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17 pages, 1735 KiB

Open AccessArticle

Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain

by Boglárka Kántás, Rita Börzsei, Éva Szőke, Péter Bánhegyi, Ádám Horváth, Ágnes Hunyady, Éva Borbély, Csaba Hetényi, Erika Pintér and Zsuzsanna Helyes

Int. J. Mol. Sci. 2019, 20(24), 6245; https://doi.org/10.3390/ijms20246245 - 11 Dec 2019

Cited by 21 | Viewed by 4640

Abstract

Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst₄ receptor without endocrine actions. Therefore, sst₄ is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging [...] Read more.

Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst₄ receptor without endocrine actions. Therefore, sst₄ is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst₄-linked G-protein activation on stable receptor expressing cells (1 nM to 10 μM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1–C4) bind to the same binding site of the sst₄ receptor with similar interaction energy to high-affinity reference sst₄ agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC₅₀: 37 nM) ligand. In vivo testing of the actions of orally administered C1 and C2 (500 µg/kg) showed that only C1 decreased the resiniferatoxin-induced acute neurogenic inflammatory thermal allodynia and mechanical hyperalgesia significantly. Meanwhile, both of them remarkably reduced partial sciatic nerve ligation-induced chronic neuropathic mechanical hyperalgesia after a single oral administration of the 500 µg/kg dose. These orally active novel sst₄ agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives. Full article

(This article belongs to the Special Issue Somatostatin)

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Review

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38 pages, 2324 KiB

Open AccessReview

Role of Somatostatin in the Regulation of Central and Peripheral Factors of Satiety and Obesity

by Ujendra Kumar and Sneha Singh

Int. J. Mol. Sci. 2020, 21(7), 2568; https://doi.org/10.3390/ijms21072568 - 7 Apr 2020

Cited by 35 | Viewed by 18994

Abstract

Obesity is one of the major social and health problems globally and often associated with various other pathological conditions. In addition to unregulated eating behaviour, circulating peptide-mediated hormonal secretion and signaling pathways play a critical role in food intake induced obesity. Amongst the [...] Read more.

Obesity is one of the major social and health problems globally and often associated with various other pathological conditions. In addition to unregulated eating behaviour, circulating peptide-mediated hormonal secretion and signaling pathways play a critical role in food intake induced obesity. Amongst the many peptides involved in the regulation of food-seeking behaviour, somatostatin (SST) is the one which plays a determinant role in the complex process of appetite. SST is involved in the regulation of release and secretion of other peptides, neuronal integrity, and hormonal regulation. Based on past and recent studies, SST might serve as a bridge between central and peripheral tissues with a significant impact on obesity-associated with food intake behaviour and energy expenditure. Here, we present a comprehensive review describing the role of SST in the modulation of multiple central and peripheral signaling molecules. In addition, we highlight recent progress and contribution of SST and its receptors in food-seeking behaviour, obesity (orexigenic), and satiety (anorexigenic) associated pathways and mechanism. Full article

(This article belongs to the Special Issue Somatostatin)

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27 pages, 1385 KiB

Open AccessReview

Somatostatin Analogs in Clinical Practice: A Review

by Mariana Gomes-Porras, Jersy Cárdenas-Salas and Cristina Álvarez-Escolá

Int. J. Mol. Sci. 2020, 21(5), 1682; https://doi.org/10.3390/ijms21051682 - 29 Feb 2020

Cited by 142 | Viewed by 19691

Abstract

Somatostatin analogs are an invaluable therapeutic option in the diagnosis and treatment of somatotropinomas, thyrotropinomas, and functioning and non-functioning gastroenteropancreatic neuroendocrine tumors. They should also be considered an effective and safe therapeutic alternative to corticotropinomas, gonadotropinomas, and prolactinomas resistant to dopamine agonists. Somatostatin [...] Read more.

