Program Official

Principal Investigator

Nissar A
Darmani
Awardee Organization

Western University Of Health Sciences
United States

Fiscal Year
2021
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Substance P tachykininergic NK1 receptor emetic signal transduction pathways

Acute (day 1) and delayed (days 3-7) nausea and vomiting are the feared and debilitating side-effects of cancer therapeutics such as cisplatin. In the absence of prophylactic therapy, nearly all patients vomit from cisplatin-like drugs. These side-effects must be controlled to maintain patient compliance and quality of life. However, the cost of the best antiemetic regimen (Akynzeo) containing a serotonin 5-HT3 receptor (5-HT3R) antagonist and a substance P (SP) neurokinin NK1 receptor (NK1R)-antagonist is over $500 per pill in the USA and can only protect up to 80% of patients. Cisplatin-like drugs release serotonin (5-HT) and SP which stimulate their corresponding cell membrane-bound extracellular emetic receptors in both the gut and brainstem emetic loci to evoke vomiting. Of critical importance to this application, major gaps exist in the emesis field in that there is a lack of understanding of i) activation of emetic intracellular signaling mechanisms following stimulation of discussed emetic receptors; and ii) whether potential point(s) of signal convergence (e.g. Ca2+) exist among diverse emetic signaling cascades. As new cancer therapeutics are being developed, it becomes vital that we define shared fundamental intracellular signaling molecules that underlie induction of emesis versus cancer suppression, so that we can develop safer cancer therapeutics without emesis, which will save time, effort and research dollars. Although the emetic signaling cascade(s) downstream of NK1R remain unknown, we recently have identified the intracellular 5-HT3R emetic cascade [17,18]. Unlike the narrow-spectrum 5-HT3R blockers, NK1R antagonists exhibit broad-spectrum antiemetic efficacy against diverse causes of vomiting. Thus, a full understanding of NK1R emetic signals may allow us to identify unique intracellular signal(s) whose antagonists/inhibitors would suppress cancer formation without vomiting. Indeed, SP via NK1Rs plays a central role in the development of CNS tumors and its corresponding antagonists possess cancer chemotherapeutic potential [15,16]. Furthermore, our preliminary data strongly suggest that the phospholipase C (PLC) cascade and its interaction with the Akt/GSK-3aβ pathway are major players in NK1R-evoked vomiting. The purpose of this application is to take a broad approach involving pharmacological, behavioral, calcium imaging, immunohistochemical and Western blot techniques, to delineate the NK1R-mediated emetic signal transduction involving activation of phospholipase C and corresponding downstream signals including the role of extracellular Ca2+ influx and intracellular Ca2+ release in vomiting, as well as whether the evoked emesis can be modulated by the Akt/GSK-3αβ pathway. Not only there is scant information regarding intracellular mechanisms of emesis, but also there is an urgent and unmet need for alternative broad-spectrum antiemetics for protection of all cancer patients suffering from vomiting caused by cytotoxic chemotherapeutics. The findings of this proposal will introduce not only several new highly potent classes of antiemetics, but may also help reveal the potential of universal antiemetics, which will lower the cost of prevention of nausea and vomiting in diverse patient communities suffering from cancer, HIV or gastrointestinal disorders.

