Systemic Treatment with Fas-Blocking Peptide Attenuates Apoptosis in Brain Ischemia

Abstract

Apoptosis plays a crucial role in neuronal injury, with substantial evidence implicating Fas-mediated cell death as a key factor in ischemic strokes. To address this, inhibition of Fas-signaling has emerged as a promising strategy in preventing neuronal cell death and alleviating brain ischemia. However, the challenge of overcoming the blood–brain barrier (BBB) hampers the effective delivery of therapeutic drugs to the central nervous system (CNS). In this study, we employed a 30 amino acid-long leptin peptide to facilitate BBB penetration. By conjugating the leptin peptide with a Fas-blocking peptide (FBP) using polyethylene glycol (PEG), we achieved specific accumulation in the Fas-expressing infarction region of the brain following systemic administration. Notably, administration in leptin receptor-deficient db/db mice demonstrated that leptin facilitated the delivery of FBP peptide. We found that the systemic administration of leptin-PEG-FBP effectively inhibited Fas-mediated apoptosis in the ischemic region, resulting in a significant reduction of neuronal cell death, decreased infarct volumes, and accelerated recovery. Importantly, neither leptin nor PEG-FBP influenced apoptotic signaling in brain ischemia. Here, we demonstrate that the systemic delivery of leptin-PEG-FBP presents a promising and viable strategy for treating cerebral ischemic stroke. Our approach not only highlights the therapeutic potential but also emphasizes the importance of overcoming BBB challenges to advance treatments for neurological disorders.

Eye Drop with Fas-Blocking Peptide Attenuates Age-Related Macular Degeneration

“…In a previous study, we successfully demonstrated the effective inhibition of Fas/FasL ligation by FBP that disrupted Fas-signaling in neuronal cells [ 54 , 55 ]. To evaluate the safety profile of FBP, we assessed its cytotoxic effects on a human retinal pigment epithelial cell line (ARPE-19).…”

Intranasal Delivery of Anti-Apoptotic siRNA Complexed with Fas-Signaling Blocking Peptides Attenuates Cellular Apoptosis in Brain Ischemia

“…Having established the efficacy of the FBP9R-mediated siRNA delivery system in targeting Fas-mediated apoptosis and Bax, we investigated the therapeutic implications in the context of cerebral ischemia modeled by the MCAO model. Cerebral ischemia is characterized by an intricate cascade of events following an ischemic injury that involve apoptotic pathways [ 37 , 55 , 56 ]. In our study, we highlight the therapeutic effects of FBP9R, a targeted siRNA delivery system, in the MCAO ischemic stroke model.…”

“…These factors collectively contribute to the potential for enhanced therapeutic efficacy and a more favorable safety profile. Research previously conducted by our group and others has explored intranasal delivery across various therapeutic realms, including anti-cancer drugs, Fas-blocking peptides, insulin, morphine, corticosteroids, and more in the treatment of brain-associated diseases [ 11 , 36 , 37 , 38 , 39 ]. Other studies have investigated the intranasal delivery of therapeutic agents for ischemic stroke treatment, encompassing small chemicals, peptides, proteins, and exosomes [ 11 , 40 , 41 , 42 , 43 ], suggesting intranasal delivery as a valuable tool in modern drug development and therapeutics.…”

“…In our previous research, we demonstrated the ability of ligand-conjugated cell-penetrate peptides (CPP) to deliver siRNA through membrane inversion or receptor-mediated endocytosis [ 29 , 37 , 44 , 45 , 46 , 47 , 48 ]. Notably, the intranasal delivery of a fusion peptide composed of a neuronal cell-specific ligand and nona-arginine (9R) complexed with siRNA showed promising results, demonstrating specific localization in the brain and notable therapeutic efficacy in a virus-mediated encephalitis model [ 45 ].…”

The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain

“…The BBB restricts the passage of highly polar molecules, such as sugars, amino acids, peptides, and nucleosides, isolating the brain from many essential compounds [ 16 , 17 , 18 , 19 ]. Various modifications of their side chains have been explored to facilitate the penetration of these impermeable molecules [ 16 , 20 , 21 , 22 ]. One strategy involves the use of hydrocarbon “staples” to link the side chains of polar molecules, and the other is the use of N-methyl phenylalanine-rich peptides, which have been investigated as highly versatile BBB shuttles [ 23 , 24 , 25 ].…”