Expression of functional receptors and transmitter enzymes in cultured Muller cells

Kubrusly, Regina Célia Cussa; Cunha, Maria Cristina Caldas da; Reis, Ricardo Augusto de Melo; Soares, Heline Costa; Ventura, Ana Lúcia Marques; Kurtenbach, Eleonora; Mello, Maria Cristina Fialho de; Mello, Fernando G. de

doi:10.1016/j.brainres.2005.01.031

Cited by 46 publications

(34 citation statements)

References 36 publications

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“…PACAP is also present in the embryonic retinas, and according to recent studies, it may play a role during the development of the retina (Olianas et al, 1997;Bagnoli et al, 2003;Mathieu et al, 2004). PACAP receptors have also been demonstrated in the retina: the selective PAC1 receptor is predominant in the retina, and is present in amacrine and Muller cells in the inner nuclear layer and in the ganglion cells Seki et al, 1997;Kubrusly et al, 2005). In vitro studies on the neuroprotective effects of PACAP against glutamate-induced toxicity have demonstrated that PACAP treatment leads to a significant elevation in cAMP levels and MAP kinase activity, and the observed protective effect along with the MAP kinase activation are reduced in the presence of the selective protein kinase A antagonist, H89 (Morio et al, 1996;Shoge et al, 1999;Frechilla et al, 2001;Silveira et al, 2002).…”

Section: Discussionmentioning

confidence: 93%

Degree of damage compensation by various pacap treatments in monosodium glutamate-induced retinal degeneration

et al. 2005

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Pituitary adenylate cyclase activating polypeptide (PACAP) has been shown to be neuroprotective in retinal ischemia and monosodium L-glutamate (MSG)-induced retinal degeneration. Here we describe how different MSG treatments (1x and 3x application) cause retinal damage and finally lead to the destruction of the entire inner retina and how PACAP attenuates this effect. Newborn rats from both sexes were injected subcutaneously with 2 mg/g bodyweight MSG on postnatal days 1, 5 and 9. The left eye was left intact while we injected 5 microl PACAP38 solution (100 pmol) into the vitreous of the right eye with a Hamilton syringe at the time of (i) the first, (ii) the first two or (iii) all three MSG injections. Histological analysis has shown that the above described MSG treatment caused the entire inner plexiform layer (IPL) to degenerate, and the inner nuclear (INL) and ganglion cell layers (GCL) seemed fused. One time PACAP38 treatment at the first MSG application did not change the degenerative capacity of MSG. However, if animals received PACAP38 into the vitreous of the eye at the first 2 or all 3 times, a substantial protective effect could be observed. The IPL remained well discernible, the INL retained 2-3 cell rows and the number of cells in the GCL was substantially higher than in the MSG-treated retinas, and was not significantly different from that observed in the control tissue. We conclude that (i) 2 or 3 times PACAP treatment attenuates retinal degeneration; (ii) one PACAP treatment does not provide protection against repeated excitotoxic insults, and (iii) repeated application of PACAP under these experimental conditions may lead to a primed state in which further neurotoxic insults are ineffective.

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Section: Discussionmentioning

confidence: 93%

Degree of damage compensation by various pacap treatments in monosodium glutamate-induced retinal degeneration

et al. 2005

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“…On the other hand, treatment with 50 ng/ml BDNF not only reduces the response to muscimol, but also increases the number of cells responding to KCl or AMPA Cell Mol Neurobiol (2011) 31:835-846 843 Although in our experiments calcium shifts in glia cells were only observed after ATP stimulation, purified cultured Müller glia display several characteristics that are seen in retina neurons. For instance, these cells in culture accumulate cyclic AMP induced by catecholamines (Kubrusly et al 2008), display GABA uptake properties (De Sampaio Schitine et al 2007) and PACAP-induced activation of adenylyl cyclase (Kubrusly et al 2005). They also express glutamic acid decarboxylase, beta 2 nicotine acetylcholine receptors, enzymes of catecholamine metabolism, including tyrosine hydroxylase (Kubrusly et al 2005(Kubrusly et al , 2008Seki et al 2006), glutamate (Ramirez and Lamas 2009), and muscarinic acetylcholine receptors (Wakakura et al 1998).…”

