Comparison of the Anti-inflammatory Properties of Two Nicotinic Acetylcholine Receptor Ligands, Phosphocholine and pCF3-diEPP.

Activation of nicotinic acetylcholine receptors (nAChRs) expressed by innate immune cells can attenuate pro-inflammatory responses. Silent nAChR agonists, which down-modulate inflammation but have little or no ionotropic activity, are of outstanding clinical interest for the prevention and therapy of numerous inflammatory diseases. Here, we compare two silent nAChR agonists, phosphocholine, which is known to interact with nAChR subunits α7, α9, and α10, and pCF3-N,N-diethyl-N'-phenyl-piperazine (pCF3-diEPP), a previously identified α7 nAChR silent agonist, regarding their anti-inflammatory properties and their effects on ionotropic nAChR functions. The lipopolysaccharide (LPS)-induced release of interleukin (IL)-6 by primary murine macrophages was inhibited by pCF3-diEPP, while phosphocholine was ineffective presumably because of instability. In human whole blood cultures pCF3-diEPP inhibited the LPS-induced secretion of IL-6, TNF-α and IL-1ß. The ATP-mediated release of IL-1ß by LPS-primed human peripheral blood mononuclear leukocytes, monocytic THP-1 cells and THP-1-derived M1-like macrophages was reduced by both phosphocholine and femtomolar concentrations of pCF3-diEPP. These effects were sensitive to mecamylamine and to conopeptides RgIA4 and [V11L; V16D]ArIB, suggesting the involvement of nAChR subunits α7, α9 and/or α10. In two-electrode voltage-clamp measurements pCF3-diEPP functioned as a partial agonist and a strong desensitizer of classical human α9 and α9α10 nAChRs. Interestingly, pCF3-diEPP was more effective as an ionotropic agonist at these nAChRs than at α7 nAChR. In conclusion, phosphocholine and pCF3-diEPP are potent agonists at unconventional nAChRs expressed by monocytic and macrophage-like cells. pCF3-diEPP inhibits the LPS-induced release of pro-inflammatory cytokines, while phosphocholine is ineffective. However, both agonists signal via nAChR subunits α7, α9 and/or α10 to efficiently down-modulate the ATP-induced release of IL-1ß. Compared to phosphocholine, pCF3-diEPP is expected to have better pharmacological properties. Thus, low concentrations of pCF3-diEPP may be a therapeutic option for the treatment of inflammatory diseases including trauma-induced sterile inflammation.

Nicotine for the treatment of Tourette's syndrome.

Recent evidence has demonstrated that nicotine may obtund the symptoms of Tourette's syndrome (TS). TS is a neuropsychiatric disorder characterized by motor and vocal tics, obsessions and compulsions, and frequently with impulsivity, distractibility, and visual-motor deficits. While neuroleptics, such as haloperidol, are most effective for treatment of the motor and vocal tics of TS, these medications have many side effects. In this article, we review the evidence, consistent with findings in animals, that administration of nicotine (either 2 mg nicotine gum or 7 mg transdermal nicotine patch) potentiates the therapeutic properties of neuroleptics in treating TS patients and that a single patch may be effective for a variable number of days. These findings suggest that transdermal nicotine could serve as an effective adjunct to neuroleptic therapy for TS.

Transdermal nicotine and haloperidol in Tourette's disorder: a double-blind placebo-controlled study.

BACKGROUND: Preclinical animal and open-trial clinical trials using nicotine gum and the transdermal nicotine patch found that treatment with nicotine potentiates the effects of neuroleptics in reducing the dyskinetic symptoms of Tourette's disorder. We sought to verify and expand these findings in a prospective double-blind placebo-controlled trial. METHOD: Seventy patients with DSM-IV Tourette's disorder were treated with either transdermal nicotine (7 mg/24 hours) or placebo patches in a 33-day, randomized, double-blind study. Each patient received an individually based optimal dose of haloperidol for at least 2 weeks prior to random assignment to nicotine or placebo treatment. A new patch was worn each day for the first 5 days. On the sixth day, the dose of haloperidol was reduced by 50%. Daily patch applications were then continued for an additional 2 weeks (through day 19), at which time the patch was discontinued, but the 50% dose of haloperidol was continued for an additional 2 weeks (through day 33). Clinical and safety assessments were made at each visit. RESULTS: Patients who completed all 19 days of nicotine (N = 27) or placebo (N = 29) patch treatment were used in efficacy analyses. As documented by the Clinician- and Parent-rated Global Improvement scales, transdermal nicotine was superior to placebo in reducing the symptoms of Tourette's disorder. The Yale Global Tic Severity Scale was less sensitive in detecting a placebo/drug difference than were the global improvement scores, suggesting that some of the improvement may not have been related to treatment-related changes in tic severity, but to the emotional and behavioral symptoms. The side effects of nausea and vomiting were significantly more common in the nicotine group (71% [N = 25] and 40% [N = 14]) than in the placebo group (17% [N = 6] and 9% [N = 3]) (nausea, p = .0001; vomiting, p = .004). CONCLUSION: Transdermal nicotine was superior to placebo in reducing behavioral symptoms when patients were receiving an optimal dose of haloperidol, when the dose of haloperidol was reduced by 50%, and when the patch had been discontinued for 2 weeks. These findings confirm earlier open-label findings and suggest that combining nicotinic receptor modulation and neuroleptics could be a therapeutic option for the treatment of Tourette's disorder. While side effects limit chronic use of nicotine, it may be useful on a p.r.n. basis. Further clinical research is warranted to investigate the use of novel nicotinic receptor modulating agents with improved safety profiles over nicotine.

Case study: long-term potentiation of neuroleptics with transdermal nicotine in Tourette's syndrome.

Sixteen Tourette's syndrome patients, aged 9 to 15 years, whose symptoms were not controlled with neuroleptics, were followed for various lengths of time after the application of a transdermal nicotine patch (TNP) (7 mg/24 hours) as part of an ongoing case study. While there was a broad range in individual response, application on the TNP produced significant reductions (p < .001) in Yale Global Tic Severity Scale scores relative to baseline, with an average duration of effect lasting between 1 and 2 weeks. Side effects, for the most part, were transient. Clinical implications for the use of TNP as an adjunct to neuroleptic treatment of Tourette's syndrome are discussed.