Neuroprotection by rat Müller glia against high glucose-induced neurodegeneration through a mechanism involving ERK1/2 activation

Andrea Matteucci, Lucia Gaddini, Marika Villa, Monica Varano, Mariacristina Parravano, Valentina Monteleone, Francesca Cavallo, Lanfranco Leo, Cinzia Mallozzi, Fiorella Malchiodi-Albedi, Flavia Pricci

Research output: Contribution to journalArticlepeer-review


Müller cell activation is an early finding in diabetic retinopathy (DR), but its physiopathologic role in the disease is still unclear, especially in the early phases. We investigated on Müller glial activation in primary rat retinal cultures, exposed to High Glucose (HG), and in retinas from streptozotocin (stz)-induced diabetic rats. First of all, we checked if the presence of Müller glia influenced HG neurotoxicity. In mixed glial/neuronal retinal cultures, a single HG administration (sHG) for 48h induced activation of Müller glia, in absence of neuronal damage. In contrast, in pure neuronal cultures, a marked neurotoxic effect was detected, suggesting that in this cell model Müller glia protect neurons from HG neurotoxicity. To better mimic the diabetic milieu, where retinal cells are constantly bathed in hyperglycemic fluid, and to further characterize astrocytic neuroprotective ability, mixed retinal cultures were exposed to repeated daily replacement of HG (rHG). In this paradigm, starting from 48h, increased apoptosis and synaptic loss were observed, even in the presence of Müller cells. Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), whose activation triggers a prosurvival pathway, was increased by sHG, while it was down-regulated by rHG, suggesting that ERK1/2 activation is involved in neuroprotection. Consistently, in presence of ERK1/2 inhibitor PD98059, sHG exerted a proapoptotic effect also in glial/neuronal retinal cultures. In line with the invitro data, early changes in diabetic retinas from stz-injected rats included Müller cell activation and increased pERK1/2 levels, but no signs of neuronal damage. These results suggest that, in the early phases of DR, Müller glial activation does not contribute to neurodegeneration, but may indeed have a neuroprotective activity against HG-induced neurotoxicity through a mechanism involving pERK1/2.

Original languageEnglish
Pages (from-to)20-29
Number of pages10
JournalExperimental Eye Research
Publication statusPublished - 2014


  • Apoptosis
  • Diabetic retinopathy
  • Extracellular signal-regulated kinase 1/2
  • High glucose
  • Müller cells
  • Neurotoxicity
  • Primary retinal cultures
  • Streptozotocin

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience


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