Abstract:Glucagon-like peptide-2 (GLP-2) is a peptide hormone that belongs to the glucagon-derived peptide family. We have previously shown that analogues of the sister hormone Glucagon-like peptide-1 (GLP-1) showed neuroprotective effects. Here we investigated the effect of a GLP-2 agonist in a cell model of Parkinsonʼs disease (PD) created by treating SH-SY5Y or Neuro-2a cells with 1-Methyl-4-phenyl-pyridine ion (MPP+). Cell viability and cell cytotoxicity was detected by MTT and LDH assays, respectively. The protein… Show more
“…In fact, today nearly 50 drugs acting via GPCRs have been approved by the Food and Drug Administration for various therapeutic interventions ( 106 ), some acting via neuropeptide systems: a substance P antagonist for treatment of chemotherapy-induced nausea ( 108 ), orexin antagonists for treatment of insomnia ( 109 ), and CGRP antibodies/antagonists for treatment of migraine ( 110 ). Finally, GLPR1 agonists are not only useful for treatment of metabolic syndrome ( 111 ) but together with GIPR and GLPR2 agonists they have in animal experiments/models (e.g., AD and Parkinson’s disease) been shown to reduce chronic inflammation and mitochondrial damage, improve memory, and reduce plaque load ( 112 , 113 ). In fact, recently a clinical trial has been initiated by Novo Nordisk, the Danish pharmaceutical company, with an agonist (Rybelsus) at the peptide receptor GLP1R for treatment of AD.…”
Human prefrontal cortex (hPFC) is a complex brain region involved in cognitive and emotional processes and several psychiatric disorders. Here, we present an overview of the distribution of the peptidergic systems in 17 subregions of hPFC and three reference cortices obtained by microdissection and based on RNA sequencing and RNAscope methods integrated with published single-cell transcriptomics data. We detected expression of 60 neuropeptides and 60 neuropeptide receptors in at least one of the hPFC subregions. The results reveal that the peptidergic landscape in PFC consists of closely located and functionally different subregions with unique peptide/transmitter–related profiles. Neuropeptide-rich PFC subregions were identified, encompassing regions from anterior cingulate cortex/orbitofrontal gyrus. Furthermore, marked differences in gene expression exist between different PFC regions (>5-fold; cocaine and amphetamine–regulated transcript peptide) as well as between PFC regions and reference regions, for example, for somatostatin and several receptors. We suggest that the present approach allows definition of, still hypothetical, microcircuits exemplified by glutamatergic neurons expressing a peptide cotransmitter either as an agonist (hypocretin/orexin) or antagonist (galanin). Specific neuropeptide receptors have been identified as possible targets for neuronal afferents and, interestingly, peripheral blood-borne peptide hormones (leptin, adiponectin, gastric inhibitory peptide, glucagon-like peptides, and peptide YY). Together with other recent publications, our results support the view that neuropeptide systems may play an important role in hPFC and underpin the concept that neuropeptide signaling helps stabilize circuit connectivity and fine-tune/modulate PFC functions executed during health and disease.
“…In fact, today nearly 50 drugs acting via GPCRs have been approved by the Food and Drug Administration for various therapeutic interventions ( 106 ), some acting via neuropeptide systems: a substance P antagonist for treatment of chemotherapy-induced nausea ( 108 ), orexin antagonists for treatment of insomnia ( 109 ), and CGRP antibodies/antagonists for treatment of migraine ( 110 ). Finally, GLPR1 agonists are not only useful for treatment of metabolic syndrome ( 111 ) but together with GIPR and GLPR2 agonists they have in animal experiments/models (e.g., AD and Parkinson’s disease) been shown to reduce chronic inflammation and mitochondrial damage, improve memory, and reduce plaque load ( 112 , 113 ). In fact, recently a clinical trial has been initiated by Novo Nordisk, the Danish pharmaceutical company, with an agonist (Rybelsus) at the peptide receptor GLP1R for treatment of AD.…”
Human prefrontal cortex (hPFC) is a complex brain region involved in cognitive and emotional processes and several psychiatric disorders. Here, we present an overview of the distribution of the peptidergic systems in 17 subregions of hPFC and three reference cortices obtained by microdissection and based on RNA sequencing and RNAscope methods integrated with published single-cell transcriptomics data. We detected expression of 60 neuropeptides and 60 neuropeptide receptors in at least one of the hPFC subregions. The results reveal that the peptidergic landscape in PFC consists of closely located and functionally different subregions with unique peptide/transmitter–related profiles. Neuropeptide-rich PFC subregions were identified, encompassing regions from anterior cingulate cortex/orbitofrontal gyrus. Furthermore, marked differences in gene expression exist between different PFC regions (>5-fold; cocaine and amphetamine–regulated transcript peptide) as well as between PFC regions and reference regions, for example, for somatostatin and several receptors. We suggest that the present approach allows definition of, still hypothetical, microcircuits exemplified by glutamatergic neurons expressing a peptide cotransmitter either as an agonist (hypocretin/orexin) or antagonist (galanin). Specific neuropeptide receptors have been identified as possible targets for neuronal afferents and, interestingly, peripheral blood-borne peptide hormones (leptin, adiponectin, gastric inhibitory peptide, glucagon-like peptides, and peptide YY). Together with other recent publications, our results support the view that neuropeptide systems may play an important role in hPFC and underpin the concept that neuropeptide signaling helps stabilize circuit connectivity and fine-tune/modulate PFC functions executed during health and disease.
