Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy.

Identified in 1973, somatostatin (SST) is a cyclic hormone peptide with a short biological half-life. Somatostatin receptors (SSTRs) are widely expressed in the whole body, with five subtypes described. The interaction between SST and its receptors leads to the internalization of the ligand-receptor complex and triggers different cellular signaling pathways. Interestingly, the expression of SSTRs is significantly enhanced in many solid tumors, especially gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). Thus, somatostatin analogs (SSAs) have been developed to improve the stability of the endogenous ligand and so extend its half-life. Radiolabeled analogs have been developed with several radioelements such as indium-111, technetium-99 m, and recently gallium-68, fluorine-18, and copper-64, to visualize the distribution of receptor overexpression in tumors. Internal metabolic radiotherapy is also used as a therapeutic strategy (e.g., using yttrium-90, lutetium-177, and actinium-225). With some radiopharmaceuticals now used in clinical practice, somatostatin analogs developed for imaging and therapy are an example of the concept of personalized medicine with a theranostic approach. Here, we review the development of these analogs, from the well-established and authorized ones to the most recently developed radiotracers, which have better pharmacokinetic properties and demonstrate increased efficacy and safety, as well as the search for new clinical indications.

Assessment of change in quality of life, carcinoid syndrome symptoms and healthcare resource utilization in patients with carcinoid syndrome.

BACKGROUND: There is limited information on changes over time in carcinoid syndrome (CS) symptoms and quality of life (QoL). This study assessed change in CS symptoms and QoL in patients treated with somatostatin analogs (SSAs) using the Functional Assessment of Cancer Therapy-General (FACT-G) and Patient-Reported Outcomes Measurement Information System (PROMIS)-29 instruments. METHODS: Patients ≥18 years old with CS symptoms and treated with SSA or non-SSA agents in the United States were recruited through a patient advocacy group to complete a two-part, anonymous online survey. Time point (T) 1 survey was fielded from July-October 2016, and T2 survey followed 6 months later. Clinical characteristics and SSA treatment duration were assessed at T1. FACT-G and PROMIS-29 QoL surveys were administered and CS symptoms were assessed at T1 and T2; proportions of patients not experiencing symptoms were compared by McNemar's test. Healthcare resource utilization (HRU) was assessed for the T1-T2 interval, and mean difference in QoL score from T1 to T2 by SSA duration was calculated. RESULTS: Of 117 participants at T1, 89 (76%) completed the T2 survey and served as the study sample; 11 (13%) were treated with SSAs for > 0-2 years, 37 (42%) for > 2-5 years, and 39 (45%) for > 5 years. A higher proportion of patients at T2 vs. T1 reported the following symptoms as not applicable: diarrhea (16% vs. 7%, p < 0.05), flushing (28% vs. 18%, p < 0.05), wheezing (78% vs 66%, p = 0.008). Most patients (89%) had a physical exam and a mean of 7.2 healthcare provider visits between T1 and T2. Patients treated with SSAs for ≤2 years had a mean positive change of 3.7 in their FACT-G total score between surveys, and 6.0 in an additional set of CS-specific questions. Patients receiving SSAs for > 2 years did not appear to associate with a clinically meaningful improvement in QoL score as assessed by FACT-G between T1 and T2; patients also had no clinically meaningful improvement as assessed by PROMIS-29. CONCLUSIONS: There may be clinically important improvement in QoL as measured by FACT-G in patients in earlier years of receiving SSA, which may not appear in later years of SSA treatment.

Protocolo clínico e diretrizes terapêuticas da acromegalia / Clinical protocol and therapeutic guidelines for acromegaly

