Effect of MCI-9042, a 5-HT2 receptor antagonist, on retinal ganglion cell death and retinal ischemia

Inoue-Matsuhisa, E.; Sogo, Shunji; Mizota, Atsushi; Taniai, Mariko; Takenaka, Hisashi; Mano, Tomoo

doi:10.1016/s0014-4835(02)00333-0

Cited by 14 publications

(5 citation statements)

References 38 publications

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“…As a cause for the triggering of apoptosis, excitatory mechanisms are suggested. 36,43,50,[100][101][102][103][104][105][106][107][108][109][110] Regarding the potential excitotoxicity of glutamate, it is noteworthy that glutamate transporters like GLAST and EEAC1, as well as glutamate receptors, are downregulated in glaucomatous eyes following astrocyte activation. 102,111,112 As a consequence, deficient glutamate removal from the extracellular space might represent an interaction by which astrocyte or glial activation can result in RGC death.…”

Section: The Demise Of Retinal Ganglion Cells As a Central Hallmark Omentioning

confidence: 99%

The Pathogenesis of Glaucoma in the Interplay with the Immune System

Rieck

2013

Invest. Ophthalmol. Vis. Sci.

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Glaucoma was previously thought to be caused only through an elevated intraocular pressure as a sole trigger. Emerging evidence indicates that the pathogenesis of glaucoma depends on several interacting pathogenetic mechanisms, which include mechanical effects by an increased IOP, decreased neutrophine-supply, hypoxia, excitotoxicity, oxidative stress and the involvement of autoimmune processes. These autoimmune processes within the central nervous system are a highly organized response of the innate immunity. Through the recognition of neuronal epitopes, the long-term induction of the innate immune response and its transition to an adaptive form might be central to the pathophysiology of the glaucoma disease. Regardless of the pathogenic mechanism, the consequences are always the establishment of extensive degenerative processes in the optic nerve head, the retinal ganglion cells and the axons of the optic nerve, which will lead in the irreversible destruction of these neurons. This review article summarizes the current knowledge concerning the pathogenesis of glaucoma, with special focus on its interplay with the immune system.

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Section: The Demise Of Retinal Ganglion Cells As a Central Hallmark Omentioning

confidence: 99%

The Pathogenesis of Glaucoma in the Interplay with the Immune System

Rieck

2013

Invest. Ophthalmol. Vis. Sci.

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“…The neuroprotective effects of 5-HT 2 antagonists in rats suggest that serotonin increases the sensitivity of ionotropic glutamate receptors in the retina but also makes the retina more vulnerable to ischemia. 132 Histaminergic retinopetal axons might contribute to the etiology of diabetic retinopathy through their interactions with retinal blood vessels. The axons undergo degenerative changes in the retinas of streptozotocin-diabetic rats, 20 and in a preliminary clinical trial, a combination of HR1 and HR2 antagonists decreased the permeability of the blood-retinal barrier in diabetic patients with nonproliferative diabetic retinopathy.…”

mentioning

confidence: 99%

Retinopetal Axons in Mammals: Emphasis on Histamine and Serotonin

Gastinger

Tian

Horváth

et al. 2006

Current Eye Research

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Since 1892, anatomical studies have demonstrated that the retinas of mammals, including humans, receive input from the brain via axons emerging from the optic nerve. There are only a small number of these retinopetal axons, but their branches in the inner retina are very extensive. More recently, the neurons in the brain stem that give rise to these axons have been localized, and their neurotransmitters have been identified. One set of retinopetal axons arises from perikarya in the posterior hypothalamus and uses histamine, and the other arises from perikarya in the dorsal raphe and uses serotonin. These serotonergic and histaminergic neurons are not specialized to supply the retina; rather, they are a subset of the neurons that project via collaterals to many other targets in the central nervous system, as well. They are components of the ascending arousal system, firing most rapidly when the animal is awake and active. The contributions of these retinopetal axons to vision may be predicted from the known effects of serotonin and histamine on retinal neurons. There is also evidence suggesting that retinopetal axons play a role in the etiology of retinal diseases. Keywordscentrifugal; efferent; histamine; primate; serotonin MORPHOLOGY AND FUNCTIONS OF RETINOPETAL AXONS IN MAMMALSIn mammalian retinas, three types of retinopetal axons have been distinguished by morphological criteria. The first type gives rise to terminals in the outer strata of the inner plexiform layer (IPL). Typically, the axons terminate along the border with the inner nuclear Copyright (Figs. 1A and 1C). Using the Golgi method, axons with this pattern of branching have been identified in dog 1 and chimpanzee 2 retinas. The second type of retinopetal axon is larger in diameter, varicose, and terminates in the outer plexiform layer (OPL). In rats, these axons are labeled with antibodies to serotonin after loading the retina with a related indoleamine, 5,7-dihydroxytryptamine (5,7-DHT). They originate from perikarya in the optic chiasm or the preoptic area of the hypothalamus. 3 Retinopetal axons similar to these are labeled with neurofilament antibodies in the mouse retina. 4 Neurons that project from the anterior hypothalamus to the retina have been identified in a prosimian, 5 but their terminals in the retina have not been described.The third type of retinopetal axon branches extensively in IPL (Fig. 1B). Using the Golgi method, Polyak described axons like these in macaque retinas. 2 They run in the optic fiber layer (OFL), and they give off a nearly vertical branch to the IPL, where they branch extensively in a broad band in the center of the layer. In the mouse retina, axons with a similar branching pattern are labeled with neurofilament antibodies. 4 These axons are also labeled using reduced silver stains in monkey 6,7 and human 8,9 retinas. These studies confirmed and extended Polyak's descriptions, and they also demonstrated clear morphological differences between retinopetal axons and those of ganglion cells with intraretin...

