Comparative Study of Action Mechanisms of Dimebon and Memantine on AMPA- and NMDA-Subtypes Glutamate Receptors in Rat Cerebral Neurons

Abstract

Dimebon in low concentrations potentiated activity of AMPA-receptors in rat cerebellar Purkinje neurons, while memantine produced only an insignificant potentiation in a small group of these cells. In cortical neurons of rat brain memantine efficiently blocked NMDA-induced currents in dimebon-insensitive neurons. By contrast, its effect was far weaker in neurons, where the blocking action of dimebon on NMDA-receptors was most pronounced. It was hypothesized that the differences in the effects of memantine and dimebon are determined by their interaction with different sites of NMDA-receptors.

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

“…The memory-enhancing effects of dimebon may indicate simultaneous activity toward AMPA, NMDA, dopamine and serotonin receptors, all of which have been involved in inhibitory and appetitive hippocampus-dependent learning (Ungerer et al, 1998;Orsetti et al, 2001;Rogawski and Wenk, 2003;LaLumiere et al, 2003;Lynch and Gall, 2006;Balschun et al, 2006;Da Silva Costa et al, 2009;Benchenane et al, 2010). In particular, it has been hypothesised that dimebon's activity as a positive modulator of AMPA receptors and low affinity non-competitive blocker of NMDA receptors via a multi-drug mechanism, can explain the pro-cognitive action of this compound (Grigorev et al, 2003;Grigoriev 2009). …”

“…Evaluation of dimebon against a set of biochemical targets indicated that dimebon inhibits alpha-adrenergic receptors (alpha1A, alpha1B, and alpha1D, and alpha2A, alpha 2B, and alpha 2C), histamine H1 and H2 receptors and serotonin receptors (5-HT-2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6, and 5-HT7), dopamine receptors (D, D2S, and D3), and imidazoline I2 receptors (Schaffhauser et al, 2009;Giorgetti et al, 2010). At low concentrations, dimebon potentiates the activity of AMPA-receptors and blocks NMDA-receptors in neurons (Grigorev et al, 2003).…”

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…Latrepirdine is proposed to interact with glutamate Reduces oxidative stress, reduces amyloid plaques, improves memory deficits in transgenic mouse models of AD No major effect on cognitive function [132][133][134][135][136][137][138][139] AD = Alzheimer's disease; ROS = reactive oxygen species; SOD = superoxide dismutase; MitoQ = mitoquinone mesylate; AMPK = adenosine monophosphate-activated protein kinase; NAD = nicotinamide adenine dinucleotide; SIRT1 = sirtuin 1 receptors, block voltage-dependent calcium channels, and inhibit mitochondrial permeability, thereby suppressing unnecessary mitophagy or apoptosis [153,154]. In a Phase II clinical trial in patients with moderate AD, it significantly improved cognitive function over placebo [155].…”

Dimebon (Latrepirdine) Enhances Mitochondrial Function and Protects Neuronal Cells from Death

“…Dimebon exhibits a rich pharmacological profile and binds to histamine-, adrenergic-, dopamine-, and serotonin-receptors [25,27]. It is known to be a weak inhibitor of acetylcholinesterase (IC 50 = 8-42 µM) [24], N-methyl-Daspartate (NMDA) receptors (IC 50 = 10 µM) [25,28], and voltage-gated calcium channels (IC 50 = 50 µM) [25,29]. In addition, µM concentrations of Dimebon have previously been shown to protect against neuronal cell death induced by Aβ 25−35 [24] and to modulate the mitochondrial permeability transition pore (10-200 µM) [20].…”