INTRODUÇÃO: A acromegalia é uma doença crônica e insidiosa. Em aproximadamente 98% dos casos, é causada por adenomas hipofisários secretores do hormônio de crescimento (GH) ­ os somatotropinomas. Nesses casos, a doença pode ser esporádica ou familiar. Em cerca de 2%, é causada pela hipersecreção eutópica ou ectópica do hormônio liberador de GH (GHRH) e, muito raramente, pela secreção ectópica de GH. O excesso de GH estimula a secreção hepática de insulin-like growth factor-I (IGF-1), que causa a maioria das manifestações clínicas da acromegalia. Os tumores hipofisários produtores de GH se originam de uma proliferação clonal benigna dos somatotrofos (células produtoras de GH localizadas na hipófise anterior), envolvendo mecanismos genéticos, hormonais e de sinalização intracelular. O pico de incidência da acromegalia ocorre entre os 30 e 50 anos; pacientes mais jovens em geral exibem tumores mais agressivos. Em relação ao tamanho, classificam-se como microadenomas (com menos de 1 cm) ou macroadenomas (com 1 cm ou mais), sendo que mais de 70% dos tumores causadores de acromegalia são do segundo tipo 1,2. Os tumores hipofisários exibem grande heterogeneidade de comportamento biológico, podendo apresentar pelo menos 5 subtipos, de acordo com sua estrutura à microscopia eletrônica. . A resposta às diversas modalidades terapêuticas parece depender dessa heterogeneidade e da presença ou interação com receptores específicos dopaminérgicos e somatostatinérgicos e seus diversos subtipos. DIAGNÓSTICO: O diagnóstico de acromegalia é feito pela suspeita clínica, por comprovação de excesso hormonal em exames laboratoriais e por exames de imagem para determinação da causa de excesso de GH. CRITÉRIOS DE INCLUSÃO: Devem ser incluídos neste Protocolo todos os pacientes com diagnóstico de acromegalia confirmado por manifestações clínicas e comprovação laboratorial de excesso hormonal (elevação de IGF-1 e de GH). Exames de imagem (RM ou TC) também são obrigatórios para identificação da causa da doença. TRATAMENTO: O tratamento da acromegalia pode envolver procedimentos cirúrgicos, radioterapia e terapia medicamentosa. Para esta última, estão disponíveis no mercado brasileiro três classes de medicamentos: agonistas da dopamina, análogos da somatostatina e antagonistas do receptor de GH. Para a atuação das duas primeiras classes, é necessária a presença de receptores funcionais específicos no adenoma hipofisário secretor de GH; já a ação do antagonista do receptor de GH independe das características moleculares do adenoma, pois atua bloqueando a ação do GH em nível periférico. Neste Protocolo, incluem-se as duas primeiras classes: agonistas da dopamina (cabergolina) e análogos da somatostatina (octreotida e lanreotida). Um novo medicamento dessa segunda classe farmacológica, o pamoato de pasireotida, foi testado em pacientes com acromegalia demonstrando eficácia similar ou até superior aos análogos de primeira geração30,31. Por ser um medicamento com registro recente no Brasil, a sua incorporação ainda não foi avaliada pela CONITEC. Por sua vez, o antagonista do receptor de GH (pegvisomanto) foi reavaliado recentemente pela CONITEC, por parecer técnico científico (PTC), no qual a sua incorporação não foi aprovada em função das limitações metodológicas dos estudos disponíveis, que trazem incertezas quanto aos benefícios do pegvisomanto na redução dos sinais e sintomas da doença, bem como pelo alto custo do medicamento. Dessa forma, o pegvisomanto não foi incluído neste PCDT. A acromegalia deve ser monitorizada não só para o controle dos sintomas, mas também para a diminuição da mortalidade15. Além do tratamento da doença, os pacientes também devem receber tratamento para as complicações decorrentes, como hipertensão arterial sistêmica, diabete mélito e doenças cardíacas. MONITORIZAÇÃO: A avaliação da resposta ao tratamento depende da modalidade terapêutica adotada. Para avaliação da resposta ao tratamento dos pacientes submetidos a tratamento cirúrgico, devem ser solicitadas dosagens séricas de IGF-1 e GH após sobrecarga de glicose 3-6 meses depois do procedimento. No caso de diabéticos, devem ser realizadas dosagens de IGF-1 e GH basal sem sobrecarga de glicose. Nos pacientes em uso de análogos da somatostatina ou agonista da dopamina a dosagem de GH após sobrecarga de glicose não é útil para monitorar a resposta terapêutica. Nesses casos, dosagens de IGF-1 e de GH devem ser efetuadas. A acromegalia será considerada controlada quando a dosagem de IGF-1 estiver dentro do nível normal para sexo e idade e o nadir de GH após sobrecarga de glicose for abaixo de 1 ng/mL (1). Recentemente, foi recomendado um novo ponto de corte para o GH após sobrecarga de glicose (0,4 ng/mL). Pelo maior embasamento do ponto de corte, 1 ng/mL será o nível utilizado para corresponder à cura . Se houver discrepância entre as dosagens de GH e IGF-1, o julgamento clínico pode ser importante e norteará a conduta. Essa situação pode ocorrer em cerca de 25% dos pacientes e está associada ao uso de ensaio ultrassensíveis de GH e tratamento com análogos de somatostatina. ACOMPANHAMENTO PÓS-TRATAMENTO: Os pacientes com acromegalia devem manter acompanhamento por toda a vida, pela possibilidade de recidiva da doença, com avaliações clínica e laboratorial trimestrais no primeiro ano e, após, anualmente. Essa periodicidade pode ser modificada de acordo com a resposta aos tratamentos e com resultados de exames laboratoriais. As comorbidades associadas (hipertensão, diabete mélito, cardiomiopatia acromegálica) também devem ser avaliadas e acompanhadas no seguimento dos pacientes. DELIBERAÇÃO FINAL: Os membros da CONITEC presentes na reunião do plenário realizada nos dias 5 e 6 de dezembro de 2018, deliberaram, por unanimidade, recomendar a atualização do Protocolo Clínico e Diretrizes Terapêuticas da Acromegalia. O tema será encaminhado para a decisão do Secretário da SCTIE. Foi assinado o Registro de Deliberação nº 403/2018.

