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Molecular Neurodegeneration

, 3:15

First Online: 21 October 2008Received: 21 August 2008Accepted: 21 October 2008


BackgroundDimebon is an antihistamine compound with a long history of clinical use in Russia. Recently, Dimebon has been proposed to be useful for treating neurodegenerative disorders. It has demonstrated efficacy in phase II Alzheimer-s disease AD and Huntington-s disease HD clinical trials. The mechanisms responsible for the beneficial actions of Dimebon in AD and HD remain unclear. It has been suggested that Dimebon may act by blocking NMDA receptors or voltage-gated Ca channels and by preventing mitochondrial permeability pore transition.

ResultsWe evaluated the effects of Dimebon in experiments with primary striatal neuronal cultures MSN from wild type WT mice and YAC128 HD transgenic mice. We found that Dimebon acts as an inhibitor of NMDA receptors IC50 = 10 μM and voltage-gated calcium channels IC50 = 50 μM in WT and YAC128 MSN. We further found that application of 50 μM Dimebon stabilized glutamate-induced Ca signals in YAC128 MSN and protected cultured YAC128 MSN from glutamate-induced apoptosis. Lower concentrations of Dimebon 5 μM and 10 μM did not stabilize glutamate-induced Ca signals and did not exert neuroprotective effects in experiments with YAC128 MSN. Evaluation of Dimebon against a set of biochemical targets indicated that Dimebon inhibits α-Adrenergic receptors α1A, α1B, α1D, and α2A, Histamine H1 and H2 receptors and Serotonin 5-HT2c, 5-HT5A, 5-HT6 receptors with high affinity. Dimebon also had significant effect on a number of additional receptors.

ConclusionOur results suggest that Ca and mitochondria stabilizing effects may, in part, be responsible for beneficial clinical effects of Dimebon. However, the high concentrations of Dimebon required to achieve Ca stabilizing and neuroprotective effects in our in vitro studies 50 μM indicate that properties of Dimebon as cognitive enhancer are most likely due to potent inhibition of H1 histamine receptors. It is also possible that Dimebon acts on novel high affinity targets not present in cultured MSN preparation. Unbiased evaluation of Dimebon against a set of biochemical targets indicated that Dimebon efficiently inhibited a number of additional receptors. Potential interactions with these receptors need to be considered in interpretation of results obtained with Dimebon in clinical trials.

Electronic supplementary materialThe online version of this article doi:10.1186-1750-1326-3-15 contains supplementary material, which is available to authorized users.

Jun Wu, Qin Li contributed equally to this work.

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Autor: Jun Wu - Qin Li - Ilya Bezprozvanny

Fuente: https://link.springer.com/

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