. This organization forms a coherent disease framework and presents conserved targets for therapeutic intervention that are not limited to specific risk factors.
Neuroprotection in the treatment of glaucoma - A focus on connexin43 gap junction channel blockers
2015, European Journal of Pharmaceutics and Biopharmaceutics
Citation Excerpt :
There is limited information on the exact mechanisms of optic nerve damage in glaucoma. Increased IOP is believed to lead to excitotoxicity [7,8], an accelerated rate of apoptosis resulting in loss of retinal ganglion cells (RGC) [9,10] and compressive damage to the optic nerve [11]. The lamina cribrosa, a recognized site of optic nerve damage, generally helps to maintain the pressure changes between the inside of the eye and the surrounding tissue [12].
Glaucoma is a form of optic neuropathy and a common cause of blindness, affecting over 60 million people worldwide with an expected rise to 80 million by 2020. Successful treatment is challenging due to the various causes of glaucoma, undetectable symptoms at an early stage and inefficient delivery of drugs to the back of the eye. Conventional glaucoma treatments focus on the reduction of elevated intraocular pressure (IOP) using topical eye drops. However, their efficacy is limited to patients who suffer from high IOP glaucoma and do not address the underlying susceptibility of retinal ganglion cells (RGC) to degeneration. Glaucoma is known as a neurodegenerative disease which starts with RGC death and eventually results in damage of the optic nerve. Neuroprotective strategies therefore offer a novel treatment option for glaucoma by not only preventing neuronal loss but also disease progression. This review firstly gives an overview of the pathophysiology of glaucoma as well as current treatment options including conventional and novel delivery strategies. It then summarizes the rational for neuroprotection as a novel therapy for glaucomatous neuropathies and reviews current potential neuroprotective strategies to preserve RGC, with a focus on connexin43 (Cx43) gap junction channel blockers.
Glaucoma - Diabetes of the brain: A radical hypothesis about its nature and pathogenesis
2014, Medical Hypotheses
Citation Excerpt :
Glaucoma is a progressive ocular neurodegeneration and second leading cause of blindness with more than 60 million people affected worldwide [1]. The hallmark of glaucoma is gradual loss of retinal ganglion cells (RGCs) [2] by apoptosis [3]. Glaucoma has certain molecular and mechanistic similarities with other degenerative disorders of the central nervous system (CNS) like Alzheimer’s disease (AD) and Parkinson’s disease (PD).
Glaucoma is the leading cause of irreversible blindness characterized by irremediable loss of retinal ganglion cells. Its risk increases with progressing age and elevated intraocular pressure. Studies have established that glaucoma is a neurodegenerative disorder in which the damage involves many brain tissues from retina to the lateral geniculate nucleus. Despite lot of research, complete pathomechanism of glaucoma is not known and there is no treatment available except modification of intraocular pressure pharmacologically and/or surgically. We here present a hypothesis inspired by studies across many areas of molecular and clinical sciences in an integrative manner that leads to a uniquely unconventional understanding of this disorder. Our hypothesis postulates that glaucoma may possibly be the diabetes of the brain. Based on the remarkable similarities between glaucoma and diabetes we propose glaucoma also to be a type of diabetes. Glaucoma and diabetes share many aspects from various molecular mechanisms to involvement of insulin and possible use of antidiabetics in glaucoma therapy. Additionally, Alzheimer’s disease has already been proposed to be diabetes type-3. We show that Alzheimer’s disease is cerebral glaucoma and diabetes at the same time which, by transitive property of similarities, again leads to our hypothesis that glaucoma is diabetes of the brain. Our proposition may lead to appreciation of certain important facets of glaucoma which have previously not been given due consideration. It also may lead to an alternative classification of diabetes as pancreatic and brain diabetes thereby widening the vision arena of the understanding of both these disorders.
Leptin as a neuroprotective agent in glaucoma
2013, Medical Hypotheses
Glaucoma is a disease characterized by progressive optic nerve degeneration and is the leading cause of irreversible blindness worldwide. More than 60 million people globally are affected by glaucoma, of which 8 million people suffer from bilateral blindness, making glaucoma the second leading cause of bilateral blindness worldwide. Current management of glaucoma is aimed at reducing intraocular pressure via a number of different strategies. Current treatments do not attempt to correct the underlying pathology of glaucoma, which is the cell degeneration and ultimate death of retinal ganglion cells, thereby limiting their clinical efficacy.
A neuroprotective approach to glaucoma management would address the underlying pathology and would, in theory, be beneficial to all patients regardless of risk and causative factors. Here it is proposed that leptin could be used as a potential neuroprotective agent in the management of glaucoma. Leptin has shown neuroprotective promise in a number of neurodegenerative diseases, and there has been increasing evidence that glaucomatous neurodegeneration is analogous to other neurodegenerative diseases in the central nervous system. Leptin could target retinal ganglion cell death by a number of mechanisms, namely apoptosis, oxidative stress and excitotoxicity reduction. This article presents evidence linking current understanding about leptin’s neuroprotective effect and the molecular mechanisms underlying glaucoma.
Is the medication used to achieve the target intraocular pressure in glaucoma therapy of relevance? - An exemplary analysis on the basis of two beta-blockers
2010, Progress in Retinal and Eye Research
Citation Excerpt :
The resultant rise in Na+, coupled with membrane depolarisation, leads to reversal of the Na+/Ca2+-exchanger linked to non-N-methyl-d-aspartic acid (NMDA) receptors; (Li and Stys, 2000; Smith et al., 2000) which imports damaging quantities of Ca2+ into the cell. All drugs that prevent Ca2+ overload by modifying the entry of Ca2+ into the cell are promising candidates for neuroprotectants in glaucoma therapy (Garcia-Valenzuela et al., 1995; Kerrigan et al., 1997; Nickells and Zack, 1996; Okisaka et al., 1997). Free radical and excessive increase of excitatory amino acids, such as glutamate, are thought to be involved in the initiation of the retinal and ganglion cell degeneration.
Glaucoma, the most common optic neuropathy (GON) is characterised by the loss of retinal ganglion cells and their axons, as well as tissue remodelling of both the retina and the optic nerve head with corresponding visual field defects. Elevated intraocular pressure (IOP) is generally regarded as the major risk factor for glaucoma and its reduction is the most common target for therapy of GON. There are indications that the greater the IOP reduction, the better is the visual field prognosis. This article investigates, on the basis of two beta-blockers, betaxolol and timolol, whether the amount of IOP reduction is truly a good surrogate for successful glaucoma therapy with respect to visual field outcome.
Contrary to what is generally expected, our analysis of the literature exemplifies that despite a smaller IOP reduction, patients treated with betaxolol had a smaller rate of visual field deterioration than patients treated with timolol. Based on the dissociation of IOP reduction and visual field prognosis, we postulate that for successful treatment in glaucoma not only the amount of IOP reduction is relevant but also the drug by which the reduction is achieved. This seeming paradox phenomenon highlights that ocular hypotensive drugs have relevant effects on GON other than IOP-related. Some of these effects on retinal ganglion cells (neuroprotection) or on ocular blood flow are mediated by calcium- and sodium channels.
Future studies on glaucoma treatment should focus on their effect on visual field function, and not just on IOP. This should particularly be considered when comparing drugs from different classes.

