Mechanisms contributing to inhibition of retinal ganglion cell death by cell permeable peptain-1 under glaucomatous stress
Mechanisms contributing to inhibition of retinal ganglion cell death by cell permeable peptain-1 under glaucomatous stress
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Abstract This study assesses the neuroprotective potential of CPP-P1, a conjugate of an anti-apoptotic peptain-1 (P1) and a cell-penetrating peptide (CPP) in in vitro, in vivo, and ex vivo glaucoma models.Primary retinal ganglion cells (RGCs) were subjected to either neurotrophic factor (NF) deprivation for 48 h or endothelin-3 (ET-3) treatment for 24 h and received either CPP-P1 or vehicle.RGC survival was analyzed using a Live/Dead assay.
Axotomized human retinal explants were treated with CPP-P1 or vehicle for seven days, stained with RGC marker RBPMS, and RGC survival was analyzed.Brown Norway (BN) rats with elevated intraocular pressure (IOP) received weekly intravitreal injections of CPP-P1 or vehicle for six weeks.RGC function was evaluated using a pattern electroretinogram (PERG).
RGC and axonal damage were also assessed.RGCs from ocular hypertensive rats treated with CPP-P1 or vehicle for seven days were isolated for transcriptomic analysis.RGCs subjected to 48 h of NF deprivation fairytale once upon a time theme party were used for qPCR target confirmation.
NF deprivation led to a significant loss of RGCs, which was markedly reduced by CPP-P1 treatment.CPP-P1 also decreased ET-3-mediated RGC death.In ex vivo human retinal explants, CPP-P1 decreased RGC loss.
IOP elevation resulted in significant RGC loss in mid-peripheral and peripheral retinas compared to that in naive rats, which was significantly reduced by CPP-P1 treatment.PERG amplitude decline in IOP-elevated rats was mitigated by CPP-P1 treatment.Following IOP elevation in BN rats, the transcriptomic analysis showed over 6,000 differentially expressed genes in the CPP-P1 group compared to the vehicle-treated group.
Upregulated pathways included CREB signaling and synaptogenesis.A significant increase in Creb1 mRNA and elevated phosphorylated Creb were observed in CPP-P1-treated RGCs.Our study showed that CPP-P1 is neuroprotective through CREB signaling enhancement in several settings that mimic glaucomatous conditions.
The findings from this study are significant as they address the pressing lost vape quest q ultra need for the development of efficacious therapeutic strategies to maintain RGC viability and functionality associated with glaucoma.