Somatostatin analogs are an invaluable therapeutic option in the diagnosis and treatment of somatotropinomas, thyrotropinomas, and functioning and non-functioning gastroenteropancreatic neuroendocrine tumors. They should also be considered an effective and safe therapeutic alternative to corticotropinomas, gonadotropinomas, and prolactinomas resistant to dopamine agonists. Somatostatin analogs have also shown to be useful in the treatment of other endocrine diseases (congenital hyperinsulinism, Graves’ orbitopathy, diabetic retinopathy, diabetic macular edema), non-endocrine tumors (breast, colon, prostate, lung, and hepatocellular), and digestive diseases (chronic refractory diarrhea, hepatorenal polycystosis, gastrointestinal hemorrhage, dumping syndrome, and intestinal fistula). Full article

(This article belongs to the Special Issue Somatostatin)

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12 pages, 207 KiB

Open AccessReview

Treatment of Advanced Hepatocellular Carcinoma with Somatostatin Analogues: A Review of the Literature

by Hendrik Reynaert and Isabelle Colle

Int. J. Mol. Sci. 2019, 20(19), 4811; https://doi.org/10.3390/ijms20194811 - 27 Sep 2019

Cited by 13 | Viewed by 2758

Abstract

Hepatocellular carcinoma, one of the most dreaded complications of cirrhosis, is a frequent cancer with high mortality. Early primary liver cancer can be treated by surgery or ablation techniques, but advanced hepatocellular carcinoma remains a challenge for clinicians. Most of these patients have [...] Read more.

Hepatocellular carcinoma, one of the most dreaded complications of cirrhosis, is a frequent cancer with high mortality. Early primary liver cancer can be treated by surgery or ablation techniques, but advanced hepatocellular carcinoma remains a challenge for clinicians. Most of these patients have underlying cirrhosis, which complicates or even precludes treatment. Therefore, efficacious treatments without major side effects are welcomed. Initial results of treatment of advanced hepatocellular carcinoma with somatostatin analogues were promising, but subsequent trials have resulted in conflicting outcomes. This might be explained by different patient populations, differences in dosage and type of treatment and differences in somatostatin receptor expression in the tumor or surrounding tissue. It has been shown that the expression of somatostatin receptors in the tumor might be of importance to select patients who could benefit from treatment with somatostatin analogues. Moreover, somatostatin receptor expression in hepatocellular carcinoma has been shown to correlate with recurrence, prognosis, and survival. In this review, we will summarize the available data on treatment of primary liver cancer with somatostatin analogues and analyze the current knowledge of somatostatin receptor expression in hepatocellular carcinoma and its possible clinical impact. Full article

(This article belongs to the Special Issue Somatostatin)

21 pages, 2370 KiB

Open AccessReview

Somatostatin as an Active Substance in the Mammalian Enteric Nervous System

by Slawomir Gonkowski and Liliana Rytel

Int. J. Mol. Sci. 2019, 20(18), 4461; https://doi.org/10.3390/ijms20184461 - 10 Sep 2019

Cited by 25 | Viewed by 5992

Abstract

Somatostatin (SOM) is an active substance which most commonly occurs in endocrine cells, as well as in the central and peripheral nervous system. One of the parts of the nervous system where the presence of SOM has been confirmed is the enteric nervous [...] Read more.

Somatostatin (SOM) is an active substance which most commonly occurs in endocrine cells, as well as in the central and peripheral nervous system. One of the parts of the nervous system where the presence of SOM has been confirmed is the enteric nervous system (ENS), located in the wall of the gastrointestinal (GI) tract. It regulates most of the functions of the stomach and intestine and it is characterized by complex organization and a high degree of independence from the central nervous system. SOM has been described in the ENS of numerous mammal species and its main functions in the GI tract are connected with the inhibition of the intestinal motility and secretory activity. Moreover, SOM participates in sensory and pain stimuli conduction, modulation of the release of other neuronal factors, and regulation of blood flow in the intestinal vessels. This peptide is also involved in the pathological processes in the GI tract and is known as an anti-inflammatory agent. This paper, which focuses primarily on the distribution of SOM in the ENS and extrinsic intestinal innervation in various mammalian species, is a review of studies concerning this issue published from 1973 to the present. Full article

