1. Comparison of the anti-inflammatory and anti-nociceptive effects of cortistatin-14 and somatostatin-14 in distinct in vitro and in vivo model systems
Ágnes Kemény, Zsuzsanna Helyes, János Szolcsányi, Katalin Sándor, Éva Szoke, Teréz Bagoly, Krisztián Elekes, Adrienn Markovics, Rita Börzsei, Erika Pintér J Mol Neurosci . 2012 Jan;46(1):40-50. doi: 10.1007/s12031-011-9577-4.
We showed that somatostatin (SST) exerts anti-inflammatory and anti-nociceptive effects through somatostatin receptor subtypes 4 and 1 (sst(4)/sst(1)). Since cortistatin (CST) is a structurally similar peptide, we aimed at comparing the sst(1)- and sst(4)-binding and activating abilities, as well as the effects of SST-14 and CST-14 on inflammatory and nociceptive processes. CST-14 concentration-dependently displaced radiolabeled SST-14 binding, induced similar sst(1) and sst(4)-activation with a less potency, and exerted significantly greater inhibitory effect on endotoxin-stimulated interleukin (IL)-1β production of murine peritoneal macrophages. Capsaicin-induced calcitonin gene-related peptide release from peripheral sensory nerve terminals of isolated rat tracheae was significantly decreased by 2 μM CST and 100 nM SST, but concentration-response correlation was not found. Mustard oil-evoked acute neurogenic plasma protein extravasation in the rat hindpaw skin, carrageenan-induced mouse paw edema, mechanical hyperalgesia, and IL-1β, tumor necrosis factor-α production, as well as mild heat injury-evoked thermal hyperalgesia were similarly attenuated by both peptides. In the latter case, i.pl. and i.p. injections exerted equal inhibitory actions. CST-14 and SST-14 similarly diminish both acute neurogenic and cellular inflammatory processes, as well as mechanical and heat hyperalgesia, in which their inhibitory effect on sensory nerve endings is likely to be involved. However, CST-14 exerts remarkably greater inhibition on cytokine production.
2. Cloning, mRNA expression, and chromosomal mapping of mouse and human preprocortistatin
J Peelle-Kirley, P E Danielson, W N Frankel, P Ruiz-Lozano, P E Foye, L de Lecea, J G Sutcliffe Genomics . 1997 Jun 15;42(3):499-506. doi: 10.1006/geno.1997.4763.
Cortistatin is a 14-residue putative neuropeptide with strong structural similarity to somatostatin and is expressed predominantly in cortical GABAergic interneurons of rats. Administration of cortistatin into the brain ventricles specifically enhances slow-wave sleep, presumably by antagonizing the effects of acetylcholine on cortical excitability. Here we report the identification of cDNAs corresponding to mouse and human preprocortistatin and the mRNA distribution and gene mapping of mouse cortistatin. Analysis of the nucleotide and predicted amino acid sequences from rat and mouse reveals that the 14 C-terminal residues of preprocortistatin, which make up the sequence that is most similar to somatostatin, are conserved between species. Lack of conservation of other dibasic amino acid residues whose cleavage by prohormone convertases would give rise to additional peptides suggests that cortistatin-14 is the only active peptide derived from the precursor. As in the rat, mouse preprocortistatin mRNA is present in GABAergic interneurons in the cerebral cortex and hippocampus. The preprocortistatin gene maps to mouse chromosome 4, in a region showing conserved synteny with human 1p36. The human putative cortistatin peptide has an arginine for lysine substitution, compared to the rat and mouse products, and is N-terminally extended by 3 amino acids.
3. Cortistatin-14 mediates its anticonvulsant effects via sst2 and sst3 but not ghrelin receptors
Giuseppe Di Giovanni, Jessica Coppens, Yvette Michotte, Ann Van Eeckhaut, Jeanelle Portelli, Najat Aourz, Dimitri De Bundel, Ilse Smolders CNS Neurosci Ther . 2014 Jul;20(7):662-70. doi: 10.1111/cns.12259.
Cortistatin (CST)-14, a neuropeptide that is structurally and functionally related to somatostatin-14 (SRIF) binds all five somatostatin receptor subtypes (sst1-sst5). Using in vivo microdialysis and telemetry-based electroencephalographic recordings, we provide the first experimental evidence for anticonvulsive effects of CST-14 in a pilocarpine-induced seizure model in rats and mice and for the involvement of sst2 and sst3 receptors in these anticonvulsant actions of CST-14. Both receptor subtypes are required for the anticonvulsant effects of CST-14 given that co-perfusion of a selective sst2 antagonist (cyanamid15486) or a selective sst3 antagonist (SST3-ODN-8) reversed anticonvulsant effect of CST-14, and this, independently of each other. Next, as the ghrelin receptor has been proposed as a target for the biological effects of CST-14, we used ghrelin receptor knockout mice and their wild type littermates to study the involvement of this receptor in the anticonvulsive actions of CST-14. Our results show a significant decrease in seizure duration in both genotypes when CST-14 treated mice were compared with corresponding control animals receiving only pilocarpine. In addition, this CST-14-induced decrease was comparable in both genotypes. We here thus provide the first evidence that ghrelin receptors are not involved in mediating anticonvulsant actions of CST-14 in vivo.