Publications

  • Zhong W, Darmani NA. The Contribution of Phospholipase C in Vomiting in the Least Shrew (Cryptotis Parva) Model of Emesis. Frontiers in pharmacology. 2021 Sep 10;12:736842. doi: 10.3389/fphar.2021.736842. eCollection 2021. PMID: 34566660
  • Belkacemi L, Sun Y, Darmani NA. Evidence for Bell-Shaped Dose-Response Emetic Effects of Temsirolimus and Analogs: The Broad-Spectrum Antiemetic Efficacy of a Large Dose of Temsirolimus Against Diverse Emetogens in the Least Shrew (Cryptotis parva). Frontiers in pharmacology. 2022 Apr 4;13:848673. doi: 10.3389/fphar.2022.848673. eCollection 2022. PMID: 35444553
  • Zhong W, Chebolu S, Darmani NA. Intracellular emetic signaling cascades by which the selective neurokinin type 1 receptor (NK1R) agonist GR73632 evokes vomiting in the least shrew (Cryptotis parva). Neurochemistry international. 2019 Jan;122:106-119. Epub 2018 Nov 16. PMID: 30453005
  • Chung DJ, Madison GP, Aponte AM, Singh K, Li Y, Pirooznia M, Bleck CKE, Darmani NA, Balaban RS. Metabolic design in a mammalian model of extreme metabolism, the North American least shrew (Cryptotis parva). The Journal of physiology. 2022 Feb;600(3):547-567. Epub 2021 Dec 13. PMID: 34837710
  • Zhong W, Chebolu S, Darmani NA. Intracellular emetic signaling evoked by the L-type Ca2+ channel agonist FPL64176 in the least shrew (Cryptotis parva). European journal of pharmacology. 2018 Sep 5;834:157-168. Epub 2018 Jun 30. PMID: 29966616
  • Belkacemi L, Darmani NA. Dopamine receptors in emesis: Molecular mechanisms and potential therapeutic function. Pharmacological research. 2020 Nov;161:105124. Epub 2020 Aug 16. PMID: 32814171
  • Zhong W, Darmani NA. The pivotal role of glycogen synthase kinase 3 (GSK-3) in vomiting evoked by specific emetogens in the least shrew (Cryptotis parva). Neurochemistry international. 2020 Jan;132:104603. Epub 2019 Nov 15. PMID: 31738972
  • Zhong W, Chebolu S, Darmani NA. Central and peripheral emetic loci contribute to vomiting evoked by the Akt inhibitor MK-2206 in the least shrew model of emesis. European journal of pharmacology. 2021 Jun 5;900:174065. Epub 2021 Mar 26. PMID: 33775646
  • Darmani NA, Henry DA, Zhong W, Chebolu S. Ultra-low doses of the transient receptor potential vanilloid 1 agonist, resiniferatoxin, prevents vomiting evoked by diverse emetogens in the least shrew (Cryptotis parva). Behavioural pharmacology. 2020 Feb;31(1):3-14. PMID: 31503071
  • Belkacemi L, Zhong W, Darmani NA. Signal transduction pathways involved in dopamine D2 receptor-evoked emesis in the least shrew (Cryptotis parva). Autonomic neuroscience : basic & clinical. 2021 Jul;233:102807. Epub 2021 Apr 10. PMID: 33865060
  • Zhong W, Shahbaz O, Teskey G, Beever A, Kachour N, Venketaraman V, Darmani NA. Mechanisms of Nausea and Vomiting: Current Knowledge and Recent Advances in Intracellular Emetic Signaling Systems. International journal of molecular sciences. 2021 May 28;22. (11). PMID: 34071460
  • Zhong W, Darmani NA. Intracellular vomit signals and cascades downstream of emetic receptors: Evidence from the least shrew (Cryptotis parva) model of vomiting. Remedy open access. 2017;2. Epub 2017 Oct 31. PMID: 30854512
  • Zhong W, Darmani NA. Role of PI3K/Akt/GSK-3 Pathway in Emesis and Potential New Antiemetics. Journal of cellular signaling. 2020 Dec;1(4):155-159. PMID: 33426544
  • Zhong W, Darmani NA. The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Cryptotis parva). Frontiers in pharmacology. 2021 Apr 29;12:647021. doi: 10.3389/fphar.2021.647021. eCollection 2021. PMID: 33995059
  • Darmani NA, Belkacemi L, Zhong W. Δ9-THC and related cannabinoids suppress substance P- induced neurokinin NK1-receptor-mediated vomiting via activation of cannabinoid CB1 receptor. European journal of pharmacology. 2019 Dec 15;865:172806. Epub 2019 Nov 15. PMID: 31738934