Diagnostic approach to subcutaneous nodules in patients with neuroendocrine tumours treated with depot somatostatin analogs: a cross-sectional study.

BACKGROUND: The presence of cutaneous nodules in patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs) receiving depot somatostatin analogs (SSAs) is a diagnostic challenge as differential diagnosis between injection site reactions and metastases is essential. OBJECTIVE: To characterize the clinical, radiological, cytological and histopathological features of subcutaneous nodules in patients with GEP-NETs treated with SSAs. MATERIALS AND METHODS: Retrospective, cross-sectional study of patients with GEP-NETs treated with SSAs in whom subcutaneous nodules were detected on routine abdominal computed tomography (CT) scans. High resolution and colour Doppler ultrasonography was performed. Those patients with inconclusive radiological studies went through fine-needle aspiration cytology (FNAC) and/or biopsy. RESULTS: Twelve patients (five males, seven females) were included (six midgut carcinoid NETs, six pancreatic NETs). Three patients received intramuscular depot octreotide, seven subcutaneous lanreotide, and two both treatments. CT scan findings were nonspecific. Sonography revealed a hyperechoic pattern in recent injections, and a hypoechoic pattern with a characteristic hyperechoic peripheral rim in long-term injections (more than 3 months after injection). On colour Doppler sonography, nodules showed no signs of intralesional vascularity. Fine-needle aspiration cytology (FNAC) was performed in five patients, revealing a characteristic acellular proteinaceous material. Biopsy in four patients showed different reactional infiltrates around the acellular material. CONCLUSIONS: High resolution and colour Doppler ultrasonography may be very useful for the differential diagnosis of subcutaneous nodules in patients with GEP-NETs treated with SSAs. FNAC and a biopsy are useful tests for confirmation of the diagnosis in patients with inconclusive findings. We propose a management algorithm.

Inhibition of Transient Receptor Potential Melastatin 3 ion channels by G-protein ßγ subunits.

Transient receptor potential melastatin 3 (TRPM3) channels are activated by heat, and chemical ligands such as pregnenolone sulphate (PregS) and CIM0216. Here, we show that activation of receptors coupled to heterotrimeric Gi/o proteins inhibits TRPM3 channels. This inhibition was alleviated by co-expression of proteins that bind the ßγ subunits of heterotrimeric G-proteins (Gßγ). Co-expression of Gßγ, but not constitutively active Gαi or Gαo, inhibited TRPM3 currents. TRPM3 co-immunoprecipitated with Gß, and purified Gßγ proteins applied to excised inside-out patches inhibited TRPM3 currents, indicating a direct effect. Baclofen and somatostatin, agonists of Gi-coupled receptors, inhibited Ca2+ signals induced by PregS and CIM0216 in mouse dorsal root ganglion (DRG) neurons. The GABAB receptor agonist baclofen also inhibited inward currents induced by CIM0216 in DRG neurons, and nocifensive responses elicited by this TRPM3 agonist in mice. Our data uncover a novel signaling mechanism regulating TRPM3 channels.

Somatostatin depresses the excitability of subicular bursting cells: Roles of inward rectifier K+ channels, KCNQ channels and Epac.