View all citing articles on Scopus

View full text

Article preview

Japanese Journal of Ophthalmology

Abstract

References (12)

Selective effects of experimental glaucoma on axonal transport by retinal ganglion cells to the dorsal lateral geniculate nucleus

Invest Ophthalmol Vis Sci

Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis

Invest Ophthalmol Vis Sci

Neuronal and non-neuronal influences on retinal ganglion cell survival, axonal regrowth and connectivity after axotomy

Ann NY Acad Sci

Treatment of the adult retina with microglial suppressing factors retards axotomy-induced neuronal degradation and changes axonal regeneration in vivo and in vitro

J Neurosci

Internucleosomal DNA cleavage and neuronal survival/death

J Cell Bio1

Programmed cell death of retinal ganglion cells during experimental glaucoma

Exp Eye Res

Cited by (90)

Potential role of P2X7 receptor in neurodegenerative processes in a murine model of glaucoma

All roads lead to glaucoma: Induced retinal injury cascades contribute to a common neurodegenerative outcome

Neuroprotection in the treatment of glaucoma - A focus on connexin43 gap junction channel blockers

Glaucoma - Diabetes of the brain: A radical hypothesis about its nature and pathogenesis

Leptin as a neuroprotective agent in glaucoma

Is the medication used to achieve the target intraocular pressure in glaucoma therapy of relevance? - An exemplary analysis on the basis of two beta-blockers

Laboratory investigationApoptosis in retinal ganglion cell decrease in human glaucomatous eyes

Abstract

Selective effects of experimental glaucoma on axonal transport by retinal ganglion cells to the dorsal lateral geniculate nucleus

Invest Ophthalmol Vis Sci

Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis

Invest Ophthalmol Vis Sci

Neuronal and non-neuronal influences on retinal ganglion cell survival, axonal regrowth and connectivity after axotomy

Ann NY Acad Sci

Treatment of the adult retina with microglial suppressing factors retards axotomy-induced neuronal degradation and changes axonal regeneration in vivo and in vitro

J Neurosci

Internucleosomal DNA cleavage and neuronal survival/death

J Cell Bio1

Programmed cell death of retinal ganglion cells during experimental glaucoma

Exp Eye Res

Laboratory investigation
Apoptosis in retinal ganglion cell decrease in human glaucomatous eyes