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“…Reactivity of glial cells are activated by up-regulated expression of glial fibrillary acidic protein (GFAP) [2], with the release of massive amounts of glutamate from injured neurons which is suggested to be neurotoxic [3]. Neuronal cell death was observed by the presence of pyknotic nuclei, especially in the cells in ganglion cell layer (GCL) [4], [5], [6], [7], [8]. Moreover, increased extracellular water transport and accumulation was present in inner retina, which is characterized by increased extracellular fluid volume, increased aquaporin-4 (AQP-4) immunoreactivity and swelling of retinal glial cells, leading to inner retinal edema [9].…”

Section: Introductionmentioning

confidence: 99%

Selective Over-Expression of Endothelin-1 in Endothelial Cells Exacerbates Inner Retinal Edema and Neuronal Death in Ischemic Retina

et al. 2011

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The level of endothelin-1 (ET-1), a potent vasoconstrictor, was associated with retinopathy under ischemia. The effects of endothelial endothelin-1 (ET-1) over-expression in a transgenic mouse model using Tie-1 promoter (TET-1 mice) on pathophysiological changes of retinal ischemia were investigated by intraluminal insertion of a microfilament up to middle cerebral artery (MCA) to transiently block the ophthalmic artery. Two-hour occlusion and twenty-two-hour reperfusion were performed in homozygous (Hm) TET-1 mice and their non-transgenic (NTg) littermates. Presence of pyknotic nuclei in ganglion cell layer (GCL) was investigated in paraffin sections of ipsilateral (ischemic) and contralateral (non-ischemic) retinae, followed by measurement of the thickness of inner retinal layer. Moreover, immunocytochemistry of glial fibrillary acidic protein (GFAP), glutamine synthetase (GS) and aquaporin-4 (AQP4) peptides on retinal sections were performed to study glial cell reactivity, glutamate metabolism and water accumulation, respectively after retinal ischemia. Similar morphology was observed in the contralateral retinae of NTg and Hm TET-1 mice, whereas ipsilateral retina of NTg mice showed slight structural and cellular changes compared with the corresponding contralateral retina. Ipsilateral retinae of Hm TET-1 mice showed more significant changes when compared with ipsilateral retina of NTg mice, including more prominent cell death in GCL characterized by the presence of pyknotic nuclei, elevated GS immunoreactivity in Müller cell bodies and processes, increased AQP-4 immunoreactivity in Müller cell processes, and increased inner retinal thickness. Thus, over-expression of endothelial ET-1 in TET-1 mice may contribute to increased glutamate-induced neurotoxicity on neuronal cells and water accumulation in inner retina leading to edema.

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Effect of MCI-9042, a 5-HT2 receptor antagonist, on retinal ganglion cell death and retinal ischemia

Cited by 14 publications

References 38 publications

The Pathogenesis of Glaucoma in the Interplay with the Immune System

The Pathogenesis of Glaucoma in the Interplay with the Immune System

Retinopetal Axons in Mammals: Emphasis on Histamine and Serotonin

Selective Over-Expression of Endothelin-1 in Endothelial Cells Exacerbates Inner Retinal Edema and Neuronal Death in Ischemic Retina

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