Selective Receptor Modulation by Truncated Neuropeptide Y (3-36) Dissociates Vasoconstriction from Neuroprotection in Experimental Glaucoma.

Neuropeptide Y (NPY) is a multifunctional peptide with neuroprotective properties, but its therapeutic use in the retina and optic nerve may be limited by vasoconstrictive effects mediated through Y1 receptor activation. This study evaluated the vascular effects of full-length NPY (1-36) and its N-terminally truncated analog, NPY (3-36), in the mouse retina. Retinal vascular responses were assessed using fluorescein angiography (FFA) after intravitreal administration of different NPY analogs. NPY (1-36) caused transient vasoconstriction via Y1 receptor-mediated calmodulin and pMLC activation. In contrast, NPY (3-36) selectively activates Y2 and Y5 receptors without inducing vasoconstrictive effects. Furthermore, NPY (3-36) through receptor activation preserved retinal ganglion cell density, axonal integrity, and inner retinal function while reducing astrocytic and microglial activation under elevated intraocular pressure. These findings suggest that NPY (3-36) could be a safer therapeutic candidate for glaucoma, highlighting the critical role of receptor-specific modulation to enhance neuroprotection without causing adverse vascular complications.