Somatostatin receptor subtype 4 activation is involved in anxiety and depression-like behavior in mouse models

Scheich, Bálint; Gaszner, Balázs; Kormos, Viktória; László, Kristóf; Ádori, Csaba; Borbély, Éva; Hajna, Zsófia; Tékus, Valéria; Bölcskei, Kata; Ábrahám, István M.; Pintér, Erika; Szolcsányi, Janós; Helyes, Zsuzsanna

doi:10.1016/j.neuropharm.2015.09.021

Cited by 45 publications

(48 citation statements)

References 63 publications

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“…In the case of SST INs, we observed a significantly higher percentage of co-localisation with SSTR4 in L4 1 3 than in other layers. It was shown that SST INs and SSTR4 play regulatory roles in anxiety and mild stress-induced responses in the amygdala (Li et al 2013;Scheich et al 2016Scheich et al , 2017. Thus, it can be supposed that, in the barrel cortex, SSTR4 may be involved in fear-induced plastic changes, as our research has indicated the involvement of SST INs in this type of plasticity (Cybulska-Klosowicz et al 2013).…”

Section: Discussionmentioning

confidence: 52%

Somatostatin receptors (SSTR1-5) on inhibitory interneurons in the barrel cortex

et al. 2019

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Inhibitory interneurons in the cerebral cortex contain specific proteins or peptides characteristic for a certain interneuron subtype. In mice, three biochemical markers constitute non-overlapping interneuron populations, which account for 80-90% of all inhibitory cells. These interneurons express parvalbumin (PV), somatostatin (SST), or vasoactive intestinal peptide (VIP). SST is not only a marker of a specific interneuron subtype, but also an important neuropeptide that participates in numerous biochemical and signalling pathways in the brain via somatostatin receptors (SSTR1-5). In the nervous system, SST acts as a neuromodulator and neurotransmitter affecting, among others, memory, learning, and mood. In the sensory cortex, the co-localisation of GABA and SST is found in approximately 30% of interneurons. Considering the importance of interactions between inhibitory interneurons in cortical plasticity and the possible GABA and SST co-release, it seems important to investigate the localisation of different SSTRs on cortical interneurons. Here, we examined the distribution of SSTR1-5 on barrel cortex interneurons containing PV, SST, or VIP. Immunofluorescent staining using specific antibodies was performed on brain sections from transgenic mice that expressed red fluorescence in one specific interneuron subtype (PV-Ai14, SST-Ai14, and VIP-Ai14 mice). SSTRs expression on PV, SST, and VIP interneurons varied among the cortical layers and we found two patterns of SSTRs distribution in L4 of barrel cortex. We also demonstrated that, in contrast to other interneurons, PV cells did not express SSTR2, but expressed other SSTRs. SST interneurons, which were not found to make chemical synapses among themselves, expressed all five SSTR subtypes.

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Section: Discussionmentioning

confidence: 52%

Somatostatin receptors (SSTR1-5) on inhibitory interneurons in the barrel cortex

et al. 2019

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“…Its actions include increased locomotor activity (Viollet et al, 2008), memory and learning (Vecsei and Widerlov, 1988; Gastambide et al, 2009), and sleep (Steiger, 2007; Xu et al, 2015), as well as changes in autonomic cardiovascular and gastric functions (e.g., sympatho-inhibitory effect with lowering of heart rate and blood pressure, stimulation of gastric secretion and transit) (Brown and Taché, 1981; Martinez et al, 2000; Bou Farah et al, 2016), immune functions (Gonzalez-Rey et al, 2015) and ingestive behaviors (e.g., increased feeding and drinking; Stengel et al, 2015). Of importance in relation with stress, injection of somatostatin into the brain influences emotional processes exerting anxiolytic and anti-depressant effects (Engin and Treit, 2009; Scheich et al, 2016). However, in contrast to other anxiolytics such as benzodiazepines, somatostatin exerts pro-cognitive effects under healthy (Liguz-Lecznar et al, 2016) and Alzheimer's disease conditions (Epelbaum et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response

Stengel

Taché

2017

Front. Neurosci.

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Corticotropin-releasing factor (CRF) is the hallmark brain peptide triggering the response to stress and mediates—in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA) axis—other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a broader anti-stress effect by blunting the endocrine, autonomic, behavioral (with a focus on food intake) and visceral gastrointestinal motor responses through the involvement of distinct somatostatin receptor subtypes.

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“…Therefore, small molecule nonpeptide analogs were synthesized for drug developmental purposes. J-2156 is a 1-naphthalenesulfonylamino-peptidomimetic, which is a sst 4 "superagonist" [31], having potent anti-inflammatory, analgesic and antidepressant actions [15,[32][33][34][35].NNC26-9100 and L-803,087 are compounds of other structurally distinct classes of highly selective small molecule sst 4 agonists [36,37], and they are widely used as reference materials [9]. In previous studies, NNC26-9100 and L-803,087 were effective in models of different neurological diseases, such as Alzheimer's disease and epilepsy [38,39], but they are not suitable for oral administration, which presumably contributed to them not being candidates for drug development.Here, we report the sst 4 receptor binding and activation of novel small molecule pyrrolo-pyrimidine molecules (Compound 1 = C1, Compound 2 = C2, Compound 3 = C3, Compound4 = C4) ( Figure 1) [40], as well as their effects in an acute neurogenic inflammatory hyperalgesia model mimicking peripheral and central sensitization mechanisms and in a translationally relevant chronic neuropathic pain model.…”

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confidence: 99%

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

Kántás

Börzsei

Szöke

et al. 2019

IJMS

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Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst 4 receptor without endocrine actions. Therefore, sst 4 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 sst 4 -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 sst 4 receptor with similar interaction energy to high-affinity reference sst 4 agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC 50 : 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 sst 4 agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives. strongly limited by its diverse effects and rapid degradation and consequently short elimination half-life (<3 min) [9]. However, stable and potent synthetic analogs could be potential analgesic candidates.A wide range of somatostatin effects are mediated via five inhibitory G-protein-coupled receptor subtypes (GPCRs) [10,11] which have seven transmembrane domains (TMDs). They are divided into two classes on the basis of their phylogeny, structural homologies and pharmacological properties. The somatotropin release-inhibiting factor 1 (SRIF1) receptor class involves sst 2 , sst 3 and sst 5 mediating important endocrine actions of somatostatin (e.g., inhibition of growth hormone, insulin, glucagon secretion), and the SRIF2 class includes sst 1 and sst 4 [10]. It is well known that sst 4 receptor is present in the dorsal root ganglia cells and spinal cord dorsal horn, and can also mediate analgesic effects along with the δ-opioid receptor [12,13]. We provided several lines of evidence that the broad anti-inflammatory, antinociceptive and anti-hyperalgesic effects of somatostatin are mediated by the sst 4 receptor without influencing endocrine functions [1,4,[14][15][16][17]. Therefore, the sst 4 receptor has become a well-established novel drug target and the development of sst 4 agonists has recently been included in the scope of several pharmaceutical companies [13,[18][19][20][21][22][23].Several hepta-and octapeptide somatostatin analogs, such as 25], were shown to induce anti-inflammatory and antinociceptive effects [13,[26][27][28][29], predominantly via sst 4 activ...

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Somatostatin receptor subtype 4 activation is involved in anxiety and depression-like behavior in mouse models

Cited by 45 publications

References 63 publications

Somatostatin receptors (SSTR1-5) on inhibitory interneurons in the barrel cortex

Somatostatin receptors (SSTR1-5) on inhibitory interneurons in the barrel cortex

Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response

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

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