Palanivel Viswanthram, Gupta Vivek, Chitranshi Nitin, Tietz Ole, Vander Wall Roshana, Blades Reuben, Maha Thananthirige Kanishka Pushpitha, Salkar Akanksha, Shen Chao, Mirzaei Mehdi, Gupta Veer, Graham Stuart L, Basavarajappa Devaraj
Faculty of Medicine, Health and Human Sciences, Macquarie Medical School, Macquarie University, North Ryde, Sydney, NSW 2109, Australia.
Faculty of Medicine, Health and Human Sciences, Dementia Research Centre, Macquarie Medical School, Macquarie University, North Ryde, Sydney, NSW 2109, Australia.
PNAS Nexus. 2024 Jul 26;3(8):pgae299. doi: 10.1093/pnasnexus/pgae299. eCollection 2024 Aug.
Neuropeptide Y (NPY), an endogenous peptide composed of 36 amino acids, has been investigated as a potential therapeutic agent for neurodegenerative diseases due to its neuroprotective attributes. This study investigated the neuroprotective effects of NPY in a mouse model of glaucoma characterized by elevated intraocular pressure (IOP) and progressive retinal ganglion cell degeneration. Elevated IOP in mice was induced through intracameral microbead injections, accompanied by intravitreal administration of NPY peptide. The results demonstrated that NPY treatment preserved both the structural and functional integrity of the inner retina and mitigated axonal damage and degenerative changes in the optic nerve under high IOP conditions. Further, NPY treatment effectively reduced inflammatory glial cell activation, as evidenced by decreased expression of glial fibrillary acidic protein and Iba-1. Notably, endogenous NPY expression and its receptors (NPY-Y1R and NPY-Y4R) levels were negatively affected in the retina under elevated IOP conditions. NPY treatment restored these changes to a significant extent. Molecular analysis revealed that NPY mediates its protective effects through the mitogen-activated protein kinase (MAPK) and PI3K/Akt signaling pathways. These findings highlight the therapeutic potential of NPY in glaucoma treatment, underscoring its capacity to preserve retinal health, modulate receptor expression under stress, reduce neuroinflammation, and impart protection against axonal impairment.
神经肽Y（NPY）是一种由36个氨基酸组成的内源性肽，因其神经保护特性而被研究作为神经退行性疾病的潜在治疗剂。本研究在以眼压升高（IOP）和进行性视网膜神经节细胞变性为特征的青光眼小鼠模型中研究了NPY的神经保护作用。通过前房内微珠注射诱导小鼠眼压升高，并同时玻璃体内注射NPY肽。结果表明，在高眼压条件下，NPY治疗可维持视网膜内层的结构和功能完整性，并减轻视神经的轴突损伤和退行性变化。此外，NPY治疗有效降低了炎症性胶质细胞的活化，这可通过胶质纤维酸性蛋白和离子钙结合衔接分子1表达的降低得到证明。值得注意的是，在眼压升高的条件下，视网膜内源性NPY表达及其受体（NPY-Y1R和NPY-Y4R）水平受到负面影响。NPY治疗在很大程度上恢复了这些变化。分子分析表明，NPY通过丝裂原活化蛋白激酶（MAPK）和PI3K/Akt信号通路介导其保护作用。这些发现突出了NPY在青光眼治疗中的治疗潜力，强调了其保护视网膜健康、调节应激下受体表达、减少神经炎症以及防止轴突损伤的能力。