(This article belongs to the Special Issue Somatostatin)

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31 pages, 1948 KiB

Open AccessReview

Biological and Biochemical Basis of the Differential Efficacy of First and Second Generation Somatostatin Receptor Ligands in Neuroendocrine Neoplasms

by Federico Gatto, Federica Barbieri, Marica Arvigo, Stefano Thellung, Jessica Amarù, Manuela Albertelli, Diego Ferone and Tullio Florio

Int. J. Mol. Sci. 2019, 20(16), 3940; https://doi.org/10.3390/ijms20163940 - 13 Aug 2019

Cited by 35 | Viewed by 7245

Abstract

Endogenous somatostatin shows anti-secretory effects in both physiological and pathological settings, as well as inhibitory activity on cell growth. Since somatostatin is not suitable for clinical practice, researchers developed synthetic somatostatin receptor ligands (SRLs) to overcome this limitation. Currently, SRLs represent pivotal tools [...] Read more.

Endogenous somatostatin shows anti-secretory effects in both physiological and pathological settings, as well as inhibitory activity on cell growth. Since somatostatin is not suitable for clinical practice, researchers developed synthetic somatostatin receptor ligands (SRLs) to overcome this limitation. Currently, SRLs represent pivotal tools in the treatment algorithm of neuroendocrine tumors (NETs). Octreotide and lanreotide are the first-generation SRLs developed and show a preferential binding affinity to somatostatin receptor (SST) subtype 2, while pasireotide, which is a second-generation SRL, has high affinity for multiple SSTs (SST₅ > SST₂ > SST₃ > SST₁). A number of studies demonstrated that first-generation and second-generation SRLs show distinct functional properties, besides the mere receptor affinity. Therefore, the aim of the present review is to critically review the current evidence on the biological effects of SRLs in pituitary adenomas and neuroendocrine tumors, by mainly focusing on the differences between first-generation and second-generation ligands. Full article

(This article belongs to the Special Issue Somatostatin)

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13 pages, 676 KiB

Open AccessReview

Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future

by Anna Kathrin Stueven, Antonin Kayser, Christoph Wetz, Holger Amthauer, Alexander Wree, Frank Tacke, Bertram Wiedenmann, Christoph Roderburg and Henning Jann

Int. J. Mol. Sci. 2019, 20(12), 3049; https://doi.org/10.3390/ijms20123049 - 22 Jun 2019

Cited by 132 | Viewed by 11473

Abstract

In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and [...] Read more.

In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). Both the PROMID (placebo-controlled, prospective, randomized study in patients with metastatic neuroendocrine midgut tumors) and the CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine tumors) trial showed a statistically significant prolongation of time to progression/progression-free survival (TTP/PFS) upon SSA treatment, compared to placebo. Moreover, the combination of SSA with peptide receptor radionuclide therapy (PRRT) in small intestinal NETs has proven efficacy in the phase 3 neuroendocrine tumours therapy (NETTER 1) trial. PRRT is currently being tested for enteropancreatic NETs versus everolimus in the COMPETE trial, and the potential of SSTR-antagonists in PRRT is now being evaluated in early phase I/II clinical trials. This review provides a synopsis on the pharmacological development of SSAs and their use as antisecretory drugs. Moreover, this review highlights the clinical evidence of SSAs in monotherapy, and in combination with other treatment modalities, as applied to the antiproliferative management of neuroendocrine tumors with special attention to recent high-quality phase III trials. Full article

(This article belongs to the Special Issue Somatostatin)

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21 pages, 2060 KiB

Open AccessReview

Diversity and Function of Somatostatin-Expressing Interneurons in the Cerebral Cortex

by Therese Riedemann

Int. J. Mol. Sci. 2019, 20(12), 2952; https://doi.org/10.3390/ijms20122952 - 17 Jun 2019

Cited by 44 | Viewed by 10810

Abstract

Inhibitory interneurons make up around 10–20% of the total neuron population in the cerebral cortex. A hallmark of inhibitory interneurons is their remarkable diversity in terms of morphology, synaptic connectivity, electrophysiological and neurochemical properties. It is generally understood that there are three distinct [...] Read more.

