Cortistatin (neuropeptide)

Cortistatin is a neuropeptide with strong structural similarity to somatostatin (both peptides belong to the same family). It binds to all known somatostatin receptors, and shares many pharmacological and functional properties with somatostatin, including the depression of neuronal activity. However, it also has many properties distinct from somatostatin, such as induction of slow-wave sleep, apparently by antagonism of the excitatory effects of acetylcholine on the cortex, reduction of locomotor activity, and activation of cation selective currents not responsive to somatostatin. == Diagnostic Uses ==

Diagnostic uses for Inflammatory Bowel Disease, Parkinson’s Disease, and Osteoarthritis Cortistatin is a cyclic neuropeptide related tosomatostatin that has emerged as a potential endogenous antiin-flammatory factor based on its production by, and binding to, immune cell. Studies from say the use of Cortistatin treatment significantly help the clinical and histopathologic severity of the inflammatory colitis, stopping body weight loss, diarrhea, and inflammation. There was also a notable increase in the survival rate of the colitic mice. The use of Cortistatin treatment’s therapeutic effect was associated with notable down-regulation of inflammatory and the down-regulation of the Th1-driven autoimmune response. This includes the regulation of a wide spectrum of inflammatory mediators. Also, there was partial involvement of regulatory IL-10-secreting T cells in this therapeutic effect. The most important factor fro this Cortistatin Treatment was that it was therapeutically effective in colitis and it avoided the recurrence of the disease. This work in Cortistatin Treatment identifies cortistatin as a potential antiinflammatory factor with the capacity to deactivate the intestinal inflammatory response and restore mucosal immune tolerance at multiple levels. Another study tested Cortistatin to treat Osteoarthritis on mice. Osteoarthritis is a degenerative joint disease caused by the breakdown of cartilage. The tumor necrosis factor (TNF-α) is known to play a critical role in Osteoarthritis. The results showed that Cortistatin competitively bounded to TNFR1 as well as TNFR2. Cortistatin suppressed the proinflammatory function of TNF-α. Notably, both the spontaneous and surgically induced Osteoarthritis models indicated that deficiency of Cortistatin led to an accelerated Osteoarthritis-like phenotype. Analysis of TNFR1- and TNFR2-knockout mice found that TNFRs might be involved in the protective role of Cortistatin in Osteoarthritis. Mice treated with cortistatin for 3 consecutive days starting 6 days after TNBS administration and the onset of disease quickly reversed the lost body weight. Cortistatin treatment completely removed established colitis and reduced the disease recurrence. Mice treated with cortistatin 12 h after TNBS injection survived and did not suffer disease recurrence after a second administration of TNBS. Another study tested Cortistatin treatments on a preclinical mouse model of Parkinson’s disease induced by acute exposure to the neurotoxin 1-methil-4-phenyl1-1,2,3,6-tetrahydropyridine (MPTP). Researchers observed that treatment with cortistatin mitigated the MPTP-induced loss of dopaminergic neurons, which are in the substantia nigra and their connections to the striatum. The study found that cortistatin administration improved the locomotor activity of mice intoxicated with 1-methil-4-phenyl1-1,2,3,6-tetrahydropyridine. The study also found that cortistatin diminished the presence and activation of glial cells in the affected brain regions of 1-methil-4-phenyl1-1,2,3,6-tetrahydropyridine-treated mice. Cortistatin also reduced the production of immune mediators and also promoted the expression of neurotrophic factors in the striatum of mice. In conclusion, these findings again suggest that cortistatin could emerge as a potential antiinflammatory factor and that cortistatin has neuroprotective properties to regulate the progression of Parkinson’s disease. == Structure ==

Structure of Cortistatin Cortistatin is a 112 amino acid protein that is encoded by the Preprocortistatin Gene, which contains multiple sites at which endoproteolysis may occur. Preprocortistatin is cleaved at the two C-terminal dibasic cleavage sites, KK and KR, to produce rCST14 and rCST29 analogously to SST14 and SST28. The ratio of rCST14:rCST29:preprocortistatin in tissue culture cells was found to be 41:55:4.5 and the ratio of secreted peptides rCST14:rCST29 was shown to be approximately 2:1. The two peptides are produced approximately equally the rCST14 form is preferentially released compared to rCST29. The enzymes used to process cortistatin are not known, but the Mouse AtT-20 Cells has the convertases PC1 and PC2 . PC1 and PC2 have been shown to be highly expressed in the cerebral cortex . The cerebral cortex is a major site of cortistatin expression. PC1 and PC have also been involved in preprosomatostatin processing , making them suitable enzymes for in vivo processing of preprocortistatin. Peptide rCST14 shares 11 of its 14 residues with peptide SST14, which includes the two cysteine residues that supply the peptide cyclic. The Cyclic rCST14 does not possess a particular conformation in solution because it is determined by the circular dichroism and nuclear magnetic resonance spectroscopy. The 29/28mer and 14mer processing products are the relevant peptides from the preprocortistatin gene and preprosomatostatin gene. Within the N-terminal 15/14 residues of the 29/28mer statin peptides, there is a notable similarity between the residues of somatostatin and cortistatin. A finding was that only one residue is conserved between peptides rCST14 and rCST29 in this region in rat and human peptides, and there were no identifiable regions of structurally or functionally homologous amino acids found. The two residues were conserved in the mouse. Also within the N-terminal, the amino acid sequence is highly conserved between somatostatins cloned from different species, with one amino acid difference between human and chicken, and two differences between human and frog clones. The function, if any, that this region plays in cortistatin signaling in vivo is still to be determined, however the significant structural differences may mediate a physiologically relevant differences in peptides CST29 and SST28 function. The 14mer cortistatin and somatostatin peptides are similar in structure, with the rat peptides sharing 11 of their 14 residues. Most of their structural differences lie outside of the cyclic portion of the peptide. In the N-terminal, extra-cyclic residues in CST14 are a Pro for rat and ouse or Asp-Arg-Met-Pro for human and in SST14, there is an Ala-Gly pair in this position. The C-terminal portion of SST14 ends in the amino acid Cys that forms the part of the Cys–Cys loop, whereas an amino acid Lys residue is predicted to be C-terminal of this Cys for all of the known CST14 peptides. However it was not clear if this extracyclic C-terminal CST14 Lys residue is present in a mature peptide because it represents an attractive site for proteolysis by the carboxypeptidase enzymes. Although radio-immunoassay of the HPLC fractions of brain extracts identifies a peptide with a more identical elution profile to CST14 Inside the Cys–Cys loop, for rat and mouse CST14 peptides are identical in sequence, with the human form containing one difference. The difference is that in the human form, Arg follows the N-terminal Cys residue, which is a Lys in the other CST14 peptides. The Cys–Cys loop of CST14 peptides is different from the SST14 peptides because of a Ser residue present two positions N-terminal of the C-terminal Cys, which is a Thr residue in SST14. With that said, a notable number of these structural differences have been shown to have physiological and pharmacological significance for Protein Cortistatin . == Synthesis ==

Synthesis of Cortistatin For Synthesis of Cortistatin is was speculated that cortistatins A and J may derive from cortistatin L or a precursor of the same oxidation state, and Cortistatin L might in turn be derived by C2 oxidation of cortistatin K. Cortistatins A, J, K, and L have been synthesized in parallel processes from like intermediates prepared from a single compound. The cortistatins Synthesis are an identified class of marine natural products characterized by an unusual steroidal skeleton. The unusual steroidal skeleton has been found to be able to inhibit the proliferation of various mammalian cells in culture by an unknown mechanism. ==References==