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

作者：Matteucci Andrea; Gaddini Lucia; Villa Marika; Varano Monica; Parravano Mariacristina; Monteleone Valentina; Cavallo Francesca; Leo Lanfranco; Mallozzi Cinzia; Malchiodi Albedi Fiorella^*; Pricci Flavia

来源：Experimental Eye Research, 2014, 125: 20-29.

DOI：10.1016/j.exer.2014.05.011

• diabetic retinopathy
• primary retinal cultures
• streptozotocin
• apoptosis
• neurotoxicity
• Muller cells
• extracellular signal-regulated kinase 1/2
• high glucose

Muller 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 Muller 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 Muller glia influenced HG neurotoxicity. In mixed glial/neuronal retrial cultures, a single HG administration (sHG) for 48 h induced activation of Muller glia, in absence of neuronal damage. In contrast, in pure neuronal cultures, a marked neurotoxic effect was detected, suggesting that in this cell model Muller 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 48 h, increased apoptosis and synaptic loss were observed, even in the presence of Muller 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 in vitro data, early changes in diabetic retinas from stz-injected rats included Muller cell activation and increased pERK1/2 levels, but no signs of neuronal damage. These results suggest that, in the early phases of DR, Muller glial activation does not contribute to neurodegeneration, but may indeed have a neuroprotective activity against HG-induced neurotoxicity through a mechanism involving pERK1/2.

• 出版日期2014-8