palonosetron and Disease-Models--Animal

Nausea, vomiting, and renal injury are the common adverse effects associated with cisplatin. Cisplatin is excreted via the multidrug and toxin release (MATE) transporter, and the involvement of the MATE transporter in cisplatin-induced kidney injury has been reported. The MATE transporter is also involved in the excretion of ondansetron, but the effects of 5-HT

Topics: Acute Kidney Injury; Aged; Animals; Benzimidazoles; Cisplatin; Disease Models, Animal; Female; Granisetron; Humans; Kidney; Male; Mice; Middle Aged; Nausea; Ondansetron; Organic Cation Transport Proteins; Palonosetron; Renal Elimination; Retrospective Studies; Serotonin 5-HT3 Receptor Antagonists; Vomiting

Since westernized diet-induced insulin resistance is a risk factor in Alzheimer's disease (AD) development, and lipopolysaccharide (LPS) coexists with amyloid β (Aβ)1-42 in these patients, our AD novel model was developed to resemble sporadic AD by injecting LPS into high fat/fructose diet (HFFD)-fed rats. The neuroprotective potential of palonosetron and/or methyllycaconitine, 5-HT3 receptor and α7 nAChR blockers, respectively, was evaluated after 8 days of daily administration in HFFD/LPS rats. All regimens improved histopathological findings and enhanced spatial memory (Morris Water Maze); however, palonosetron alone or with methyllycaconitine promoted animal performance during novel object recognition tests. In the hippocampus, all regimens reduced the expression of glial fibrillary acidic protein and skewed microglia M1 to M2 phenotype, indicated by the decreased M1 markers and the enhanced M2 related parameters. Additionally, palonosetron and its combination regimen downregulated the expression of ASC/TMS1, as well as levels of inflammasome downstream molecules and abated cleaved caspase-1, interleukin (IL)-1β, IL-18 and caspase-11. Furthermore, ACh and 5-HT were augmented after being hampered by the insult. Our study speculates that blocking 5-HT3 receptor using palonosetron overrides methyllycaconitine to combat AD-induced neuroinflammation and inflammasome cascade, as well as to restore microglial function in a HFFD/LPS novel model for sporadic AD.

Topics: Aconitine; Alzheimer Disease; Amyloid beta-Peptides; Animals; CARD Signaling Adaptor Proteins; Cognition; Diet, Western; Disease Models, Animal; Hippocampus; Humans; Inflammasomes; Inflammation; Insulin Resistance; Interleukin-18; Lipopolysaccharides; Microglia; Palonosetron; Peptide Fragments; Pyroptosis; Rats; Receptors, Serotonin, 5-HT3; Risk Factors; Spatial Memory

Serotonin type 3 (5-HT(3)) receptor partial agonists are being targeted as potential new drugs for the treatment of irritable bowel syndrome (IBS). Two new chemical series bearing indazole and indole cores have exhibited nanomolar binding affinity for the h5-HT(3)A receptor. A range of partial agonist activities in HEK cells heterologously expressing the h5-HT(3)A receptor were measured for the indazole series. Excellent 5-HT(3) receptor selectivity, favorable in vitro metabolic stability and CYP inhibition properties, and good oral in vivo potency in the murine von Bezold-Jarisch reflex model is exemplified thereby indicating the series to have potential utility as improved IBS agents.

Topics: Animals; Cell Line; Disease Models, Animal; Humans; Imidazoles; Indoles; Irritable Bowel Syndrome; Mice; Microsomes, Liver; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Agonists

Palonosetron is the only 5-HT(3) receptor antagonist approved for the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), the endogenous ligand acting preferentially on neurokinin-1 (NK-1) receptors, not serotonin (5-HT), is the dominant mediator of delayed emesis. However, palonosetron does not bind to the NK-1 receptor. Recent data have revealed cross-talk between the NK-1 and 5HT(3) receptor signaling pathways; we postulated that if palonosetron differentially inhibited NK-1/5-HT(3) cross-talk, it could help explain its efficacy profile in delayed emesis. Consequently, we evaluated the effect of palonosetron, granisetron, and ondansetron on SP-induced responses in vitro and in vivo. NG108-15 cells were preincubated with palonosetron, granisetron, or ondansetron; antagonists were removed and the effect on serotonin enhancement of SP-induced calcium release was measured. In the absence of antagonist, serotonin enhanced SP-induced calcium-ion release. After preincubation with palonosetron, but not ondansetron or granisetron, the serotonin enhancement of the SP response was inhibited. Rats were treated with cisplatin and either palonosetron, granisetron, or ondansetron. At various times after dosing, single neuronal recordings from nodose ganglia were collected after stimulation with SP; nodose ganglia neuronal responses to SP were enhanced when the animals were pretreated with cisplatin. Palonosetron, but not ondansetron or granisetron, dose-dependently inhibited the cisplatin-induced SP enhancement. The results are consistent with previous data showing that palonosetron exhibits distinct pharmacology versus the older 5-HT(3) receptor antagonists and provide a rationale for the efficacy observed with palonosetron in delayed CINV in the clinic.

Topics: Action Potentials; Animals; Antiemetics; Antineoplastic Agents; Calcium; Cell Line; Cisplatin; Disease Models, Animal; Dose-Response Relationship, Drug; Isoquinolines; Male; Neurokinin-1 Receptor Antagonists; Neurons; Nodose Ganglion; Palonosetron; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin 5-HT3 Receptor Antagonists; Substance P; Vomiting

Cancer chemotherapy drugs, such as cisplatin, potently produce nausea and vomiting. Acute effects of these treatments are partly controlled by antiemetic drugs, but the delayed effects (>24 h), especially nausea, are more difficult to treat. It is unknown what brain pathways produce this delayed sickness. Our prior data show that brain Fos expression is increased for at least 48 h after cisplatin treatment in the rat, a nonvomiting species. Here, we extend these observations by using house musk shrews (Suncus murinus), a species with an emetic response. Compared with saline injection, cisplatin treatment (30 mg/kg ip) induced Fos expression in hindbrain areas known to play a role in the generation of emesis, the dorsal motor nucleus (DMN), the area postrema, and the nucleus of the solitary tract (NTS), for up to 48 h. Cisplatin also stimulated Fos expression in the parabrachial nucleus (PBN) of the midbrain and the central nucleus of the amygdala (CeA) for at least 48 h after treatment. When animals were pretreated with the antiemetic palonosetron, a long-term serotonin type 3 (5-HT(3)) receptor antagonist, cisplatin-induced Fos expression was significantly attenuated in the NTS, DMN, and CeA at 6 h but not at 48 h. These results indicate that cisplatin activates a neural system that includes the dorsal vagal complex and forebrain in the musk shrew, which is partially suppressed by a 5-HT(3) receptor antagonist. Our findings suggest the existence of an extensive neural system that could be targeted to reduce nausea, vomiting, and malaise in cancer patients receiving chemotherapy.

Topics: Amygdala; Animals; Antiemetics; Antineoplastic Agents; Area Postrema; Brain; Cisplatin; Disease Models, Animal; Female; Isoquinolines; Mesencephalon; Palonosetron; Proto-Oncogene Proteins c-fos; Quinuclidines; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Shrews; Solitary Nucleus; Time Factors; Vomiting