The hippocampus is a crucial component for cognitive and emotional processing. The subiculum provides much of the output for this structure but the modulation and function of this region is surprisingly under-studied. The neuromodulator somatostatin (SST) interacts with five subtypes of SST receptors (sst1 to sst5 ) and each of these SST receptor subtypes is coupled to Gi proteins resulting in inhibition of adenylyl cyclase (AC) and decreased level of intracellular cAMP. SST modulates many physiological functions including cognition, emotion, autonomic responses and locomotion. Whereas SST has been shown to depress neuronal excitability in the subiculum, the underlying cellular and molecular mechanisms have not yet been determined. Here, we show that SST hyperpolarized two classes of subicular neurons with a calculated EC50 of 0.1 µM. Application of SST (1 µM) induced outward holding currents by primarily activating K+ channels including the G-protein-activated inwardly-rectifying potassium channels (GIRK) and KCNQ (M) channels, although inhibition of cation channels in some cells may also be implicated. SST-elicited hyperpolarization was mediated by activation of sst2 receptors and required the function of G proteins. The SST-induced hyperpolarization resulted from decreased activity of AC and reduced levels of cAMP but did not require the activity of either PKA or PKC. Inhibition of Epac2, a guanine nucleotide exchange factor, partially blocked SST-mediated hyperpolarization of subicular neurons. Furthermore, application of SST resulted in a robust depression of subicular action potential firing and the SST-induced hyperpolarization was responsible for its inhibitory action on LTP at the CA1-subicilum synapses. Our results provide a novel cellular and molecular mechanism that may explain the roles of SST in modulation of subicular function and be relevant to SST-related physiological functions.

Evidence That Endogenous Somatostatin Inhibits Episodic, but Not Surge, Secretion of LH in Female Sheep.

Two modes of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion are necessary for female fertility: surge and episodic secretion. However, the neural systems that regulate these GnRH secretion patterns are still under investigation. The neuropeptide somatostatin (SST) inhibits episodic LH secretion in humans and sheep, and several lines of evidence suggest SST may regulate secretion during the LH surge. In this study, we examined whether SST alters the LH surge in ewes by administering a SST receptor (SSTR) 2 agonist (octreotide) or antagonist [CYN154806 (CYN)] into the third ventricle during an estrogen-induced LH surge and whether endogenous SST alters episodic LH secretion. Neither octreotide nor CYN altered the amplitude or timing of the LH surge. Administration of CYN to intact ewes during the breeding season or anestrus increased LH secretion and increased c-Fos in a subset GnRH and kisspeptin cells during anestrus. To determine if these stimulatory effects are steroid dependent or independent, we administered CYN to ovariectomized ewes. This SSTR2 antagonist increased LH pulse frequency in ovariectomized ewes during anestrus but not during the breeding season. This study provides evidence that endogenous SST contributes to the control of LH secretion. The results demonstrate that SST, acting through SSTR2, inhibits episodic LH secretion, likely acting in the mediobasal hypothalamus, but action at this receptor does not alter surge secretion. Additionally, these data provide evidence that SST contributes to the steroid-independent suppression of LH pulse frequency during anestrus.

Medical therapy for polycystic liver disease.

Introduction Somatostatin analogues and rapamycin inhibitors are two classes of drugs available for the management of polycystic liver disease but their overall impact is not clearly established. This article systematically reviews the literature on the medical management of polycystic liver disease. The outcomes assessed include reduction in liver volume and the impact on quality of life. Methods The English language literature published between 1966 and August 2014 was reviewed from a MEDLINE(®), PubMed, Embase™ and Cochrane Library search. Search terms included 'polycystic', 'liver', 'sirolimus', 'everolimus', 'PCLD', 'somatostatin', 'octreotide', 'lanreotide' and 'rapamycin'. Both randomised trials and controlled studies were included. References of the articles retrieved were also searched to identify any further eligible publications. The studies included were appraised using the Jadad score. Results Seven studies were included in the final review. Five studies, of which three were randomised trials, investigated the role of somatostatin analogues and the results showed a mean reduction in liver volume ranging from 2.9% at six months to 4.95 ±6.77% at one year. Only one randomised study examined the influence of rapamycin inhibitors. This trial compared dual therapy with everolimus and octreotide versus octreotide monotherapy. Liver volume reduced by 3.5% and 3.8% in the control and intervention groups respectively but no statistical difference was found between the two groups (p=0.73). Two randomised trials investigating somatostatin analogues assessed quality of life using SF-36(®). Only one subdomain score improved in one of the trials while two subdomain scores improved in the other with somatostatin analogue therapy. Conclusions Somatostatin analogues significantly reduce liver volumes after six months of therapy but have only a modest improvement on quality of life. Rapamycin inhibitors do not confer any additional advantage.

