Cyclosomatostatin

IC50: N/A

Cyclosomatostatin is a non-selective somatostatin receptor antagonist.

Somatostatin is a regulatory hormone or tissue factor playing an inhibitory role in the normal regulation of several organ systems including hypothalamus and pituitary gland, central nervous system, gastrointestinal tract as well as pancreas.

In vitro: Although cyclosomatostatin could fully block the effect of somatostatin, it only partially reversed the inhibitory effect of cortistatin, a new anti-inflammatory peptide. This observation was further supported by the fact that cyclosomatostatin reversed the antiinfl ammatory effect of somatostatin and octreotide in vitro completely, while only partially reversing the effect of cortistatin [1].

In vivo: The effect of cortistatin was found to be dose dependent, with dose as low as 0.5 nmol (50 μg/kg) being partially protective. In contrast, cyclosomatostatin, somatostatin as well as octreotide were not protective [1].

Clinical trial: As the precursor of cyclosomatostatin, somatostatin has already been introduced in the clinical practice in some macrophage populations. Somatostatin shows protective effect in certain inflammatory disorders including pancreatitis and liver injury. However, somatostatin is not protective in lethal septic shock [1].

Reference:
[1] Gonzalez-Rey E,Chorny A,Robledo G,Delgado M.  Cortistatin, a new antiinflammatory peptide with therapeutic effect on lethal endotoxemia. J Exp Med.2006 Mar 20;203(3):563-71.

Cyclosomatostatin- and haloperidol-induced catalepsy in Wistar rats: Differential responsiveness to sleep deprivation.[Pubmed:29990558]

Neurosci Lett. 2018 Sep 25;684:72-77.

Total sleep deprivation (SD) has been found to mitigate motor dysfunctions in Parkinson's disease. Apparently, the similar sensitivity of an animal model for parkinsonism would support the model's validity. Recently, we described catalepsy induced in Wistar rats by somatostatin antagonist, Cyclosomatostatin (cSST); this model simulates such a disease-associated abnormality as a fall in brain somatostatin levels. To evaluate the similarity between the cSST model and Parkinson's disease, we assessed here the responsiveness of cSST-induced catalepsy to 1-h and 3-h SD. In parallel, the influence of SD on catalepsy induced by a dopamine receptor antagonist, haloperidol, was examined. It was found that the short-term SD failed to influence cataleptic responses of both types (sleep deprived rats and undisturbed ones displayed a similar duration of immobility, p>0.05). By contrast, 3-h SD suppressed (p<0.01) cSST-induced catalepsy, however, enhanced (p<0.01) cataleptic response to haloperidol. Thus, the anti-cataleptic effect of SD appears to be cSST-specific. These findings support the validity of the cSST-induced catalepsy in Wistar rats as a model for parkinsonian motor dysfunctions.

Somatostatin antagonist induces catalepsy in the aged rat.[Pubmed:23274508]

Psychopharmacology (Berl). 2013 May;227(2):273-6.

RATIONALE: Extrapyramidal motor signs are the major features of Parkinson's disease (PD). It is unclear whether there is a link between these signs and such PD-associated factors as brain somatostatin deficiency and aging. OBJECTIVES: This study aimed to examine whether an inhibition of the brain somatostatin system can initiate catalepsy, a model of extrapyramidal disorders, in young and aged rats. METHODS: The animals of 100-110 and 540-560 days of age were used. Catalepsy was measured using the bar test. The inhibition of the brain somatostatin activity was simulated by intracerebroventricular administration of a somatostatin antagonist, Cyclosomatostatin. RESULTS: Cyclosomatostatin dose-dependently induced catalepsy in aged, but not in young rats. The cataleptic response was reversed by a somatostatin analog, octreotide. CONCLUSIONS: The combination of aging and brain somatostatin deficiency can lead to catalepsy in rats. Since both factors are frequently observed in PD patients, the present results might be of relevance for pathogenesis of extrapyramidal signs in this disease.

Somatostatin inhibits activation of dorsal cutaneous primary afferents induced by antidromic stimulation of primary afferents from an adjacent thoracic segment in the rat.[Pubmed:18640104]

Brain Res. 2008 Sep 10;1229:61-71.

To investigate the effect of somatostatin on the cross-excitation between adjacent primary afferent terminals in the rats, we recorded single unit activity from distal cut ends of dorsal cutaneous branches of the T10 and T12 spinal nerves in response to antidromic stimulation of the distal cut end of the T11 dorsal root in the presence and absence of somatostatin and its receptor antagonist applied to the receptive field of the recorded nerve. Afferent fibers were classified based upon their conduction velocity. Mean mechanical thresholds decreased and spontaneous discharge rates increased significantly in C and Adelta but not Abeta fibers of the T10 and T12 spinal nerves in both male and female rats following antidromic electrical stimulation (ADES) of the dorsal root from adjacent spinal segment (DRASS) indicating cross-excitation of thin fiber afferents. The cross-excitation was not significantly different between male and female rats. Microinjection of somatostatin into the receptive field of recorded units inhibited the cross-excitation. This inhibitory effect, in turn, was reversed by the somatostation receptor antagonist cyclo-somatostatin (c-SOM). Application of c-SOM alone followed by ADES of DRASS significantly decreased the mechanical thresholds and increased the discharge rates of C and Adelta fibers, indicating that endogenous release of somatostatin plays a tonic inhibitory role on the cross-excitation between peripheral nerves. These results suggest that somatostatin could inhibit the cross-excitation involved in peripheral hyperalgesia and have a peripheral analgesic effect.

The putative somatostatin antagonist, cyclo-(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr[BZL]), may act as potent antiproliferative agonist.[Pubmed:12182954]

Peptides. 2002 Aug;23(8):1503-6.

The cyclic somatostatin (SST) analogue, cyclo-(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr[BZL]) (cSSTA), has been widely used as somatostatin antagonist. In the human neuroblastoma cell line SH-SY5Y the cyclopeptide acts as a somatostatin receptor agonist. Similar to SST, cSSTA inhibits cell proliferation, activates the protein tyrosine phosphatase SHP-2, and stimulates the activity of mitogen-activated protein kinase. These results suggest that in SH-SY5Y neuroblastoma cells somatostatin receptors may exist which exhibit altered antagonist binding properties.

Somatostatin antagonist analog increases GH, insulin, and glucagon release in the rat.[Pubmed:6129618]

Peptides. 1982 Sep-Oct;3(5):811-4.

We have utilized the relative structural simplicity of several short, cyclic, highly active somatostatin analogs in the search for competitive antagonists of somatostatin. During an attempted synthesis of cyclo(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr), catalytic hydrogenation of the protected peptide intermediate unexpectedly gave cyclo [7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)] in which the benzyl protecting group on Thr could not be removed even upon prolonged treatment under standard conditions. Injection of this new peptide into the rat completely blocked the inhibitory effects of exogenous somatostatin on GH, insulin, and glucagon release. Indeed, in fasted rats, basal hepatic portal insulin and glucagon levels were significantly increased after analog treatment. Plasma GH levels in Nembutal-anesthetized and stimulated rats were also increased after injection of the analog. These results provide strong evidence that endogenous somatostatin exerts local tonic control of pituitary and pancreatic secretions. The availability of a somatostatin anatagonist should be of considerable value in elucidating the roles of somatostatin in these and many other physiological processes.