pica and Inflammation

Xiaobanxia Decoction (XBXD), a traditional antiemetic formula, is effective in preventing chemotherapy-induced nausea and vomiting (CINV), but its underlying mechanism has not been fully clarified.. To investigate whether the antiemetic mechanisms of XBXD against CINV is associated with the reduction of GSDME-mediated pyroptosis and the alleviation of gastrointestinal inflammation induced by cisplatin.. We established the in vivo pica rat model and the in vitro small intestinal epithelial cell (IEC-6 cell) injury model by cisplatin challenge. The levels of ROS, IL-1β, IL-18, HMGB1 were measured by ELISA. The histopathological changes of gastrointestinal (GI) tissues were examined by HE staining. The expression and localization of GSDME in GI tissues were determined by IHC. The GSDME mRNA expression in GI tissues was determined by RT-PCR. The IEC-6 cell viability was detected by CCK-8. The morphology of IEC-6 cells was observed by optical microscope and scanning electron microscopy. Pyroptosis was examined using Hoechst33342/PI staining. The intracellular ROS levels were measured with the fluorescent probe DCFH-DA. The expression levels of JNK, p-JNK, Bax, Bcl-2, caspase-9, caspase-3 and GSDME in GI tissues and IEC-6 cells were determined by WB.. We found that the cumulative kaolin intake (pica behavior, analogous to emesis) significantly increased in cisplatin-treated rats, accompanied by significant inflammatory pathological changes of GI tissues. XBXD decreased the cumulative kaolin intake and alleviated GI inflammation in cisplatin-treated rats by inhibiting the activation of the ROS/JNK/Bax signaling pathway and by reducing GSDME-mediated pyroptosis. Additionally, cisplatin damaged IEC-6 cells by activating GSDME-dependent pyroptosis. XBXD reduced GSDME-mediated IEC-6 cell pyroptotic death by regulating the ROS/JNK/Bax signaling pathway.. This study suggested that GSDME-mediated pyroptosis greatly contributes to the occurrence of CINV, and suppressing GSDME-mediated pyroptosis is the important antiemetic mechanism of XBXD.

Topics: Animals; Antiemetics; Antineoplastic Agents; bcl-2-Associated X Protein; Caspase 3; Cisplatin; Inflammation; Kaolin; Nausea; Pica; Pyroptosis; Rats; Reactive Oxygen Species; Vomiting

Small molecule phosphodiesterase (PDE) 4 inhibitors have long been known to show therapeutic benefit in various preclinical models of psychiatric and neurologic diseases because of their ability to elevate cAMP in various cell types of the central nervous system. Despite the registration of the first PDE4 inhibitor, roflumilast, for the treatment of chronic obstructive pulmonary disease, the therapeutic potential of PDE4 inhibitors in neurologic diseases has never been fulfilled in the clinic due to severe dose-limiting side effects such as nausea and vomiting. In this study, we describe the detailed pharmacological characterization of GSK356278 [5-(5-((2,4-dimethylthiazol-5-yl)methyl)-1,3,4-oxadiazol-2-yl)-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine], a potent, selective, and brain-penetrant PDE4 inhibitor that shows a superior therapeutic index to both rolipram and roflumilast in various preclinical species and has potential for further development in the clinic for the treatment of psychiatric and neurologic diseases. GSK356278 inhibited PDE4B enzyme activity with a pIC50 of 8.8 and bound to the high-affinity rolipram binding site with a pIC50 of 8.6. In preclinical models, the therapeutic index as defined in a rodent lung inflammation model versus rat pica feeding was >150 compared with 0.5 and 6.4 for rolipram and roflumilast, respectively. In a model of anxiety in common marmosets, the therapeutic index for GSK356278 was >10 versus <1 for rolipram. We also demonstrate that GSK356278 enhances performance in a model of executive function in cynomolgus macaques with no adverse effects, a therapeutic profile that supports further evaluation of GSK356278 in a clinical setting.

Topics: Aminopyridines; Animals; Anti-Anxiety Agents; Behavior, Animal; Benzamides; Callithrix; Cerebral Cortex; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclopropanes; Drug Evaluation, Preclinical; Ferrets; Inflammation; Isoenzymes; Macaca fascicularis; Male; Nootropic Agents; Oxadiazoles; Phosphodiesterase 4 Inhibitors; Pica; Rats; Rolipram; Thiazoles