Parallel Inhibition of Dopamine Amacrine Cells and Intrinsically Photosensitive Retinal Ganglion Cells in a Non-Image-Forming Visual Circuit of the Mouse Retina.

An inner retinal microcircuit composed of dopamine (DA)-containing amacrine cells and melanopsin-containing, intrinsically photosensitive retinal ganglion cells (M1 ipRGCs) process information about the duration and intensity of light exposures, mediating light adaptation, circadian entrainment, pupillary reflexes, and other aspects of non-image-forming vision. The neural interaction is reciprocal: M1 ipRGCs excite DA amacrine cells, and these, in turn, feed inhibition back onto M1 ipRGCs. We found that the neuropeptide somatostatin [somatotropin release inhibiting factor (SRIF)] also inhibits the intrinsic light response of M1 ipRGCs and postulated that, to tune the bidirectional interaction of M1 ipRGCs and DA amacrine cells, SRIF amacrine cells would provide inhibitory modulation to both cell types. SRIF amacrine cells, DA amacrine cells, and M1 ipRGCs form numerous contacts. DA amacrine cells and M1 ipRGCs express the SRIF receptor subtypes sst(2A) and sst4 respectively. SRIF modulation of the microcircuit was investigated with targeted patch-clamp recordings of DA amacrine cells in TH-RFP mice and M1 ipRGCs in OPN4-EGFP mice. SRIF increases K(+) currents, decreases Ca(2+) currents, and inhibits spike activity in both cell types, actions reproduced by the selective sst(2A) agonist L-054,264 (N-[(1R)-2-[[[(1S*,3R*)-3-(aminomethyl)cyclohexyl]methyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]spiro[1H-indene-1,4'-piperidine]-1'-carboxamide) in DA amacrine cells and the selective sst4 agonist L-803,087 (N(2)-[4-(5,7-difluoro-2-phenyl-1H-indol-3-yl)-1-oxobutyl]-L-arginine methyl ester trifluoroacetate) in M1 ipRGCs. These parallel actions of SRIF may serve to counteract the disinhibition of M1 ipRGCs caused by SRIF inhibition of DA amacrine cells. This allows the actions of SRIF on DA amacrine cells to proceed with adjusting retinal DA levels without destabilizing light responses by M1 ipRGCs, which project to non-image-forming targets in the brain.

Delta Cell Hyperplasia in Adult Goto-Kakizaki (GK/MolTac) Diabetic Rats.

Reduced beta cell mass in pancreatic islets (PI) of Goto-Kakizaki (GK) rats is frequently observed in this diabetic model, but knowledge on delta cells is scarce. Aiming to compare delta cell physiology/pathology of GK to Wistar rats, we found that delta cell number increased over time as did somatostatin mRNA and delta cells distribution in PI is different in GK rats. Subtle changes in 6-week-old GK rats were found. With maturation and aging of GK rats, disturbed cytoarchitecture occurred with irregular beta cells accompanied by delta cell hyperplasia and loss of pancreatic polypeptide (PPY) positivity. Unlike the constant glucose-stimulation index for insulin PI release in Wistar rats, this index declined with GK age, whereas for somatostatin it increased with age. A decrease of GK rat PPY serum levels was found. GK rat body weight decreased with increasing hyperglycemia. Somatostatin analog octreotide completely blocked insulin secretion, impaired proliferation at low autocrine insulin, and decreased PPY secretion and mitochondrial DNA in INS-1E cells. In conclusion, in GK rats PI, significant local delta cell hyperplasia and suspected paracrine effect of somatostatin diminish beta cell viability and contribute to the deterioration of beta cell mass. Altered PPY-secreting cells distribution amends another component of GK PI's pathophysiology.

Efficacy and safety of an oral somatostatin DNA vaccine without antibiotic resistance gene in promoting growth of piglets.

