Tobacco cembranoids protect the function of acute hippocampal slices against NMDA by a mechanism mediated by α4β2 nicotinic receptors

Abstract

Nicotine has been reported to be neuroprotective in experimental and epidemiological studies. In addition to nicotine, tobacco and cigarette smoke contain cembranoids, which are antagonists of neuronal nicotinic receptors (nAChR). Exposure of hippocampal slices to N-methyl-D-aspartate (NMDA) decreases the population spikes (PS). This parameter has been used as a measure of excitotoxicity. Surprisingly, both nicotine and tobacco cembranoids protected against NMDA and this neuroprotection was not blocked by methyllycaconitine (MLA), an antagonist of alpha7 nAChR. On the contrary, MLA had a neuroprotective effect of its own. We examined the effect of the tobacco cembranoid (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R) on the neuroprotection against NMDA. DHbetaE, a selective antagonist of alpha4beta2 nAChR, inhibited the neuroprotection by nicotine, 4R, and MLA, suggesting the involvement of alpha4beta2 nAChRs in the neuroprotection. The cell-signaling pathways underlying the neuroprotection by 4R and by nicotine are different. The activity of phosphatidylinositol-3 kinase (PI3K) was required in both cases; however, 4R required the activity of L-type calcium channels and CAM kinase, whereas nicotine required the extracellular signal regulated kinase-1,2 (ERK) and protein kinase C (PKC). In addition, 4R did not enhance total phospho-ERK-1/2 but increased the amount of total Akt/PKB phosphorylated on the activation site and of glycogen synthase kinase 3-beta phosphorylated on the inhibitory site. Total levels of phosphoenzymes are presented instead of the ratio of phospho- over total enzyme because in preliminary experiments total ERK-1/2 levels were slightly increased by 4R. In conclusion, these findings demonstrate that there are two different nicotinic neuroprotective mechanisms mediated by alpha4beta2.

Positive and negative modulation of nicotinic receptors

“…Considering the hypothesis that hyperstimulation of the cholinergic system over the noradrenergic system results in depressed states (Shytle et al, 2002b;Arias, 2009Arias, , 2010b, the observed inhibitory synergism by Zn 2þ and antidepressants could be of clinical significance. Some cembranoids (e.g., cembra-2,7,11-triene-4,6-diol) inhibit the N-methyl-d-aspartate-induced excitotoxicity in hippocampal neurons by a mechanism mediated by a4b2 AChRs (Ferchmin et al, 2005;reviewed in Ferchmin et al, 2009). In addition to cembra-2,7,11-triene-4,6-diol, eunicin and eupalmerin acetate inhibit the behavioral sensitization to nicotine in rats (Ferchmin et al, 2001;reviewed in Ferchmin et al, 2009).…”

Smoking, nicotine and neuropsychiatric disorders

“…Other tobacco smoke ingredients, such as nitrosamines (i.e. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN) and N-nitrosodiethylamine (DEN)) and cembranoids are also ligands of nAChRs (Zevin and Benowitz, 1999;Ayers et al, 2005;Schuller, 2007;Ferchmin et al, 2005Ferchmin et al, , 2009Cai et al, 2003). Tar consists of polycyclic aromatic hydrocarbons (PAH), metallic ions, several radioactive compounds, and free radicals, as well (Frishman et al, 2006;Swan and Lessov-Schlaggar, 2007;Pryor and Stone, 1993).…”

Cannabinoid Receptor CB1 Is Involved in Nicotine-Induced Protection Against Aβ1–42 Neurotoxicity in HT22 Cells

“…Therefore, we took HT22 cells exposed to Aβ 1-42 as the cell injury model to mimic pathogenesis of AD. Since we have found that p r o t e i n k i n a s e C ( P K C ) w a s i n v o l v e d i n t h e electroacupuncture (EA)-induced neuroprotection against brain ischemia through CB1 , some other researchers reported that PKC inhibitor could reverse nicotine-induced neuroprotection against N-methyl-Daspartate (NMDA) in hippocampal slices (Ferchmin et al 2005). However, whether PKC mediates nicotine-induced neuroprotection against Aβ has not been investigated.…”