The Gerbil Elevated Plus-maze II Anxiolytic-like Effects of Selective Neurokinin NK1 Receptor Antagonists

Varty, Geoffrey B.

doi:10.1016/s0893-133x(02)00313-5

Cited by 106 publications

(64 citation statements)

References 23 publications

(41 reference statements)

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“…Thus, the IC 50 for HEK 293 fibroblast cells was approximately three times higher than the IC 50 for tumor cells, 30 as occurring in the melanoma cell lines studied here. Indeed, in the host, aprepitant exerts beneficial effects in a dose-dependent manner, such as antiemetic, 29 antidepressant, 27 anxiolytic, 28 anti-inflammatory, 42 analgesic, 43 hepatoprotector 42 and neuroprotector. 44 In summary, we describe for the first time the presence of several isoforms of the NK-1 receptor in MEL HO, COLO 858 and COLO 679 human malignant melanoma cell lines.…”

Section: Nk-1 Receptor and Aprepitant In Melanomas M Muñ Oz Et Almentioning

confidence: 99%

“…Until now, this drug has been used as an antidepressant, anxiolytic and antiemetic. [27][28][29] Despite this, we have recently reported that aprepitant is a broad-spectrum antitumor drug. 30 However, to our knowledge, the presence of NK-1 receptors in melanomas and whether the antitumor action of the NK-1 receptor antagonist aprepitant is exerted on human malignant melanomas are unknown.…”

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confidence: 99%

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The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines

Muñoz

Rosso

Robles‐Frías

et al. 2010

Laboratory Investigation

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Melanoma, the most deadly form of skin cancer, is aggressive and resistant to current therapies. It has been previously reported that the substance P and neurokinin-1 (NK-1) receptor antagonists induce cell proliferation and cell inhibition, respectively, in human melanoma cell lines. Aprepitant is a selective high-affinity antagonist of the human NK-1 receptor. Until now, this drug has been used as an anxiolytic, antidepressant and antiemetic. Moreover, the antitumor action of aprepitant has been previously reported. However, the presence of NK-1 receptors in human melanomas and whether the antitumor action of the NK-1 receptor antagonist aprepitant is exerted on human malignant melanomas have not been previously described. The aims of this study are to show the presence of NK-1 receptors in human malignant melanomas and the antitumoral action of aprepitant against several human melanoma cell lines. Immunoblot analysis was used to determine the presence of NK-1 receptors in human melanoma cell lines, and immunohistochemistry was used to demonstrate NK-1 receptors in human melanoma samples. We performed an in vitro study of the cytotoxicity of the NK-1 receptor antagonist aprepitant on human melanoma cell lines. A coulter counter was used to determine viable cell numbers, followed by application of the tetrazolium compound MTS. The DAPI method was applied to demonstrate apoptosis. We observed that NK-1 receptors were present in all the melanoma samples studied as well as in human melanoma cell lines. We also showed that melanoma cell lines expressed mRNA for the NK-1 receptor. Moreover, after using a knockdown method, we showed that NK-1 receptors are involved in the viability of tumor cells. In this study, we also report that aprepitant, at 10-60 mM concentrations, elicits cell growth inhibition in a concentration-dependent manner in all melanoma cell lines studied, that the specific antitumor action of aprepitant occurs through the NK-1 receptor and that melanoma cell death is due to apoptosis. These findings show for the first time that the NK-1 receptor may be a promising new target and that the NK-1 receptor antagonist aprepitant could be a candidate as a new antitumor drug in the treatment of human melanoma.

