Neuroprotective effects of DAAO are mediated via the ERK1/2 signaling pathway in a glaucomatous animal model.

Neuronal excitotoxicity caused by over activation of N -Methyl-D-Aspartate (NMDA) receptors is an important risk factor for the retinal ganglion cells (RGCs) death in glaucoma. D-serine played a role as a key co-agonist for NMDA receptor activity and neurotoxicity. Our previous studies have demonstrated that increased D-serine and serine racemase (SR) expression in the retina of the chronic intraocular hypertension (COH) model were detected. D-amino acid oxidase (DAAO) treatment significantly increased RGCs survival in the glaucomatous eyes. However, the molecular mechanism remains unclear. In the present study, we investigated the extracellular signal-regulated protein kinase1/2 (ERK1/2) signaling pathway involved in DAAO neuroprotective effects on RGC survival and explore the effect of inhibited ERK1/2 phosphorylation on RGC survival and Müller cell activation in a COH rat model. We found that ERK1/2 phosphorylation and p38 kinase (p38) phosphorylation increased in the COH model, while c-Jun N-terminal kinase (JNK) phosphorylation didn't change. DAAO treatment induced ERK-1/2 MAP kinase phosphorylation and its upstream regulator, p-MEK increased in the COH model. The increased p-ERK was mainly located in retinal Müller cells. In contrast, p-JNK and p-p38 protein expression was not significantly different under these conditions. Quantitative analysis of RGC survival by fluorescent labeling and TdT-mediated dUTP nick-end labeling (TUNEL) assays confirmed that p-ERK1/2 inhibition by PD98059 attenuates DAAO-mediated reductions in RGC apoptosis. Additionally, p-ERK1/2 inhibition induced elevated glial fibrillary acidic protein (GFAP) expression in Müller cells in the COH model. Together, these results suggest that the ERK1/2 signaling pathway is involved in DAAO's neuroprotective effects on RGC survival.
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