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Abstract
Retinal ganglion cells (RGCs) consume large quantities of energy to convert light information into a neuronal signal, which makes them highly susceptible to hypoxic injury. This study aimed to investigate the potential protection by baclofen, a GABAB receptor agonist of RGCs against hypoxia-induced apoptosis. Cobalt chloride (CoCl2) was applied to mimic hypoxia. Primary rat RGCs were subjected to CoCl2 with or without baclofen treatment, and RNA interference techniques were used to knock down the GABAB2 gene in the primary RGCs. The viability and apoptosis of RGCs were assessed using cell viability and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assays, Hoechst staining, and flow cytometry. The expression of cleaved caspase-3, bcl-2, bax, Akt, phospho-Akt, protein kinase RNA (PKR)-like ER kinase (PERK), phospho-PERK, eIF2α, phospho-eIF2α, ATF-4 and CCAAT/enhancer-binding protein homologous protein (CHOP) were measured using western blotting. GABAB2 mRNA expression was determined using quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Our study revealed that CoCl2 significantly induced RGC apoptosis and that baclofen reversed these effects. CoCl2-induced reduction of Akt activity was also reversed by baclofen. Baclofen prevented the activation of the PERK pathway and the increase in CHOP expression induced by CoCl2. Knockdown of GABAB2 and the inactivation of the Akt pathway by inhibitors reduced the protective effect of baclofen on CoCl2-treated RGCs. Taken together, these results demonstrate that baclofen protects RGCs from CoCl2-induced apoptosis by increasing Akt activity and by suppressing the PERK pathway and CHOP activation.
Highlights
The retina is the most metabolically active tissue in human body (Ames, 1992; Caprara and Grimm, 2012)
To determine whether baclofen could affect the survival of retinal ganglion cells (RGCs), CCK-8 assays were performed, and the results showed that cell viability was not significantly altered after 24 h of exposure to baclofen at concentrations up to 800 μM, which indicates that, under certain conditions, baclofen has no significant influence on RGC viability (Figure 2A)
We investigated the use of an in vitro model of purified rat RGC cultures to examine whether baclofen has neuroprotective effects against RGC apoptosis induced by hypoxic stress
Summary
The retina is the most metabolically active tissue in human body (Ames, 1992; Caprara and Grimm, 2012). In retinal disease such as retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration and glaucoma, an insufficient supply of oxygen or nutrients, may occur during conditions of disturbed hemodynamics or vascular defects, results in highly impaired cellular oxygen balance, and retinal neurons become hypoxic (Kaur et al, 2009, 2012; Munemasa and Kitaoka, 2012). RGCs were treated with CoCl2 to stimulate hypoxia
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