Cytisine

Neurotoxicology. 2013 Jan;34:219-25.

Cytisine confers neuronal protection against excitotoxic injury by down-regulating GluN2B-containing NMDA receptors.[Pubmed: 23022271]

Cytisine (CYT), one of the principal bioactive components derived from the seeds of Cytisus laborinum L, has been widely used for central nervous system (CNS) diseases treatment.
METHODS AND RESULTS:
The present study investigated the protective effect of CYT on cultured cortical neural injury induced by N-methyl-d-aspartate (NMDA). Our data showed that CYT conferred protective effect against loss of cellular viability induced by brief exposure to 200 μM NMDA in a concentration-dependent manner. CYT significantly inhibited the neuronal apoptosis induced by NMDA exposure by reversing intracellular Ca(2+) overload and balancing Bcl-2 and Bax expression levels. Furthermore, CYT significantly reversed the up-regulation of GluN2B-containing NMDA receptors by exposure to NMDA, but it did not affect the level of GluN2A-containing NMDA receptors.
CONCLUSIONS:
These findings suggest that CYT protects cortical neurons, at least partially, by inhibiting the level of GluN2B-containing NMDA receptors and regulating Bcl-2 family.

Pharmacol Rep. 2013;65(1):195-200.

Cytisine inhibits the anticonvulsant activity of phenytoin and lamotrigine in mice.[Pubmed: 23563038]

Cytisine (CYT), the most commonly used drug for smoking cessation in Poland, was experimentally found to induce convulsions. There is a lack of studies on the influence of CYT on the anticonvulsant activity of antiepileptic drugs (AEDs).
METHODS AND RESULTS:
The effects of CYT on the anticonvulsant activity of six AEDs were examined in maximal electroshock (MES)-induced seizures in mice. Single intraperitoneal (ip) administration of CYT in a subthreshold dose of 2 mg/kg antagonized the protective activity of ip phenytoin and lamotrigine against MES-induced seizures in mice. A dose of 1 mg/kg did not reverse the protective activity of phenytoin and lamotrigine. CYT in a dose of 2 mg/kg had no effect on the anticonvulsive activity of carbamazepine, oxcarbazepine, phenobarbital, and valproate magnesium.
CONCLUSIONS:
CYT ability to antagonize the anticonvulsive activity of phenytoin and lamotrigine can be of serious concern for epileptic smokers, who might demonstrate therapeutic failure to these drugs resulting in possible breakthrough seizure attacks.

N Engl J Med. 2014 Dec 18;371(25):2353-62.

Cytisine versus nicotine for smoking cessation.[Pubmed: 25517706]

Placebo-controlled trials indicate that Cytisine, a partial agonist that binds the nicotinic acetylcholine receptor and is used for smoking cessation, almost doubles the chances of quitting at 6 months. We investigated whether Cytisine was at least as effective as nicotine-replacement therapy in helping smokers to quit.
METHODS AND RESULTS:
We conducted a pragmatic, open-label, noninferiority trial in New Zealand in which 1310 adult daily smokers who were motivated to quit and called the national quitline were randomly assigned in a 1:1 ratio to receive Cytisine for 25 days or nicotine-replacement therapy for 8 weeks. Cytisine was provided by mail, free of charge, and nicotine-replacement therapy was provided through vouchers for low-cost patches along with gum or lozenges. Low-intensity, telephone-delivered behavioral support was provided to both groups through the quitline. The primary outcome was self-reported continuous abstinence at 1 month. At 1 month, continuous abstinence from smoking was reported for 40% of participants receiving Cytisine (264 of 655) and 31% of participants receiving nicotine-replacement therapy (203 of 655), for a difference of 9.3 percentage points (95% confidence interval, 4.2 to 14.5). The effectiveness of Cytisine for continuous abstinence was superior to that of nicotine-replacement therapy at 1 week, 2 months, and 6 months. In a prespecified subgroup analysis of the primary outcome, Cytisine was superior to nicotine-replacement therapy among women and noninferior among men. Self-reported adverse events over 6 months occurred more frequently in the Cytisine group (288 events among 204 participants) than in the group receiving nicotine-replacement therapy (174 events among 134 participants); adverse events were primarily nausea and vomiting and sleep disorders.
CONCLUSIONS:
When combined with brief behavioral support, Cytisine was found to be superior to nicotine-replacement therapy in helping smokers quit smoking, but it was associated with a higher frequency of self-reported adverse events.

