Preliminary data showed that the introduction of the aminomethylene unit into the GPE sequence would provide stable GPE 1-3 pseudotripeptides ( Figure 1). Thus, we obtained three novel GPE peptidomimetics (GPE1, GPE2, and GPE3), with peptide bonds reduced to an aminomethylenic group at the Gly-Pro (GPE3) or Pro- Glu (GPE1), or both the junctions (GPE2) to improve the stability against proteolytic attacks still exhibiting their biological activity ( Figure 1). Therefore, the introduction of peptide bond surrogates has been recommended as an effective strategy to prolong the lifetime of peptides, improve the biological activity or selectivity, design enzyme inhibitors, and induce conformational features. Previously, an intimate elaboration was made for the replacement and/or modification of GPE amino acid sequence to (I) improve its proteases resistance and (II) manage and retaining its neuroprotective feature. However, in the last decade, variegated neuropeptides derived from IGF-I were found to exhibit adequate protection and more favorable pharmacokinetic profile compared to IGF-I. Interestingly, phase 3 trial using Glypromate product to modulate the cognitive impairment in patients undergoing cardiac surgery with bypass was failed. Hence, GPE is proposed to be a potential target for rational design of neuroprotective agents for neurological disorders. At this point, GPE has been shown to have a binding affinity toward NMDA receptors, but not to other ionotropic glutamate subfamilies, such as (2S)-2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or kainate (KA) receptors. Additionally, amyloid-beta (Aβ) peptide is believed to induce ROS’s excessive formation via the mechanism requiring NMDA receptor activation on hippocampal neuronal cultures. Literature showed that GPE treatment has a positive impact on the proliferation and migration of mouse neural stem cells (NSCs) by altering extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase PI3K-Akt pathways associated with neuroprotective activity. GPE executes remarkable neuroprotective properties in several in vitro and in vivo models, demonstrating its involvement in traumatic brain injury and chronic neurodegeneration. It is commercially available as Glypromate. The glycine-L-proline-L-glutamate (GPE) ( Figure 1) is a naturally cleaved N-terminal tripeptide of IGF-1 via brain proteases. In vitro results suggested that treatments with novel GPE analogs might be promising therapeutic agents for treatment and/or or prevention of AD. Our analysis showed that GPE peptidomimetics modulate oxidative stress, ACh depletion, α-secretase inactivation, apoptotic, and necrotic cell death. Anti-Alzheimer potentials were determined using a wide array of techniques, such as measurements of mitochondrial viability (MTT) and lactate dehydrogenase (LDH) release assays, determination of acetylcholinesterase (AChE), α-secretase and β-secretase activities, comparisons of total antioxidant capacity (TAC) and total oxidative status (TOS) levels, flow cytometric and microscopic detection of apoptotic and necrotic neuronal death, and investigating gene expression responses via PCR arrays involving 64 critical genes related to 10 different pathways. In turn, this study was aimed to investigate the neuroprotective potentials exerted by three novel GPE peptidomimetics (GPE1, GPE2, and GPE3) using an in vitro AD model. In this context, glycine-L-proline-L-glutamate (GPE) and its analogs may open the way for developing a novel molecule for treating neurodegenerative disorders, including AD. So far, there is no effective disease-modifying therapies for Alzheimer’s Disease (AD) in clinical practice.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |