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| Neuroendocrinology and Neurogenesis Group |
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Paulo F. Santos’s group
"Neuroprotection and diabetic retinopathy"
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| Highlights |
| Diabetic retinopathy (DR), the leading cause of adult blindness, exhibits the classical findings of chronic inflammation. It is known that in diabetes there is an activation of microglial cells and a concomitant release of inflammatory mediators that cause death of retinal neurons, even before the detectable vascular lesions. We have found that in retinal cell cultures incubated in hyperglycemic conditions, a model of diabetic retinopathy, there is an increase in the exocytotic release of ATP. We have also shown that this effect contributes to the increase of intracellular calcium concentrations observed in neurons and microglial cells that were exposed to high glucose conditions. Therefore, this purinergic activation of microglial cells, as a result of the increased ATP release and its concomitant increase in intracellular calcium concentrations can be one of the mechanisms that contribute to the release of pro-inflammatory cytokines. Therefore, if microglia activation could be prevented and the release of pro-inflammatory mediators in the retina inhibited, the effects of diabetes on vision loss could be reduced, with a positive impact on the quality of life of diabetic patients. |
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| On Going Projects |
Since we have observed that retinal ATP release is increased in hyperglycemic conditions, we are evaluating if this could contribute to the release of TNF-alpha and if prevention of TNF-alpha receptor 1 activation can prevent the cell death observed in diabetic retinas.
ATP can be extracellularly converted to adenosine. Microglias, cells from the immune system, are the major responsible for the release of inflammatory mediators in the retina. These cells express all four types of receptors for adenosine (A1, A2A, A2B and A3). Activation of A2A and A3 adenosine receptors in microglial cells leads to inhibition of pro inflammatory cytokines expression and release, including TNF alpha. Preliminary results recently obtained in our laboratory have shown that activation of A2A adenosine receptors with a specific agonist CGS 21680, prevented retinal cell death observed in cultures exposed to high glucose concentrations. Therefore, since pro inflammatory mediators are responsible for the early neuronal cell death observed in diabetic retinas, can activation of adenosine receptors reduce the stimulation of retinal microglial cells and the release of those pro inflammatory mediators? If proven, this could open a new therapeutic window in the treatment of the early stages of diabetic retinopathy.
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| The team |
| Gabriel N. Ferreira Costa |
| PhD student |
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| Joana Vindeirinho |
| MSc student |
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| Publications |
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Costa, G., Pereira, T., Neto, A.M., Cristovao, A.J., Ambrosio, A.F., Santos, P.F., 2009. High glucose changes extracellular adenosine triphosphate levels in rat retinal cultures. J Neurosci Res. 87, 1375-80.
Pereira, T.D., da Costa, G.N., Santiago, A.R., Ambrosio, A.F., dos Santos, P.F., 2009 High glucose enhances intracellular Ca(2+) responses triggered by purinergic stimulation in retinal neurons and microglia. Brain Res. 1316C, 129-138.
Santiago, A.R., Gaspar, J.M., Baptista, F.I., Cristóvão, A.J., Santos, P.F., Kamphuis, W., Ambrósio, A.F., 2009. Diabetes changes the levels of ionotropic glutamate receptors in the rat retina. Mol Vis. 15, 1620-30.
I.M. Araújo, B.P. Carreira, T. Pereira, P.F. Santos, D. Soulet, Â. Inácio, B.A. Bahr, A.F. Ambrósio, C.M. Carvalho. 2007 Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons. Cell Death and Differentiation 14, 1635-1646.
A.R. Alvaro, J. Rosmaninho-Salgado, A.R. Santiago, J. Martins, C. Aveleira, P.F. Santos, T. Pereira, D. Gouveia, A.L. Carvalho, E. Grouzmann, A.F. Ambrosio, C. Cavadas (2007) NPY in rat retina is present in neurons, in endothelial cells and also in microglial and Muller cells. Neurochem Int 50, 757-763.
A.R. Santiago, A.J. Cristóvão, P.F. Santos, C.M. Carvalho e A.F: Ambrósio AF. 2007 High glucose induces caspase-independent cell death in retinal neural cells. Neurobiol. of Dis. 25, 464-472
A.R. Santiago, S.C. Rosa, P.F. Santos, A.J. Cristóvão, A.J. Barber e A.F. Ambrósio. 2006 Elevated glucose changes the expression of ionotropic glutamate receptor subunits and impairs calcium homeostasis in retinal neural cells. Invest Ophthalmol Vis Sci;47, 4130-7.
A.R. Santiago, T. S. Pereira, M. J. Garrido, A. J. Cristóvão, P. F. Santos e A. F. Ambrosio 2006 High glucose and diabetes increase the release of [(3)H]-d-aspartate in retinal cell cultures and in rat retinas. Neurochem Int. 48, 453-458.
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