1.Phase shifts to light are altered by antagonists to neuropeptide receptors.
Chan RK1, Sterniczuk R2, Enkhbold Y1, Jeffers RT1, Basu P1, Duong B1, Chow SL1, Smith VM1, Antle MC3. Neuroscience. 2016 Apr 16. pii: S0306-4522(16)30065-3. doi: 10.1016/j.neuroscience.2016.04.010. [Epub ahead of print]
The mammalian circadian clock in the suprachiasmatic nucleus (SCN) is a heterogeneous structure. Two key populations of cells that receive retinal input and are believed to participate in circadian responses to light are cells that contain vasoactive intestinal polypeptide (VIP) and gastrin-releasing peptide (GRP). VIP acts primarily through the VPAC2 receptor while GRP works primarily through the BB2 receptor. Both VIP and GRP phase shift the circadian clock in a manner similar to light when applied to the SCN, both in vivo and in vitro, indicating that they are sufficient to elicit photic-like phase shifts. However, it is not known if they are necessary signals for light to elicit phase shifts. Here we test the hypothesis that GRP and VIP are necessary signaling components for photic phase shifting the hamster circadian clock by testing two antagonists for each of these neuropeptides. The BB2 antagonist PD176252 had no effect on light-induced delays on its own, while the BB2 antagonist RC-3095 had the unexpected effect of significantly potentiating both phase delays and advances.
2.Viability of D283 medulloblastoma cells treated with a histone deacetylase inhibitor combined with bombesin receptor antagonists.
Jaeger M1, Ghisleni EC1, Fratini L1, Brunetto AL1,2, Gregianin LJ3, Brunetto AT2, Schwartsmann G1,4, de Farias CB1,2, Roesler R5,6. Childs Nerv Syst. 2016 Jan;32(1):61-4. doi: 10.1007/s00381-015-2963-4. Epub 2015 Nov 20.
PURPOSE: Medulloblastoma (MB) comprises four distinct molecular subgroups, and survival remains particularly poor in patients with Group 3 tumors. Mutations and copy number variations result in altered epigenetic regulation of gene expression in Group 3 MB. Histone deacetylase inhibitors (HDACi) reduce proliferation, promote cell death and neuronal differentiation, and increase sensitivity to radiation and chemotherapy in experimental MB. Bombesin receptor antagonists potentiate the antiproliferative effects of HDACi in lung cancer cells and show promise as experimental therapies for several human cancers. Here, we examined the viability of D283 cells, which belong to Group 3 MB, treated with an HDACi alone or combined with bombesin receptor antagonists.
3.Mechanisms Underlying the Scratching Behavior Induced by the Activation of Proteinase-Activated Receptor-4 in Mice.
Patricio ES1, Costa R1,2, Figueiredo CP1,2, Gers-Barlag K3, Bicca MA1, Manjavachi MN1, Segat GC1, Gentry C3, Luiz AP1, Fernandes ES4,5, Cunha TM6, Bevan S3, Calixto JB1. J Invest Dermatol. 2015 Oct;135(10):2484-91. doi: 10.1038/jid.2015.183. Epub 2015 May 8.
A role for proteinase-activated receptor-4 (PAR-4) was recently suggested in itch sensation. Here, we investigated the mechanisms underlying the pruriceptive actions of the selective PAR-4 agonist AYPGKF-NH2 (AYP) in mice. Dorsal intradermal (i.d.) administration of AYP elicited intense scratching behavior in mice, which was prevented by the selective PAR-4 antagonist (pepducin P4pal-10). PAR-4 was found to be coexpressed in 32% of tryptase-positive skin mast cells, and AYP caused a 2-fold increase in mast cell degranulation. However, neither the treatment with cromolyn nor the deficiency of mast cells (WBB6F1-Kit(W/Wv) mice) was able to affect AYP-induced itch. PAR-4 was also found on gastrin-releasing peptide (GRP)-positive neurons (pruriceptive fibers), and AYP-induced itch was reduced by the selective GRP receptor antagonist RC-3095. In addition, AYP evoked calcium influx in ∼1.5% of cultured DRG neurons also sensitive to TRPV1 (capsaicin) and/or TRPA1 (AITC) agonists.
4.Long-term behavioral effects of neonatal blockade of gastrin-releasing peptide receptors in rats: similarities to autism spectrum disorders.
Merali Z1, Presti-Torres J2, Mackay JC3, Johnstone J3, Du L4, St-Jean A5, Levesque D5, Kent P3, Schwartsmann G6, Roesler R7, Schroder N8, Anisman H9. Behav Brain Res. 2014 Apr 15;263:60-9. doi: 10.1016/j.bbr.2014.01.008. Epub 2014 Jan 23.
Gastrin releasing peptide, the mammalian counterpart of the amphibian peptide, bombesin, has been increasingly implicated in regulating normal brain function as well as in the pathogenesis of psychiatric and/or neurodevelopmental disorders. We have previously shown that the neonatal blockade of the gastrin-releasing peptide receptor (GRPr) in rats produces long-lasting consequences during central nervous system development that are commonly observed in neurodevelopmental disorders such as autism spectrum disorders. The present investigation assessed in further detail, long-term behavioral effects of neonatal GRPr blockade. During postnatal days 1-10, male Wistar rat pups (n=5-10/litter) were injected (subcutaneously) with the GRPr antagonist, RC-3095 (1 mg/kg), or a vehicle (control), twice daily. Following the drug treatment regimen, several behaviors were assessed (starting on postnatal day 14) including specific social behaviors (namely, group huddling characteristics, social interaction, and social approach), restrictive/repetitive and stereotyped behaviors (y-maze, repetitive novel object contact task, observation for stereotypies) and anxiety/fear-related responses (open field, elevated plus maze and contextual fear conditioning).