This study aimed to evaluate the efficacy and safety of an oral DNA vaccine against somatostatin (SS) (pGS/2SS-asd, encoding two copies of somatostatin genes) mediated by attenuated Salmonella choleraesuis C500 without antibiotic resistance gene on piglets growth. A total of 50 piglets were uniformly divided into five groups. The animals in the first three groups were orally given vaccine in dose of either 5 9 1010, 5 9 109 or 5 9 108 colony-forming units (CFU).The remaining two groups were orally administered with either bacteria C500(containing pVAX-asd plasmid without somatostatin gene) or phosphate buffered saline (PBS) as controls. The results indicated that the vaccine induced SS-specific antibodies in a dose-dependent pattern. Compared with the PBS control, animals in the high-dose group showed lower SS levels and higher growth hormone (GH) levels in sera. Average daily gain of animals in the high dose group was increased by 32.88% and 26.46% during 4 and 8 weeks,respectively. Anti-SS antibodies were positively correlated with either GH levels or average daily gain at week 8 after primary immunization (P < 0.05). Faecal,soil and water samples originating from immunized piglets and surrounding environment were collected. The target gene (the fusion gene GS/2SS) of C500(pGS/2SS-asd) was not detected by PCR amplification in these samples,indicating that the surrounding environment was not contaminated by residual recombinant bacteria. In conclusion, the vaccine without antibiotic resistance gene is attributable to improve growth performance of piglets through an influence on GH secretion. Moreover, the immunization did not contaminate the surrounding environment of animals.

Central actions of somatostatin-28 and oligosomatostatin agonists to prevent components of the endocrine, autonomic and visceral responses to stress through interaction with different somatostatin receptor subtypes.

Somatostatin was discovered four decades ago and since then its physiological role has been extensively investigated, first in relation with its inhibitory effect on growth hormone secretion but soon it expanded to extrapituitary actions influencing various stressresponsive systems. Somatostatin is expressed in distinct brain nuclei and binds to five somatostatin receptor subtypes which are also widely expressed in the brain with a distinct distribution pattern. The last few years witnessed the discovery of highly selective peptide somatostatin receptor agonists and antagonists representing valuable tools to delineate the respective pathways of somatostatin signaling. Here we review the centrally mediated actions of somatostatin and related selective somatostatin receptor subtype agonists to influence the endocrine, autonomic, and visceral components of the stress response and basal behavior as well as thermogenesis.

Somatostatin antagonist potentiates haloperidol-induced catalepsy in the aged rat.

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 aging and somatostatin deficiency. In this study, the intensity of haloperidol-induced catalepsy was examined in young and aged rats with decreased brain somatostatinergic activity. Catalepsy was measured using the bar test. The inhibition of the brain somatostatin activity was simulated by i.c.v. administration of a somatostatin antagonist, cyclosomatostatin. The drug potentiated the haloperidol-induced catalepsy in aged but not young rats. This action of cyclosomatostatin was inhibited by a somatostatin receptor agonist, octreotide. The results suggest that aging and somatostatin deficiency may be of pathogenic relevance for extrapyramidal signs in PD.

Effect of immunization with a recombinant cholera toxin B subunit/somatostatin fusion protein on immune response and growth hormone levels in mice.

Somatostatin (SS) is a hormone that inhibits growth hormone secretion. Cholera toxin B subunit (CTB) is a widely used adjuvant to improve the immunogenicity of co-administrated antigen. To block the growth hormone-inhibiting effect of SS, a fusion gene of CTB and SS was constructed and expressed in Escherichia coli. The purified CTB/SS fusion protein polymerized into a biologically active pentamer required for CTB binding to the GM1 ganglioside receptor. Immunization with the CTB/SS protein induced specific immunity against CTB and SS in mice. The serum growth hormone of the CTB/SS-treated mice increased by 29 % (P < 0.05) compared with the control. The results indicated that the CTB/SS fusion protein was effective in inducing immune response against SS as well as elevating the growth hormone level.

The putative somatostatin antagonist cyclo-somatostatin has opioid agonist effects in gastrointestinal preparations.

