Apelin-13 attenuates optic nerve damage in glaucomatous mice by regulating glucose metabolism

In patients with advanced glaucoma, lesions frequently extend beyond the eye and affect other organs. However, early distal consequences of elevated intraocular pressure (IOP) remain unclear. This study aimed to observe glucose uptake in the optic cortex during the early stages of elevated IOP and to investigate the mechanism by which Apelin13 exerts neuroprotective effects.

This study used a single anterior chamber injection of polystyrene microbeads and triblock copolymer hydrogel in 6- to 8-week-old male C57BL/6J mice and observed glucose uptake in the optic cortex during the initial phase of IOP elevation using micro-positron emission tomography/magnetic resonance imaging (PET/MRI). Pathological changes in the optic nerve and optic cortex were assessed by immunofluorescence, reactive oxygen species (ROS) kit, and and nicotinamide adenine dinucleotide phosphate (NADPH) kit. Expression of glucose transporter proteins (GLUTs) and key enzymes of the pentose phosphate pathway (PPP) was evaluated using immunofluorescence and western blot. The activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B signaling pathway was analyzed via western blot.

On day 1 of elevated IOP, the modeled eye exhibited reduced glucose uptake in the corresponding visual cortex compared with the contralateral visual cortex. Over time, the condition gradually improved, with no discernible difference between the two sides by day 21. Concurrently, along with abnormal activation of microglia and progressive reduction of retinal ganglion cells, we noted abnormal expression of glucose transporter proteins in visual cortical neurons. Additionally, elevated levels of ROS and NADPH were observed in both the retinal and brain tissues following IOP elevation. In contrast, administration of the neuroprotectant Apelin-13 mitigated the pathology induced by IOP elevation. Conversely, treatment with a PI3K inhibitor significantly diminished the protective effects of Apelin-13.

These findings imply that altered glucose metabolism in the visual center may be an early sign of optic nerve damage in patients with glaucoma. Apelin-13 may rely on the PI3K/Akt signaling pathway to regulate the redistribution of energy metabolism in the retina and visual centers, thereby mitigating oxidative stress and safeguarding neuronal cells.