Mecamylamine (Inversine®): an old antihypertensive with new research directions

Shytle, R. Douglas; Penny, Ellen; Silver, Archie A.; Goldman, J; Sanberg, Paul R.

doi:10.1038/sj.jhh.1001416

Cited by 74 publications

(61 citation statements)

References 33 publications

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“…Schuller et al have also shown that the nitrosamine 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (NNK) that is present in tobacco smoke similarly stimulates lung cancer growth through nicotinic receptors and MAPK-dependent mechanisms (23,26). Although treatment with nicotinic receptor antagonists can have significant effects on blood pressure (27), muscarinic receptor antagonists are better tolerated and are widely used for treatment of chronic obstructive pulmonary disease (COPD; ref. 28) and overactive bladder (29).…”

Section: Introductionmentioning

confidence: 99%

M3 Muscarinic Receptor Antagonists Inhibit Small Cell Lung Carcinoma Growth and Mitogen-Activated Protein Kinase Phosphorylation Induced by Acetylcholine Secretion

et al. 2007

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The importance of acetylcholine as a neurotransmitter in the nervous system is well established, but little is yet known about its recently described role as an autocrine and paracrine hormone in a wide variety of nonneuronal cells. Consistent with the expression of acetylcholine in normal lung, small cell lung carcinoma (SCLC) synthesize and secrete acetylcholine, which acts as an autocrine growth factor through both nicotinic and muscarinic cholinergic mechanisms. The purpose of this study was to determine if interruption of autocrine muscarinic cholinergic signaling has potential to inhibit SCLC growth. Muscarinic receptor (mAChR) agonists caused concentration-dependent increases in intracellular calcium and mitogen-activated protein kinase (MAPK) and Akt phosphorylation in SCLC cell lines. The inhibitory potency of mAChR subtype-selective antagonists and small interfering RNAs (siRNAs) on acetylcholine-increased intracellular calcium and MAPK and Akt phosphorylation was consistent with mediation by M3 mAChR (M3R). Consistent with autocrine acetylcholine secretion stimulating MAPK and Akt phosphorylation, M3R antagonists and M3R siRNAs alone also caused a decrease in basal levels of MAPK and Akt phosphorylation in SCLC cell lines. Treatment of SCLC cells with M3R antagonists inhibited cell growth both in vitro and in vivo and also decreased MAPK phosphorylation in tumors in nude mice in vivo. Immunohistochemical staining of SCLC and additional cancer types showed frequent coexpression of acetylcholine and M3R. These findings suggest that M3R antagonists may be useful adjuvants for treatment of SCLC and, potentially, other cancers. [Cancer Res 2007;67(8):3936-44]

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Section: Introductionmentioning

confidence: 99%

M3 Muscarinic Receptor Antagonists Inhibit Small Cell Lung Carcinoma Growth and Mitogen-Activated Protein Kinase Phosphorylation Induced by Acetylcholine Secretion

et al. 2007

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“…This indicates that in some respects, nicotine exerts a longer-term effect similar to an antagonist. Mecamylamine has a range of action across different doses, including cognitive enhancement (Mihailescu et al 1998;Giniatullin et al 2000;Buccafusco and Terry, 2002;Shytle et al 2002). …”

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confidence: 99%

Placebo-Controlled Pilot Trial of Mecamylamine for Treatment of Autism Spectrum Disorders