AIMS: Specificity of receptor antagonists used is crucial for clarifying physiological/pathophysiological roles of the respective endogenous agonist. We studied the effects (somatostatin antagonist and possibly other actions) of cyclo-somatostatin (CSST), a putative somatostatin receptor antagonist on the guinea-pig small intestine, a preparation where somatostatin causes inhibition of nerve-mediated contractions. MAIN METHODS: In isolated organ experiments, half-maximal cholinergic "twitch" contractions of the guinea-pig small intestine were evoked or tonic contractions of the rat stomach fundus strip (in the presence of physostigmine) were elicited by electrical field stimulation. The effects of somatostatin (somatostatin-14), CSST, naloxone, as well as of direct smooth muscle stimulants were examined. KEY FINDINGS: Somatostatin (10 nM-1 µM) caused transient inhibition of the twitch contraction, in a naloxone-insensitive manner. Surprisingly, CSST (0.3-1 µM) also inhibited twitch contractions (more than 50% reduction at 1 µM). This effect was prevented by the opioid receptor antagonist naloxone. Responses to acetylcholine or histamine were not or only minimally inhibited by CSST (up to 3 µM). CSST (0.3 µM in the absence or 1-10 µM in the presence of naloxone) failed to inhibit the effect of somatostatin. The SST(2) receptor antagonist CYN-154806 (3 µM) attenuated the effect of somatostatin and failed to evoke naloxone-sensitive inhibition of the twitch response. The naloxone-sensitive inhibitory effect of CSST on cholinergic contractions was also confirmed in the rat stomach fundus preparation. SIGNIFICANCE: Cyclo-somatostatin exerts opioid agonist activity in the two preparations tested, while it does not behave as a somatostatin-receptor antagonist in the guinea-pig intestine.

The anxiolytic effects of somatostatin following intra-septal and intra-amygdalar microinfusions are reversed by the selective sst2 antagonist PRL2903.

Somatostatin (SST) is a polypeptide with two biological isoforms (SST14, and SST28), and five SST receptor subtypes (sst1-5). Together, they mediate a number of neural and hormonal functions. Recently, we found that intracerebroventricular (ICV), intra-amygdalar, and intra-septal microinfusions of SST14, SST28, and a selective sst2 receptor agonist L-779976 all produced anxiolytic-like effects in the elevated plus-maze, a widely used animal model of anxiety. The receptor specificity of these anxiolytic-like effects, however, has not been conclusively established. Accordingly, the anxiolytic effects of SST in the elevated plus-maze were assessed following intra-septal or intra-amygalar microinfusions of 1) SST (1.5µg per hemisphere), 2) the highly selective sst2 receptor antagonist PRL2903 (1.5µg per hemisphere), or 3) the combination of SST and PRL2903 (each 1.5µg per hemisphere). Antagonism of the anxiolytic effects of SST in the plus-maze by PRL2903 should result in open-arm exploration that is equivalent to that of 4) vehicle-injected control rats. Both intra-septal and intra-amygdalar microinfusions of SST produced anxiolytic effects in the elevated plus-maze, consistent with results found previously after ICV microinfusions (see Engin et al., 2008; Engin and Treit, 2009; Yeung et al., 2011). More importantly, infusion of PRL2903 completely reversed the anxiolytic effects of SST in both the amygdala and the septum. These results show that somatostatin's anxiolytic effects are mediated by sst2 receptors contained in the amygdala and septum of the rat brain.

Bak Foong Pills induce an analgesic effect by inhibiting nociception via the somatostatin pathway in mice.

Dysmenorrhoea, defined as cramping pain in the lower abdomen occurring before or during menstruation, affects, to varying degrees, up to 90% of women of child-bearing age. We investigated whether BFP (Bak Foong Pills), a traditional Chinese medicine treatment for dysmenorrhoea, possesses analgesic properties. Results showed that BFP was able to significantly reduce pain responses following subchronic treatment for 3 days, but not following acute (1 h) treatment in response to acetic acid-induced writhing in C57/B6 mice. The analgesic effect was not due to inhibition of COX (cyclo-oxygenase) activity, evidenced by the lack of inhibition of prostacyclin and PGE2 (prostaglandin E2) production. Molecular analysis revealed that BFP treatment modulated the expression of a number of genes in the spinal cord of mice subjected to acetic acid writhing. RT-PCR (reverse transcription-PCR) analysis of spinal cord samples showed that both sst4 (somatostatin receptor 4) and sst2 receptor mRNA, but not µOR (µ-opiate receptor) and NK1 (neurokinin-1) receptor mRNA, were down-regulated following BFP treatment, thus implicating somatostatin involvement in BFP-induced analgesia. Administration of c-som (cyclo-somatostatin), a somatostatin antagonist, prior to acetic acid-induced writhing inhibited the analgesic effect. Thus subchronic treatment with BFP has anti-nociceptive qualities mediated via the somatostatin pathway.

