Tobacco cembranoids protect the function of acute hippocampal slices against NMDA by a mechanism mediated by α4β2 nicotinic receptors
✍ Scribed by P.A. Ferchmin; Jiukuan Hao; Dinely Perez; Mario Penzo; Hector M. Maldonado; Maria T. Gonzalez; Abimael D. Rodriguez; Jean de Vellis
- Book ID
- 102385345
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- English
- Weight
- 431 KB
- Volume
- 82
- Category
- Article
- ISSN
- 0360-4012
No coin nor oath required. For personal study only.
✦ Synopsis
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 α7 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. DHβE, a selective antagonist of α4β2 nAChR, inhibited the neuroprotection by nicotine, 4R, and MLA, suggesting the involvement of α4β2 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‐β 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 α4β2. © 2005 Wiley‐Liss, Inc.