Neuropharmacology. 2015 Mar 31;95:206-214.

Agonist and antagonist effects of cytisine in vivo.[Pubmed: 25839895]

Varenicline, the most successful smoking cessation aid, is a selective partial agonists at α4β2* nicotinic receptors. Its efficacy is likely to be shared by other drugs with similar receptor action, including Cytisine.
METHODS AND RESULTS:
The present study aimed to characterize behavioral effects of Cytisine compared with nicotine using locomotor activity tests, intracranial self-stimulation of ventral tegmental area (discrete-trial threshold current intensity titration procedure), drug discrimination (0.6 mg/kg nicotine from vehicle), physical dependence (osmotic minipumps delivering 6 mg/kg/day of nicotine) and intravenous nicotine self-administration (0.01 mg/kg per infusion) in adult Wistar rats. Cytisine (1-3 mg/kg) partially substituted for nicotine and at the highest dose tended to antagonize nicotine's discriminative stimulus effects. Nicotine (0.05-0.4 mg/kg), but not Cytisine (0.3-3 mg/kg), lowered ICSS thresholds and Cytisine dose-dependently reversed effects of nicotine. Nicotine (0.15-0.6 mg/kg), but not Cytisine (0.3-3 mg/kg), stimulated locomotor activity and Cytisine (3 mg/kg) fully reversed these effects of nicotine. Acute pretreatment with nicotine (0.15-0.6 mg/kg), but not Cytisine (0.3-3 mg/kg), reinstated extinguished nicotine self-administration. Continuous infusion of nicotine induced physical dependence, as indicated by reduced rates of food-reinforced responding induced by a challenge dose of mecamylamine. At the highest tested dose (3 mg/kg), Cytisine tended to reduce response rates irrespective of whether the rats were continuously exposed to nicotine or saline.
CONCLUSIONS:
Cytisine behaves like a weak partial agonist, mimicking effects of nicotine to a limited degree. Although Cytisine reversed several effects of nicotine, it seemed to have a reduced potential to produce withdrawal signs in nicotine-dependent subjects.

J Pharmacol Exp Ther. 2009 Apr;329(1):377-86

Cytisine-based nicotinic partial agonists as novel antidepressant compounds.[Pubmed: 19164465]

Nicotine and other nicotinic agents are thought to regulate mood in human subjects and have antidepressant-like properties in animal models. Recent studies have demonstrated that blockade of nicotinic acetylcholine receptors (nAChRs) including those containing the beta2 subunit (beta2(*)), results in antidepressant-like effects. Previous studies have shown that Cytisine, a partial agonist at alpha4/beta2(*) nAChRs, and a full agonist at alpha3/beta4(*) and alpha7 nAChRs, has antidepressant-like properties in several rodent models of antidepressant efficacy; however, it is not clear whether more selective partial agonists will also be effective in these models.
METHODS AND RESULTS:
We tested Cytisine and two derivatives, 5-bromo-Cytisine (5-Br-Cyt) and 3-(pyridin-3'-yl)-Cytisine (3-pyr-Cyt) for their ability to act as a partial agonist of different nAChR subtypes and to show antidepressant-like activity in C57/BL6 mice in the tail suspension, the forced-swim, and the novelty-suppressed feeding tests. 3-pyr-Cyt was a partial agonist with very low efficacy at alpha4/beta2(*) nAChRS but had no agonist effects at other nAChRs normally targeted by Cytisine, and it was effective in mouse models of antidepressant efficacy. Animals showed dose-dependent antidepressant-like effects in all three behavioral paradigms. 5-Br-Cyt was not effective in behavioral tests when administered peripherally, probably because of its inability to penetrate the blood-brain barrier, because it efficiently reduced immobility in the tail suspension test when administered intraventricularly.
CONCLUSIONS:
These results suggest that novel nicotinic partial agonists may provide new possibilities for development of drugs to treat mood disorders.