Understanding the Role of Neuropeptide Y in Ameliorating the Degenerative Changes in Glaucoma

Glaucoma is a complex and multifactorial disease characterized by progressive loss of retinal ganglion cells (RGCs) and optic nerve degeneration. While current treatments focus on reducing intraocular pressure (IOP), they fail to address the underlying neurodegenerative processes, emphasizing the urgent need for neuroprotective therapies. Neuropeptide Y (NPY), a multifunctional neuropeptide widely expressed in the mammalian central nervous system, has shown potent neuroprotective properties in various neurodegenerative models. This thesis investigates the therapeutic potential of NPY in mitigating glaucoma-induced neurodegeneration. The study initially investigated the effects of NPY on SH-SY5Y neuroblastoma cells under neurodegenerative conditions, such as glutamate excitotoxicity, oxidative stress, and endoplasmic reticulum (ER) stress. NPY treatment, mediated through receptor activation, effectively suppressed pro-apoptotic signaling pathways, demonstrating its protective role at the cellular level. The thesis further identifies decreased levels of NPY in glaucomatous conditions, as observed in both human post-mortem retinas and experimental glaucoma animal models. In an experimental glaucoma model, NPY receptor activation was shown to preserve inner retinal structure and function, reduce neuroinflammatory responses such as astrogliosis and microglial activation, and prevent axonal degeneration. The thesis also investigated the vasoconstrictive effects of full-length NPY (1–36), mediated through Y1 receptor activation. The findings revealed that NPY (1–36) induces transient vasoconstriction in retinal blood vessels, particularly at shorter time intervals. To address this limitation, the N-terminally truncated analog NPY (3–36) was evaluated in mouse retinas. This analog, with minimal or no affinity for Y1 receptors, showed no vasoconstrictive effects. Importantly, NPY (3–36) retained its neuroprotective efficacy through activation of Y2 and Y5 receptors. It effectively preserved RGCs, maintained inner retinal structure and function, mitigated neuroinflammation, and protected against axonal damage in experimental glaucoma models, offering a safer therapeutic alternative. This thesis establishes NPY as a promising candidate for neuroprotective treatment in glaucoma and highlights NPY (3–36) as a superior alternative, effectively addressing the limitations of full-length NPY. These findings lay the groundwork for the development of innovative neuroprotective NPY analogs aimed at preventing retinal neurodegeneration in glaucoma.<p></p>