Inhibitory interneurons make up around 10–20% of the total neuron population in the cerebral cortex. A hallmark of inhibitory interneurons is their remarkable diversity in terms of morphology, synaptic connectivity, electrophysiological and neurochemical properties. It is generally understood that there are three distinct and non-overlapping interneuron classes in the mouse neocortex, namely, parvalbumin-expressing, 5-HT_3A receptor-expressing and somatostatin-expressing interneuron classes. Each class is, in turn, composed of a multitude of subclasses, resulting in a growing number of interneuron classes and subclasses. In this review, I will focus on the diversity of somatostatin-expressing interneurons (SOM⁺ INs) in the cerebral cortex and elucidate their function in cortical circuits. I will then discuss pathological consequences of a malfunctioning of SOM⁺ INs in neurological disorders such as major depressive disorder, and present future avenues in SOM research and brain pathologies. Full article

(This article belongs to the Special Issue Somatostatin)

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13 pages, 1486 KiB

Open AccessReview

Somatostatin and the “Small-For-Size” Liver

by Amelia J. Hessheimer, Lilia Martínez de la Maza, Farah Adel Al Shwely, Arlena Sofía Espinoza, Fabio Ausania and Constantino Fondevila

Int. J. Mol. Sci. 2019, 20(10), 2512; https://doi.org/10.3390/ijms20102512 - 22 May 2019

Cited by 19 | Viewed by 4622

Abstract

“Small-for-size” livers arising in the context of liver resection and transplantation are vulnerable to the effects of increased portal flow in the immediate postoperative period. Increased portal flow is an essential stimulus for liver regeneration. If the rise in flow and stimulus for [...] Read more.

“Small-for-size” livers arising in the context of liver resection and transplantation are vulnerable to the effects of increased portal flow in the immediate postoperative period. Increased portal flow is an essential stimulus for liver regeneration. If the rise in flow and stimulus for regeneration are excessive; however, liver failure and patient death may result. Somatostatin is an endogenous peptide hormone that may be administered exogenously to not only reduce portal blood flow but also offer direct protection to different cells in the liver. In this review article, we describe key changes that transpire in the liver following a relative size reduction occurring in the context of resection and transplantation and the largely beneficial effects that peri-operative somatostatin therapy may help achieve in this setting. Full article

(This article belongs to the Special Issue Somatostatin)

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31 pages, 4737 KiB

Open AccessReview

Molecular and Cellular Mechanisms Underlying Somatostatin-Based Signaling in Two Model Neural Networks, the Retina and the Hippocampus

by Maurizio Cammalleri, Paola Bagnoli and Albertino Bigiani

Int. J. Mol. Sci. 2019, 20(10), 2506; https://doi.org/10.3390/ijms20102506 - 21 May 2019

Cited by 17 | Viewed by 11993

Abstract

Neural inhibition plays a key role in determining the specific computational tasks of different brain circuitries. This functional “braking” activity is provided by inhibitory interneurons that use different neurochemicals for signaling. One of these substances, somatostatin, is found in several neural networks, raising [...] Read more.

Neural inhibition plays a key role in determining the specific computational tasks of different brain circuitries. This functional “braking” activity is provided by inhibitory interneurons that use different neurochemicals for signaling. One of these substances, somatostatin, is found in several neural networks, raising questions about the significance of its widespread occurrence and usage. Here, we address this issue by analyzing the somatostatinergic system in two regions of the central nervous system: the retina and the hippocampus. By comparing the available information on these structures, we identify common motifs in the action of somatostatin that may explain its involvement in such diverse circuitries. The emerging concept is that somatostatin-based signaling, through conserved molecular and cellular mechanisms, allows neural networks to operate correctly. Full article

(This article belongs to the Special Issue Somatostatin)

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