Antonio Henrique Martins¹, Yancy Ferrer-Acosta²,, Sergio Rodriguez-Massó¹, Dinely Pérez³, Vesna A. Eterovic⁴, P.

A. Ferchmin⁴

1 Department of Pharmacology and Toxicology, University of Puerto Rico;

2 Department of Neuroscience, Universidad Central del Caribe;

3 Department of Biochemistry, Universidad Central del Caribe;

4 Neuroprotection for Life

Memantine was approved to treat patients with moderate to severe Alzheimer’s disease. Memantine is an uncompetitive antagonist of moderate affinity to the NMDA receptor. However, its therapeutic role cannot be exclusively attributed to its effect on the NMDA receptor.

In this study, the pharmacological profile of memantine’s neuroprotective pathway was examined using ex-vivo hippocampal slices exposed to an excitotoxic NMDA insult. We found that a nicotiniccomponent predominantly mediates the mechanism of memantine neuroprotection. We compared the neuroprotective mechanism of memantine to that of the tobacco-derived 4R-cembranoid. 4R elicits neuroprotection against NMDA excitotoxicity via inhibition of nicotinic receptors. When memantine or 4R were applied before NMDA in the presence of dihydro-β-erythroidine, an inhibitor of the α4β2 nicotinic receptor, the neuroprotection of both compounds was completely inhibited. However, when memantine, in the presence of dihydro-β-erythroidine, was applied after NMDA, some neuroprotection still was observed. The neuroprotection by either drug was not affected when co-applied with a MEK1/2 inhibitor, following the pharmacological pattern of neuroprotection of the α7 nicotinic acetylcholine antagonist methyllycaconitine (MLA), as was reported by us previously.

The Memantine curve of neuroprotection versus concentration is bell-shaped, suggesting that at higher concentrations (over 3 μM), memantine hinders the neuroprotection. However, 4R’s neuroprotection versus concentration curve is sigmoidal, suggesting that 4R would be neuroprotective over a wider range (up to 40 μM). Therefore, 4R could be potentially a better alternative than memantine to ameliorate the symptoms of AD.

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