“…Its structure (His–Phe–Arg–Trp–Pro–Gly–Pro) does not entirely preclude such activity, as phenylalanine and tryptophan residues may react with ROS [ 30 ]. In this assay, the peptide appeared to be inferior to the redoxin-mimetic peptide PSELT [ 31 ] and glucagon-like peptide-2 [ 32 ]. It could be proposed that the concentration of the peptide is not enough for this activity to manifest.…”
Stabilized melanocortin analog peptide ACTH(6–9)PGP (HFRWPGP) possesses a wide range of neuroprotective activities. However, its mechanism of action remains poorly understood. In this paper, we present a study of the proproliferative and cytoprotective activity of the adrenocorticotropic hormone fragment 6–9 (HFRW) linked with the peptide prolyine–glycyl–proline on the SH-SY5Y cells in the model of oxidative stress-related toxicity. The peptide dose-dependently protected cells from H2O2, tert-butyl hydroperoxide, and KCN and demonstrated proproliferative activity. The mechanism of its action was the modulation of proliferation-related NF-κB genes and stimulation of prosurvival NRF2-gene-related pathway, as well as a decrease in apoptosis.
“…In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned mice, GLP-2 analogue administration improved the bradykinesia and movement imbalance of mice, protected dopaminergic neurons and restored tyrosine hydroxylase expression in the substantia nigra and reduced markers of inflammation and mitochondrial dysfunction [162]. Similarly, in Neuro-2a cells treated with 1-Methyl-4-phenyl-pyridine ion, GLP-2 agonist administration protected cells against mitochondrial damage, autophagy impairments and apoptosis, whilst enhancing cell signalling for mitogenesis, and reducing oxidative stress levels [163]. Whilst the impact of GLP-2 administration on GI health and function is yet to be assessed in PD, these promising findings strongly suggest a beneficial role for GLP-2 in PD.…”
Section: Teduglutidementioning
confidence: 95%
“…Several pre-clinical studies have highlighted the efficacy of GLP-2 in mouse and cell culture models of PD [162,163]. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned mice, GLP-2 analogue administration improved the bradykinesia and movement imbalance of mice, protected dopaminergic neurons and restored tyrosine hydroxylase expression in the substantia nigra and reduced markers of inflammation and mitochondrial dysfunction [162].…”
Abnormalities in the gastrointestinal (GI) tract of Parkinson’s disease (PD) sufferers were first reported over 200 years ago; however, the extent and role of GI dysfunction in PD disease progression is still unknown. GI dysfunctions, including dysphagia, gastroparesis, and constipation, are amongst the most prevalent non-motor symptoms in PD. These symptoms not only impact patient quality of life, but also complicate disease management. Conventional treatment pathways for GI dysfunctions (i.e., constipation), such as increasing fibre and fluid intake, and the use of over-the-counter laxatives, are generally ineffective in PD patients, and approved compounds such as guanylate cyclase C agonists and selective 5-hyroxytryptamine 4 receptor agonists have demonstrated limited efficacy. Thus, identification of potential targets for novel therapies to alleviate PD-induced GI dysfunctions are essential to improve clinical outcomes and quality of life in people with PD. Unlike the central nervous system (CNS), where PD pathology and the mechanisms involved in CNS damage are relatively well characterised, the effect of PD at the cellular and tissue level in the enteric nervous system (ENS) remains unclear, making it difficult to alleviate or reverse GI symptoms. However, the resurgence of interest in understanding how the GI tract is involved in various disease states, such as PD, has resulted in the identification of novel therapeutic avenues. This review focuses on common PD-related GI symptoms, and summarizes the current treatments available and their limitations. We propose that by targeting the intestinal barrier, ENS, and/or the gut microbiome, may prove successful in alleviating PD-related GI symptoms, and discuss emerging therapies and potential drugs that could be repurposed to target these areas.
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