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Section: Nk-1 Receptor and Aprepitant In Melanomas M Muñ Oz Et Almentioning

confidence: 99%

mentioning

confidence: 99%

The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines

Muñoz

Rosso

Robles‐Frías

et al. 2010

Laboratory Investigation

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“…60 min or 120 min (NK1 antagonists) before behavioral testing in a volume of 10 ml/kg body weight. Doses and pretreatment times were selected based on internally generated pharmacokinetic and pharmacodynamic data, as well as from previously published reports in which in vivo efficacy was demonstrated (Porsolt et al, 1977a, b;Varty et al, 2002bVarty et al, , 2003. Oral administration of compounds was used whenever possible in attempt to validate the model using the anticipated clinical route of administration.…”

Section: Drugsmentioning

confidence: 99%

“…To determine whether NK1 receptor antagonists would exhibit antidepressant-like effects in the gerbil FST, three prototypic compounds (eg MK-869, L-733060, CP-122721) that have previously been reported to exhibit behavioral effects (Duffy et al, 2002;Varty et al, 2002bVarty et al, , 2003 were tested in the gerbil forced swim and LMA tests. MK-869 (0.1-30 mg/kg) dose dependently reduced immobility times, with a minimum effective dose of 1 mg/kg (F(6, 93) ¼ 26.257; po0.05) (Figure 3a).…”

Section: Effects Of Nk1 Antagonistsmentioning

confidence: 99%

“…Interestingly, the gerbil NK1 receptor shares greater sequence homology with the human NK1 receptor as compared to the rat or mouse counterpart (Beresford et al, 1991;Gitter et al, 1991), thereby making the gerbil an ideal species to test the behavioral effects of NK1 receptor antagonists. Moreover, NK1 antagonists (eg MK-869, L-733060) have been shown preclinically to exhibit anxiolytic-like effects in gerbils in several different animal models including the elevated plus maze, fear conditioning, social interaction, and shock-induced foot tapping (Ballard et al, 2001;File et al, 2001;Gentsch et al, 2002;Rupniak et al, 2003;Varty et al, 2002b); and more recently, antidepressant-like effects in the tail suspension test (Varty et al, 2003). Consistent with these reports, genetic deletion of the NK1 receptor in mice resulted in anxiolytic and antidepressant effects in the elevated plus maze, novelty suppressed feeding model and the FST (Santarelli et al, 2001;Rupniak et al, 2001), providing additional support for the hypothesis that the NK1 receptor may be an important target for antidepressant/anxiolytic therapy.…”

Section: Introductionmentioning

confidence: 99%

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Behavioral and Pharmacological Validation of the Gerbil Forced-Swim Test: Effects of Neurokinin-1 Receptor Antagonists

Wallace-Boone

Newton

Wright

et al. 2007

Neuropsychopharmacol

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Several studies have suggested that neurokinin-1 (NK1) receptor antagonists may have therapeutic potential as novel antidepressant drugs. To test these compounds preclinically, gerbils have become one of the preferred species in that they demonstrate close NK1 receptor homology with humans and bind NK1 antagonists with higher affinity than rats and mice. The intent of the present study was to determine whether the forced-swim test (FST), one of the most commonly used animal tests of antidepressant-like activity, could be adapted for use with the gerbil. Critical factors in the establishment of this assay included swim tank diameter, weight, and sex of the animals tested. Pharmacological validation of the FST using standard antidepressant compounds (eg fluoxetine, paroxetine, desipramine) resulted in decreased immobility time during the test, indicative of an antidepressant-like effect. Similar to results reported for the rat and mouse FST, the antipsychotic drug haloperidol increased immobility, whereas the psychostimulant, amphetamine decreased immobility, and anxiolytic drugs (eg buspirone) had no effect. Investigation into the locomotor effects of all compounds tested was consistent with previous reports in other species, with the exception of paroxetine, which produced hyperactivity at therapeutically effective doses in gerbils. In addition to standard antidepressants, NK1 antagonists (L-733060, MK-869, and CP-122721) all reduced immobility in the gerbil FST without affecting locomotor activity. Overall, these results suggest that the gerbil is an ideal species for use in the FST, and that this paradigm may have predictive validity for identifying novel antidepressant compounds.

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Molecular Effects of Antidepressant Treatments

Sokoloff¹

2005

Biology of Depression

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The Gerbil Elevated Plus-maze II Anxiolytic-like Effects of Selective Neurokinin NK1 Receptor Antagonists

Cited by 106 publications

References 23 publications

The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines

The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines

Behavioral and Pharmacological Validation of the Gerbil Forced-Swim Test: Effects of Neurokinin-1 Receptor Antagonists

Molecular Effects of Antidepressant Treatments

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