In vivo modulation of dopaminergic nigrostriatal pathways by cytisine derivatives: implications for Parkinson's Disease.

Nicotinic acetylcholine receptor agonists are considered potential pharmacological agents for Parkinson's disease treatment, due to their ability to improve experimental Parkinson symptomatology, reduce 3,4-dihydroxy-L-phenylalanine-induced dyskinesias and stop the neurodegenerative process at an experimental level. In the present work, the ability of the nicotinic agonist cytisine and two halogenated derivatives (3-bromocytisine and 5-bromocytisine) to induce striatal dopamine release was characterized in vivo by microdialysis. Cytisine, 5-bromocytisine and nicotine were much more efficacious than 3-bromocytisine in eliciting dopamine release in response to their local application through the microdialysis probe. Moreover, the agonists were intermittently administered before and after an intranigral injection of 6-hydroxydopamine (6-OHDA), and striatal dopamine tissue levels were assessed 8 days after the lesion. Both cytisine and its 5-bromo derivative (but not the 3-bromo derivative) significantly prevented the decrease of striatal dopamine tissue levels induced by 6-OHDA. These results suggest that the efficacy of nicotinic agonists to stimulate dopamine release in vivo through presynaptic nicotinic receptors could be related to their potential to induce striatal protection.

C3-halogenation of cytisine generates potent and efficacious nicotinic receptor agonists.

Neuronal nicotinic acetylcholine receptors subserve predominantly modulatory roles in the brain, making them attractive therapeutic targets. Natural products provide key leads in the quest for nicotinic receptor subtype-selective compounds. Cytisine, found in Leguminosae spp., binds with high affinity to alpha4beta2* nicotinic receptors. We have compared the effect of C3 and C5 halogenation of cytisine and methylcytisine (MCy) on their interaction with native rat nicotinic receptors. 3-Bromocytisine (3-BrCy) and 3-iodocytisine (3-ICy) exhibited increased binding affinity (especially at alpha7 nicotinic receptors; Ki approximately 0.1 microM) and functional potency, whereas C5-halogenation was detrimental. 3-BrCy and 3-ICy were more potent than cytisine at evoking [3H]dopamine release from striatal slices (EC50 approximately 11 nM), [3H]noradrenaline release from hippocampal slices (EC50 approximately 250 nM), increases in intracellular Ca2+ in PC12 cells and inward currents in Xenopus oocytes expressing human alpha3beta4 nicotinic receptor (EC50 approximately 2 microM). These compounds were also more efficacious than cytisine. C3-halogenation of cytisine is proposed to stabilize the open conformation of the nicotinic receptor but does not enhance subtype selectivity.

From ligand design to therapeutic efficacy: the challenge for nicotinic receptor research.

S-Nicotine, the principal psychoactive constituent of Nicotiana tabacum, underpins addiction to tobacco smoking. Although tobacco consumption is a leading cause of death worldwide, nicotine itself is also proposed to have potential therapeutic benefits for a diverse range of conditions. Nicotine interacts with its cognate receptors in the central nervous system to exert a predominantly modulatory influence, making neuronal nicotinic receptors attractive therapeutic targets. Here, we focus on three natural products as lead compounds for drug discovery programs, nicotine, epibatidine and cytisine, and consider the aims and limitations that shape these drug discovery endeavors.

Presynaptic involvement in the nicotine prevention of the dopamine loss provoked by 6-OHDA administration in the substantia nigra.

While nicotine, through stimulation of a specific sub-population of nicotinic acetylcholine receptors (nAChR) appears to protect cells in culture against a variety of insults, studies in vivo show controversial results. In a previous paper we have shown that in the 6-hydroxydopamine (6-OHDA) model of experimental parkinsonism, an intermittent administration schedule of nicotine (4 h before and 20, 44 and 68 h after 6-OHDA) was able to prevent the decrease of dopamine (DA) concentration in the corpus striatum (CS) provoked by the partial lesion of the substantia nigra (50% neuronal death after 6 micro g of 6-OHDA). To further analyze the mechanisms of nicotine effects, we performed a microdialysis study of striatal extracellular DA concentrations utilizing the nicotine administration schedule that was able to prevent DA decrease. Basal extracellular DA concentrations in the CS were maintained after 6-OHDA and were not modified by nicotine. Basal DOPAC levels were decreased after the neurotoxic administration. The response of extracellular DA to potassium chloride (KCl) challenge was significantly lower after 6-OHDA than in control animals. Nicotine significantly reversed this decrease. As previous studies have shown, the striatal DA terminals surviving the 6-OHDA toxic effect are able to keep extracellular DA concentrations close to normal, likely increasing DA synthesis. Nevertheless, the application of a releasing factor such as KCl shows the fragility of this equilibrium, exposing a decrease in the terminal number. Nicotine, through a further activation of tyrosine hydroxylase and DA synthesis or by prolonging the life of DA terminals, could reverse the effect of 6-OHDA.