Cisplatin causes over-expression of tachykinin NK1 receptors and increases ERK1/2- and PKA‐ phosphorylation during peak immediate- and delayed-phase emesis in the least shrew (Cryptotis parva) brainstem

Darmani, Nissar A.; Dey, Dilip; Chebolu, Seetha; Amos, Barry; Kandpal, Raj P.; Alkam, Tursun

doi:10.1016/j.ejphar.2012.09.008

Cited by 33 publications

(42 citation statements)

References 30 publications

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“…Although in the present investigation, the mechanism underlying the additive antiemetic efficacy of combined low doses of L-type Ca 2+ channel antagonists with 5-HT 3 R antagonists was not directly studied, the published literature points to their interaction at the signal transduction level involving Ca 2+ (Darmani et al, 2013;Hargreaves et al, 1996;Stathis et al, 2012). In fact the latter in vitro and in vivo evidence Fig.…”

Section: Discussionmentioning

confidence: 76%

“…Our previous studies have demonstrated no gender differences, so both males and females were used. Shrews were housed in groups of 5-10 on a 14:10 light:dark cycle, fed with food and water ad libitum as described previously (Darmani et al, 2013). All the shrews used were 45-60 days old and weighed between 4 and 6 g. All experiments were conducted between 9:00 and 15:00 h in accordance with the NIH guidelines and the Western University IACUC standards.…”

Section: Animalsmentioning

confidence: 99%

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Broad-spectrum antiemetic efficacy of the l-type calcium channel blocker amlodipine in the least shrew (Cryptotis parva)

Zhong

Chebolu

Darmani

2014

Pharmacology Biochemistry and Behavior

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Section: Discussionmentioning

confidence: 76%

Section: Animalsmentioning

confidence: 99%

Broad-spectrum antiemetic efficacy of the l-type calcium channel blocker amlodipine in the least shrew (Cryptotis parva)

Zhong

Chebolu

Darmani

2014

Pharmacology Biochemistry and Behavior

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“…Moreover, protein kinase Cα/βII (PKCα/βII) and ERK1/2 phosphorylation have been observed during cisplatin-induced emesis (Darmani et al, 2013 and 2015). …”

Section: Introductionmentioning

confidence: 99%

Intracellular emetic signaling evoked by the L-type Ca2+ channel agonist FPL64176 in the least shrew (Cryptotis parva)

Zhong

Chebolu

Darmani

2018

European Journal of Pharmacology

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Ca2+ plays a major role in maintaining cellular homeostasis and regulates processes including apoptotic cell death and side-effects of cancer chemotherapy including vomiting. Currently we explored the emetic mechanisms of FPL64176, an L-type Ca2+ channel (LTCC) agonist with maximal emetogenic effect at its 10 mg/kg dose. FPL64176 evoked c-Fos immunoreactivity in shrew brainstem sections containing the vomit-associated nuclei, nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus. FPL64176 also increased phosphorylation of proteins ERK1/2, PKCα/βII and Akt in the brainstem. Moreover, their corresponding inhibitors (PD98059, GF 109203X and LY294002, respectively) reduced FPL64176-evoked vomiting. A 30 min subcutaneous (s.c.) pretreatment with the LTCC antagonist nifedipine (10 mg/kg) abolished FPL64176-elicited vomiting, c-Fos expression, and emetic effector phosphorylation. Ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP3Rs) mediate intracellular Ca2+ release from the sarcoplasmic/endoplasmic reticulum. The RyR antagonist dantrolene (i.p.), or a combination of low doses of nifedipine and dantrolene, but not the IP3R antagonist 2-APB, significantly attenuated FPL64176-induced vomiting. The serotonin type 3 receptor (5-HT3R) antagonist palonosetron (s.c.), the neurokinin 1 receptor (NK1R) antagonist netupitant (i.p.) or a combination of non-effective doses of netupitant and palonosetron showed antiemetic potential against FPL64176-evoked vomiting. Serotonin (5-HT) and substance P immunostaining revealed FPL64176-induced emesis was accompanied by an increase in 5-HT but not SP-immunoreactivity in the dorsomedial subdivision of the NTS. These findings demonstrate that Ca2+ mobilization through LTCCs and RyRs, and subsequent emetic effector phosphorylation and 5-HT release play important roles in FPL64176-induced emesis which can be prevented by 5-HT3R and NK1R antagonists.

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“…[25][26][27] Furthermore, Darmani et al recently reported that cisplatin causes an over-expression of NK 1 receptor proteins in the brainstem, and that this over-expression is closely associated with the peak immediate-and delayed-phase vomiting frequencies in least shrew (Cryptotis parva). 28) Thus, brain penetration is an important determinant of the influence of NK 1 receptor antagonists on the onset and duration of antiemetic responses.…”

Section: Apomorphine-induced Emetic Responsesmentioning

confidence: 99%

Antiemetic Effects of a Potent and Selective Neurokinin-1 Receptor Antagonist, FK886, on Cisplatin- and Apomorphine-Induced Emesis in Dogs

Furukawa

Nakayama

Kikuchi

et al. 2013

Biological & Pharmaceutical Bulletin

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showed rapid onset of antiemetic activity after oral administration. At doses of 0.32 mg/kg or more, a pretreatment time of 0.5 h was sufficient for complete inhibition of apomorphine-induced emetic responses. This fast onset after oral administration was supported by pharmacokinetic data, which demonstrated plasma levels of FK886 after oral administration reached levels similar to those 30 min after intravenous administration. These results suggest that FK886 has excellent antiemetic properties in dogs, and that its rapid-onset and long-lasting properties might make it a promising antiemetic agent.

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Cisplatin causes over-expression of tachykinin NK1 receptors and increases ERK1/2- and PKA‐ phosphorylation during peak immediate- and delayed-phase emesis in the least shrew (Cryptotis parva) brainstem

Cited by 33 publications

References 30 publications

Broad-spectrum antiemetic efficacy of the l-type calcium channel blocker amlodipine in the least shrew (Cryptotis parva)

Broad-spectrum antiemetic efficacy of the l-type calcium channel blocker amlodipine in the least shrew (Cryptotis parva)

Intracellular emetic signaling evoked by the L-type Ca2+ channel agonist FPL64176 in the least shrew (Cryptotis parva)

Antiemetic Effects of a Potent and Selective Neurokinin-1 Receptor Antagonist, FK886, on Cisplatin- and Apomorphine-Induced Emesis in Dogs

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