Dataset Information

A synthetic BBB-permeable tripeptide GCF confers neuroprotection by increasing glycine in the ischemic brain.

ABSTRACT: Background: We and others have previously demonstrated that glycine is neuroprotective in cerebral ischemia-reperfusion injury. But glycine has low permeability to the blood-brain barrier (BBB). To deliver glycine into the ischemic brain to confer neuroprotection, we designed a novel glycine-containing and BBB-permeable tripeptide, the H-glycine-cysteine-phenylalanine-OH (GCF). Methods: For the synthesis of GCF, phenylalanine was included to increase the BBB permeability of the tripeptide. Cysteine was conjugated with glycine to enable the release of glycine from GCF. With the use of immunofluorescence labeling and HPLC assays, we measured the distribution and level of GCF. We used TTC labeling, LDH release, and MTT assays to evaluate the neuroprotective effect of GCF. Results: Following intravenous injection in a rat model of cerebral ischemia-reperfusion injury, GCF was intensively distributed in the ischemic neurons. Intravenous injection of GCF, but not the non-cleavable acetyl-GCF, resulted in the elevation of glycine in the ischemic brain. GCF but not acetyl-GC conferred neuroprotection in ischemic stroke animals. Conclusion: GCF protects against cerebral ischemia-reperfusion injury in the rat. In contrast to peptide drugs that exert therapeutic effect by interfering with signaling interaction, GCF acts as a BBB shuttle and prodrug to deliver glycine to confer neuroprotection, representing a novel therapeutic strategy for acute ischemic stroke.

SUBMITTER: Chen J

PROVIDER: S-EPMC9420865 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A synthetic BBB-permeable tripeptide GCF confers neuroprotection by increasing glycine in the ischemic brain.

Chen Juan J Zhuang Yang Y Zhang Ya Y Liao Huabao H Liu Rui R Cheng Jing J Zhang Zhifeng Z Sun Jiangdong J Gao Jingchen J Wang Xiyuran X Chen Shujun S Zhang Liang L Che Fengyuan F Wan Qi Q

Frontiers in pharmacology 20220815

<b>Background:</b> We and others have previously demonstrated that glycine is neuroprotective in cerebral ischemia-reperfusion injury. But glycine has low permeability to the blood-brain barrier (BBB). To deliver glycine into the ischemic brain to confer neuroprotection, we designed a novel glycine-containing and BBB-permeable tripeptide, the H-glycine-cysteine-phenylalanine-OH (GCF). <b>Methods:</b> For the synthesis of GCF, phenylalanine was included to increase the BBB permeability of the tri ...[more]

PMID: 36046828

Similar Datasets

Project description:An enormous amount of efforts have been poured to find an effective therapeutic agent for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). Among those, neurotrophic peptides that regenerate neuronal structures and increase neuron survival show a promise in slowing neurodegeneration. However, the short plasma half-life and poor blood-brain-barrier (BBB)-permeability of neurotrophic peptides limit their in vivo efficacy. Thus, an alternative neurotrophic agent that has longer plasma half-life and better BBB-permeability has been sought for. Based on the recent findings of neuroprotective polysaccharides, we searched for a BBB-permeable neuroprotective polysaccharide among natural polysaccharides that are approved for human use. Then, we discovered midi-GAGR, a BBB-permeable, long plasma half-life, strong neuroprotective and neurotrophic polysaccharide. Midi-GAGR is a 4.7kD cleavage product of low acyl gellan gum that is approved by FDA for human use. Midi-GAGR protected rodent cortical neurons not only from the pathological concentrations of co-/post-treated free reactive radicals and Aβ42 peptide but also from activated microglial cells. Moreover, midi-GAGR showed a good neurotrophic effect; it enhanced neurite outgrowth and increased phosphorylated cAMP-responsive element binding protein (pCREB) in the nuclei of primary cortical neurons. Furthermore, intra-nasally administered midi-GAGR penetrated the BBB and exerted its neurotrophic effect inside the brain for 24 h after one-time administration. Midi-GAGR appears to activate fibroblast growth factor receptor 1 (FGFR1) and its downstream neurotrophic signaling pathway for neuroprotection and CREB activation. Additionally, 14-day intranasal administration of midi-GAGR not only increased neuronal activity markers but also decreased hyperphosphorylated tau, a precursor of neurofibrillary tangle, in the brains of the AD mouse model, 3xTg-AD. Taken together, midi-GAGR with good BBB-permeability, long plasma half-life, and strong neuroprotective and neurotrophic effects has a great therapeutic potential for the treatment of neurodegenerative diseases, especially AD.

Project description:Stroke is a leading cause of mortality and morbidity with a paucity of effective pharmacological treatments. We have previously identified insulin-regulated aminopeptidase (IRAP) as a potential target for the development of a new class of drugs for the treatment of stroke, as global deletion of this gene in mice significantly protected against ischemic damage. In the current study, we demonstrate that small molecular weight IRAP inhibitors reduce infarct volume and improve neurological outcome in a hypertensive animal model of ischemic stroke. The effects of two structurally distinct IRAP inhibitors (HFI419 or SJM164) were investigated in a model of stroke where the middle cerebral artery was transiently occluded with endothelin-1 in the conscious spontaneously hypertensive rat. IRAP inhibitor was administered into the lateral ventricle at 2 or 6 h after stroke, with subsequent doses delivered at 24, 48 and 70 h post-stroke. Functional outcomes were assessed prior to drug treatment, and on day 1 and 3 post-stroke. Histological analyses and neuroinflammatory cytokine profiling were conducted at 72 and 24 h post-stroke respectively. IRAP inhibitor treatment following stroke significantly reduced infarct volume and improved neurological and motor deficits. These protective effects were maintained even when the therapeutic window was extended to 6 h. Examination of the cellular architecture at 72 h post-stroke demonstrated that IRAP expression was upregulated in CD11b positive cells and activated astrocytes. Furthermore, IRAP inhibitor treatment significantly increased gene expression for interleukin 6 and C-C motif chemokine ligand 2 in the ischemic core. This study provides proof-of-principle that selective inhibition of IRAP activity with two structurally distinct IRAP inhibitors reduces infarct volume and improves functional outcome even when the first dose is administered 6 h post-stroke. This is the first direct evidence that IRAP inhibitors are a class of drug with potential use in the treatment of ischemic stroke.

Dataset Information

A synthetic BBB-permeable tripeptide GCF confers neuroprotection by increasing glycine in the ischemic brain.

Publications

A synthetic BBB-permeable tripeptide GCF confers neuroprotection by increasing glycine in the ischemic brain.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets