Neuropeptide receptors as potential drug targets in the treatment of inflammatory conditions

Pintér, Erika; Pozsgai, Gábor; Hajna, Zsófia; Helyes, Zsuzsanna; Szolcsányi, Janós

doi:10.1111/bcp.12097

Cited by 62 publications

(46 citation statements)

References 171 publications

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“…The physiological relevance of up-regulating neuropeptides by a TNF-to-IL6 cascade may be related to their involvement in steroidogenesis in the adjacent adrenal cortex, with initiation by TNFa, and then IL6, allowing cytokine inflammatory effects occurring systemically to be temporally limited by a linked but delayed anti-inflammatory response. Such a mechanism might serve to optimize the antiseptic actions of TNFa, while minimizing damage to the host during sepsis (Mazzocchi et al 1992Andreis et al 2007;Belloni et al 2007;Kormos and Gaszner 2013;Pinter et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐6‐mediated signaling in adrenal medullary chromaffin cells

Jenkins

Sreenivasan

Carman

et al. 2016

Journal of Neurochemistry

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The pro-inflammatory cytokines, tumor necrosis factor-α and interleukin-1β/α modulate catecholamine secretion, and long-term gene regulation, in chromaffin cells of the adrenal medulla. Since interleukin-6 (IL6) also plays a key integrative role during inflammation, we have examined its ability to affect both tyrosine hydroxylase activity and adrenomedullary gene transcription in cultured bovine chromaffin cells. IL6 caused acute tyrosine/threonine phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), and serine/tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). Consistent with ERK1/2 activation, IL6 rapidly increased tyrosine hydroxylase phosphorylation (serine-31) and activity, as well as up-regulated genes, encoding secreted proteins including galanin, vasoactive intestinal peptide, gastrin releasing peptide and parathyroid hormone-like hormone. The effects of IL6 on the entire bovine chromaffin cell transcriptome were compared to those generated by G-protein coupled receptor (GPCR) agonists (histamine and pituitary adenylate cyclase-activating polypeptide) and the cytokine receptor agonists (interferon-α and tumor necrosis factor-α). Of 90 genes up-regulated by IL6, only 16 are known targets of IL6 in the immune system. Those remaining likely represent a combination of novel IL6/STAT3 targets, ERK1/2 targets and, potentially, IL6-dependent genes activated by IL6-induced transcription factors, such as hypoxia-inducible factor 1α. Notably, genes induced by IL6 include both neuroendocrine-specific genes activated by GPCR agonists, and transcripts also activated by the cytokines. These results suggest an integrative role for IL6 in the fine-tuning of the chromaffin cell response to a wide range of physiological and paraphysiological stressors, particularly when immune and endocrine stimuli converge.

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Section: Discussionmentioning

confidence: 99%

Interleukin‐6‐mediated signaling in adrenal medullary chromaffin cells

Jenkins

Sreenivasan

Carman

et al. 2016

Journal of Neurochemistry

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“…Discussing the divergent effects of all neuropeptides goes beyond the scope of this review. Selective modulation of their receptors could provide a novel approach in analgesic and anti‐inflammatory drug development …”

Section: Novel Targets With Anti‐inflammatory And/or Analgesic Potentmentioning

confidence: 99%

“…These do not only mediate pain but also local neurogenic inflammatory reaction via the release of vasoactive, proinflammatory neuropeptides such as tachykinins [e.g., substance P (SP)], calcitonin gene‐related peptide (CGRP), vasoactive intestinal polypeptide (VIP), and pituitary adenylate‐cyclase activating polypeptide (PACAP). Meanwhile, inhibitory neuropeptides (somatostatin, opioid peptides) are also simultaneously released from these nerve terminals that limit inflammation and pain locally and also via the systemic circulation . These nerve endings are activated/sensitized by a variety of different mediators produced during inflammation, such as protons, hydrogen peroxide, formaldehyde, prostaglandins (PGs), and leukotrienes.…”

Section: Introductionmentioning

confidence: 99%

Challenges to develop novel anti‐inflammatory and analgesic drugs

Botz

Bölcskei

Helyes

2016

WIREs Nanomed Nanobiotechnol

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Chronic inflammatory diseases and persistent pain of different origin represent common medical, social, and economic burden, and their pharmacotherapy is still an unresolved issue. Therefore, there is a great and urgent need to develop anti-inflammatory and analgesic agents with novel mechanisms of action, but it is a very challenging task. The main problem is the relatively large translational gap between the preclinical experimental data and the clinical results due to characteristics of the models, difficulties with the investigational techniques particularly for pain, as well as species differences in the mechanisms. We summarize here the current state-of-the-art medication and related ongoing strategies, and the novel targets with lead molecules under clinical development. The first members of the gold-standard categories, such as nonsteroidal anti-inflammatory drugs, glucocorticoids, and opioids, were introduced decades ago, and since then very few drugs with novel mechanisms of action have been successfully taken to the clinics despite considerable development efforts. Several biologics targeting different key molecules have provided breakthrough in some autoimmune/inflammatory diseases, but they are expensive, only parenterally available, their long-term side effects often limit their administration, and they do not effectively reduce pain. Some kinase inhibitors and phosphodiesterase-4 blockers have recently been introduced as new directions. There are in fact some promising novel approaches at different clinical stages of drug development focusing on transient receptor potential vanilloid 1/ankyrin 1 channel antagonism, inhibition of voltage-gated sodium/calcium channels, several enzymes (kinases, semicarbazide-sensitive amine oxidases, and matrix metalloproteinases), cytokines/chemokines, transcription factors, nerve growth factor, and modulation of several G protein-coupled receptors (cannabinoids, purinoceptors, and neuropeptides). WIREs Nanomed Nanobiotechnol 2017, 9:e1427. doi: 10.1002/wnan.1427 For further resources related to this article, please visit the WIREs website.

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“…Leukocyte infiltration in the brain boosts inflammatory activation of various cells such as microglia and astrocytes [72]. Recent studies have explored the ability of neuropeptides with physiological functions such as galanin peptides, to prevent and alleviate poststroke inflammatory responses [7374]. Several studies have demonstrated that upregulation of GalR1 is related to the increased expression of nuclear factor (NF)-κB, which is an inflammatory signaling molecule in inflammatory animal models [7576].…”

Section: Galanin In Post-stroke Inflammationmentioning

confidence: 99%

Galanin's implications for post-stroke improvement

Song

Kim

2016

Anat Cell Biol

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Stroke leads to a variety of pathophysiological conditions such as ischemic infarct, cerebral inflammation, neuronal damage, cognitive decline, and depression. Many endeavors have been tried to find the therapeutic solutions to attenuate severe neuropathogenesis after stroke. Several studies have reported that a decrease in the neuropeptide regulator ‘galanin’ is associated with neuronal loss, learning and memory dysfunctions, and depression following a stroke. The present review summarized recent evidences on the function and the therapeutic potential of galanin in post-ischemic stroke to provide a further understanding of galanin's role. Hence, we suggest that galanin needs to be considered as a therapeutic factor in the alleviation of post-stroke pathologies.

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Neuropeptide receptors as potential drug targets in the treatment of inflammatory conditions

Cited by 62 publications

References 171 publications

Interleukin‐6‐mediated signaling in adrenal medullary chromaffin cells

Interleukin‐6‐mediated signaling in adrenal medullary chromaffin cells

Challenges to develop novel anti‐inflammatory and analgesic drugs

Galanin's implications for post-stroke improvement

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