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Systemic Treatment with Fas-Blocking Peptide Attenuates Apoptosis in Brain Ischemia
Sungeun Chung1, Yujong Yi1, Irfan Ullah1,2
1Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul 04763, Republic of Korea.
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.
Insights
This study developed a leptin-peptide conjugate to overcome the blood-brain barrier, effectively inhibiting Fas-mediated apoptosis and reducing neuronal cell death in ischemic stroke models.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Apoptosis, particularly Fas-mediated cell death, is a critical mechanism in neuronal injury during ischemic stroke.
- Inhibiting Fas-signaling is a potential therapeutic strategy for stroke, but drug delivery to the central nervous system (CNS) is limited by the blood-brain barrier (BBB).
Purpose of the Study:
- To develop a novel drug delivery system to overcome the BBB for targeted inhibition of Fas-mediated apoptosis in cerebral ischemic stroke.
- To evaluate the efficacy of a leptin-peptide conjugate in reducing neuronal cell death and infarct volume in a mouse model of ischemic stroke.
Main Methods:
- Conjugation of a 30 amino acid leptin peptide with a Fas-blocking peptide (FBP) using polyethylene glycol (PEG) to create leptin-PEG-FBP.
- Systemic administration of leptin-PEG-FBP in wild-type and leptin receptor-deficient db/db mice to assess BBB penetration and therapeutic effects.
- Evaluation of Fas-mediated apoptosis, neuronal cell death, infarct volume, and functional recovery in a mouse model of ischemic stroke.
Main Results:
- Systemic administration of leptin-PEG-FBP successfully facilitated BBB penetration and targeted accumulation in the Fas-expressing infarction region.
- Leptin-PEG-FBP administration significantly inhibited Fas-mediated apoptosis, reduced neuronal cell death, decreased infarct volumes, and accelerated recovery in ischemic stroke models.
- Neither leptin nor PEG-FBP alone affected apoptotic signaling in the ischemic brain, indicating the conjugate's specific therapeutic action.
Conclusions:
- Systemic delivery of leptin-PEG-FBP is a promising and viable strategy for treating cerebral ischemic stroke by overcoming BBB limitations.
- This approach highlights the therapeutic potential of targeted drug delivery across the BBB for neurological disorders.
- The study underscores the importance of addressing BBB challenges to advance treatments for conditions like ischemic stroke.