Section: Discussionmentioning

confidence: 97%

“…Retinal damage and exposure to exogenous growth factors lead Müller cells to re-enter the cell cycle, dedifferentiate and express different transcription factors, which are normally expressed by embryonic retinal progenitors Reh 2001, 2003). As a consequence of the activation of the dedifferentiation program, Müller glia can acquire neuronal markers (Kubrusly et al 2005). Moreover, these cells are able to generate clonal neurospheres in culture and acquire the phenotype of site-specific neurons on transplantation (Das et al 2006b).…”

Section: Introductionmentioning

confidence: 99%

Functional Identification of Cell Phenotypes Differentiating from Mice Retinal Neurospheres Using Single Cell Calcium Imaging

et al. 2011

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Degeneration of neural retina causes vision impairment and can lead to blindness. Neural stem and progenitor cells might be used as a tool directed to regenerative medicine of the retina. Here, we describe a novel platform for cell phenotype-specific drug discovery and screening of proneurogenic factors, able to boost differentiation of neural retinal progenitor cells. By using single cell calcium imaging (SCCI) and a rational-based stimulation protocol, a diversity of cells emerging from differentiated retinal neurosphere cultures were identified. Exposure of retinal progenitor cultures to KCl or to α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) stimulated Ca(2+) transients in microtubule-associated protein 2 (MAP-2) positive neurons. Doublecortin (DCX) and polysialated neural cell adhesion molecule (PSA-NCAM) positive neuroblasts were distinguished from differentiated neurons on the basis of their response to muscimol. Ca(2+) fluxes in glial fibrillary acidic protein (GFAP) or glutamine synthetase (GS) positive cells were induced by ATP. To validate the platform, neurospheres were treated with brain-derived neurotrophic factor (BDNF) (proneurogenic) or ciliary neurotrophic factor (CNTF) (gliogenic factor). BDNF increased the percentage of differentiated cells expressing Tuj-1 sensitive to KCl or AMPA and reduced the population of cells responding to muscimol. CNTF exposure resulted in a higher number of cells expressing GFAP responding to ATP. All together, our data may open new perspectives for cell type-specific discovery of drug targets and screening of novel proneurogenic factors to boost differentiation of neural retina cells to treat degenerative retinal diseases.

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“…Attempts to facilitate the neurogenic program of Müller cells, e.g. by transdifferentiation of cultured Müller cells, are ongoing [265,270,273,274,275,276,277,278,279,280]. …”

Section: Müller Stem Cellsmentioning

confidence: 99%

Müller Glial Cells in Retinal Disease

Bringmann¹,

Wiedemann²

2011

Ophthalmologica

338

274

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Virtually all pathogenic stimuli activate Müller cells. Reactive Müller cells exert protective and toxic effects on photoreceptors and neurons. They contribute to oxidative stress and glutamate toxicity due to malfunctions of glutamate uptake and glutathione synthesis. Downregulation of potassium conductance disrupts transcellular potassium and water transport, resulting in neuronal hyperexcitability and edema. Protective effects of reactive Müller cells include upregulation of adenosine 5′-triphosphate (ATP)-degrading ectoenzymes, which enhances the extracellular availability of the neuroprotectant adenosine, abrogation of the osmotic release of ATP, which might protect retinal ganglion cells from apoptosis, and the release of antioxidants and neurotrophic factors. The dedifferentiation of reactive Müller cells to progenitor-like cells might have an impact on future therapeutic approaches. A better understanding of the gliotic mechanisms will be helpful in developing efficient therapeutic strategies aiming at increased protective and regenerative properties and decreased toxicity of reactive Müller cells.

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Expression of functional receptors and transmitter enzymes in cultured Muller cells

Cited by 46 publications

References 36 publications

Degree of damage compensation by various pacap treatments in monosodium glutamate-induced retinal degeneration

Degree of damage compensation by various pacap treatments in monosodium glutamate-induced retinal degeneration

Functional Identification of Cell Phenotypes Differentiating from Mice Retinal Neurospheres Using Single Cell Calcium Imaging

Müller Glial Cells in Retinal Disease

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