Suppression of ANP secretion by somatostatin through somatostatin receptor type 2.

Somatostatin is a cyclic-14 amino acid peptide which mainly distributed in digestive system and brain. Somatostatin receptor (SSTR) is a G-protein coupled receptor and all five SSTR subtypes are expressed in cardiomyocytes. The aim of this study was to investigate the effect of somatostatin on atrial natriuretic peptide (ANP) secretion and its signaling pathway. Somatostatin (0.01 and 0.1nM) decreased ANP secretion in isolated beating rat atrium in a dose-dependent manner. But atrial contractility and translocation of extracellular fluid were not changed. Somatostatin-induced decrease in ANP secretion was significantly attenuated by the pretreatment with CYN 154806 (SSTR type 2 antagonist; 0.1µM), but not by BIM 23056 (SSTR type 5 antagonist; 0.1µM) and urantide (urotensin II receptor antagonist; 0.1µM). When pretreated with an agonist for SSTR type 2 (Seglitide, 0.1nM) and SSTR type 5 (L 817818, 0.1nM), only Seglitide reduced ANP secretion similar to that of somatostatin. The suppressive effect of somatostatin on ANP secretion was attenuated by the pretreatment with an inhibitor for adenylyl cyclase (MDL-12330A, 5µM) or protein kinase A (KT 5720, 0.1µM). In diabetic rat atria, the suppressive effect of somatostatin on ANP secretion and concentration was attenuated. Real time-PCR and western blot shows the decreased level of SSTR type 2 mRNA and protein in diabetic rat atria. These data suggest that somatostatin decreased ANP secretion through SSTR type 2 and an attenuation of suppressive effect of somatostatin on ANP secretion in diabetic rat atria is due to a down-regulation of SSTR type 2.

Naloxone decreases the inhibitory effect of somatostatin on GH release induced by cigarette smoking in man.

To establish whether somatostatin (SRIH) exerts its inhibitory effect on the nicotine-induced release of GH by interacting with an opioid pathway, normal volunteers were treated with naloxone during (2 no-filter) cigarettes smoking and with SRIH. Nicotine significantly increased serum GH levels about 3.5 fold. Naloxone alone did not change GH rise induced by cigarette smoking. The stimulatory effect of GH by nicotine was completely blocked by SRIH. In the presence of both SRIH and naloxone, GH levels rose 1.5 fold in response to nicotine. Since naloxone only partially reversed the inhibiting action of SRIH, only a partial involvement of opioid peptides in SRIH action might be supposed. Alternatively, SRIH and naloxone-sensitive opiates might produce this inhibiting effect on GH rise in response to cigarette smoking through independent pathways.

Reduced somatostatin in subgenual anterior cingulate cortex in major depression.

Converging evidence suggests a central role for dysfunction of the subgenual anterior cingulate cortex (sgACC) in the pathophysiology of major depressive disorder (MDD). Underlying mechanisms may include altered GABAergic function. Expression of somatostatin (SST), an inhibitory neuropeptide localized to a subset of GABA neurons, has been shown to be lower in the dorsolateral prefrontal cortex of male MDD subjects. Here, to investigate whether alterations in SST may contribute to sgACC dysfunction in MDD, and whether the alterations display sex-specificity, we measured sgACC SST at the mRNA and precursor peptide levels in a large cohort of subjects with MDD. SST mRNA levels were analyzed by quantitative PCR (qPCR) in the postmortem sgACC from male (n=26) and female (n=25) subjects with MDD and sex-matched subjects with no psychiatric diagnosis (n=51). Prepro-SST protein levels were assessed in a subset of subjects (n=42 pairs) by semi-quantitative Western blot. The mRNA expression of SST was significantly reduced by 38% in female subjects and by 27% in male subjects with MDD. The characteristic age-related decline in SST expression was observed in control (Pearson R=-0.357, p=0.005) but not MDD (R=-0.104, p=0.234) subjects, as low expression was detected across ages in MDD subjects. Protein expression was similarly reduced by 19% in both MDD groups, and findings were more robust in female (p=0.0056) than in males (p=0.0373) compared to respective controls. In conclusion, low SST represents a robust pathological finding in MDD. Specifically, alterations in SST signaling and/or SST-bearing GABA neurons may represent a critical pathophysiological entity that contributes to sgACC dysfunction and that matches to the high female vulnerability to develop MDD.