Arnold

Aman

Hollway

et al. 2012

Journal of Child and Adolescent Psychopharmacology

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Objective: To explore possible benefits of a nicotinic acetylcholine receptor (nAChR) agent for autistic symptoms based on postmortem observation of nAChR abnormalities (deficient a4b2 nAChRs, excess a7 nAChRs) in brains of patients with autism. Method: Mecamylamine, because of its safety record in children with other disorders, was chosen for this first exploration. Twenty children with autism spectrum disorder age 4-12 years were randomly assigned for 14 weeks to placebo (n = 8) or mecamylamine (n = 12) in ascending fixed doses: 0.5 mg/day for 6 weeks, 2.5 mg for 2 weeks, then 5 mg/day for 6 weeks. Improvement was rated by a blinded independent evaluator. Because of small sample, data analysis was descriptive. Results: Eighteen participants (10 mecamylamine, 8 placebo) completed the study. All doses were well tolerated; the only side effect of note was constipation (50% compared with 25% of placebo group). Three children had clinically nonsignificant electrocardiographic QT prolongation. Both groups showed modest to moderate improvement, but differences between groups were negligible. On the primary outcome measure, the Ohio Autism Clinical Impressions Scale, 90% of the active treatment group showed improvement at some point (but only 40% sustained it), compared with 62% on placebo. Of the four in active treatment that sustained improvement, three had a maximum dose of 0.13-0.15 mg/kg/day, while those who regressed had doses ‡ 0.18 mg/kg/day. Graphed means suggested better outcome with lower mg/kg and longer medication duration. Four parents spontaneously reported reduced hyperactivity and irritability and better verbalization and continued mecamylamine at their own expense. Conclusion: Mecamylamine appeared to be safe, but not very effective in autism. The suggestion of better results at lower doses and longer exposure warrants consideration for future trials. The next step would be exploration of a more specific a4b2 nAChR agonist, such as varenicline.

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“…Previous work has also suggested the participation of nicotinic acetylcholine receptors (nAChR) (22,23) in the detection of nicotine by the peripheral taste system. The role of nAChRs in taste responses to nicotine is particularly intriguing because mecamylamine, a broad spectrum nAChR antagonist that has been used as a smoking cessation aid (24), reduces the sensitivity to peripheral sensory stimulation by cigarette smoke (25). However, hexamethonium (22), a different nAChR antagonist, inhibits taste responses to nicotine as well as to other tastants, suggesting that the inhibition resulting from nAChR antagonism may be unspecific.…”

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confidence: 99%

Nicotine activates TRPM5-dependent and independent taste pathways

Oliveira‐Maia

Stapleton-Kotloski²,

Lyall

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The orosensory responses elicited by nicotine are relevant for the development and maintenance of addiction to tobacco products. However, although nicotine is described as bitter tasting, the molecular and neural substrates encoding the taste of nicotine are unclear. Here, rats and mice were used to determine whether nicotine activates peripheral and central taste pathways via TRPM5-dependent mechanisms, which are essential for responses to other bitter tastants such as quinine, and/or via nicotinic acetylcholine receptors (nAChRs). When compared with wild-type mice, Trpm5 ؊/؊ mice had reduced, but not abolished, chorda tympani (CT) responses to nicotine. In both genotypes, lingual application of mecamylamine, a nAChR-antagonist, inhibited CT nerve responses to nicotine and reduced behavioral responses of aversion to this stimulus. In accordance with these findings, rats were shown to discriminate between nicotine and quinine presented at intensity-paired concentrations. Moreover, rat gustatory cortex (GC) neural ensemble activity could also discriminate between these two bitter tastants. Mecamylamine reduced both behavioral and GC neural discrimination between nicotine and quinine. In summary, nicotine elicits taste responses through peripheral TRPM5-dependent pathways, common to other bitter tastants, and nAChR-dependent and TRPM5-independent pathways, thus creating a unique sensory representation that contributes to the sensory experience of tobacco products. chorda tympani ͉ gustatory cortex ͉ neurophysiology ͉ preference ͉ discrimination

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Mecamylamine (Inversine®): an old antihypertensive with new research directions

Cited by 74 publications

References 33 publications

M3 Muscarinic Receptor Antagonists Inhibit Small Cell Lung Carcinoma Growth and Mitogen-Activated Protein Kinase Phosphorylation Induced by Acetylcholine Secretion

M3 Muscarinic Receptor Antagonists Inhibit Small Cell Lung Carcinoma Growth and Mitogen-Activated Protein Kinase Phosphorylation Induced by Acetylcholine Secretion

Placebo-Controlled Pilot Trial of Mecamylamine for Treatment of Autism Spectrum Disorders

Nicotine activates TRPM5-dependent and independent taste pathways

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