Possibility of a New Anti-Alzheimerʼs Disease Pharmaceutical Composition Combining Memantine and Vitamin D

Abstract

Alzheimer's disease (AD) is the leading cause of dementia. In addition to a decrease in brain cholinergic activity, AD is also marked by glutamatergic excitotoxicity that results in neuronal death, characterized clinically by a loss of learning and memory abilities. The currently available drugs for symptomatic treatment of AD (i.e. memantine and acetylcholinesterase inhibitors) only temporarily slow down the natural history of the disease process. Among them, memantine is the only one that acts as a non-competitive low-affinity modulator of N-methyl-D-aspartate (NMDA) receptors. Memantine's modulation of NMDA receptors has been reported to prevent the neuronal necrosis induced by glutamatergic calcium neurotoxicity, but not the neuronal apoptosis resulting from oxidative stress. This observation calls for new drug regimen strategies based on memantine combined with molecules having antioxidant effects, in order to create a multi-target therapy to increase neuronal protection and prevent AD progression. We wish to highlight that vitamin D is a secosteroid hormone that is suggested to have neuroprotective effects that include regulation of neuronal calcium homeostasis, as well as antioxidant, neurotrophic and anti-inflammatory properties. The combination of memantine plus vitamin D may provide, in one treatment, enhanced protection against several degenerative processes linked to AD. Based on the present rationale, a clinical trial testing this hypothesis is currently in recruitment (AD-IDEA trial; ClinicalTrials.gov identifier: NCT01409694). This new pharmaceutical composition may provide an effective solution to the problem of neuronal death and cognitive decline in AD.

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

“…74 Since both AD and PD seem to be caused by abnormal elevations in Ca 2+ , I shall develop the notion that the deleterious effect of vitamin D deficiency may be explained by an alteration in its normal role in regulating intracellular Ca 2+ homeostasis. 75,76 The brain possesses all the enzyme responsible for both vitamin D formation (vitamin D3 25-hydroxylase and 25-hydroxyvitamin D3-1α-hydroxylase) and degradation (vitamin D3 25-hydroxylase). 70,77 Neurons also express the vitamin D receptor (VDR) and VDR polymorphisms have been associated with Parkinson disease, 76 age-related decline in cognition and the incidence of depressive symptoms 78 and is also a risk factor for AD.…”

“…4). These inhibitory effects of Li + , Bcl-2 of the degenerative processes associated with AD 75 and there is every reason to suspect that it might prove efficacious in other neural diseases such as PD that are driven by a dysregulation of Ca 2+ signaling.…”

Slow Excitotoxicity in Alzheimer's Disease

“…It slows the progression of mild and moderate-to-severe AD and possibly vascular dementia, though its effects are limited [252]. Memantine acts as a non-competitive low-affinity modulator of NMDA receptors, and results in prevention of neuronal necrosis induced by glutamatergic calcium neurotoxicity, but not neuronal apoptosis resulting from oxidative stress [253]. It blocks excessive NMDA receptor activity, while leaving normal function relatively intact [254].…”

The Inhibition of Inwardly Rectifying K+Channels by Memantine in Macrophages and Microglial Cells

“…Memantine (MEM) is a derivative of amantadine and has been used to treat a variety of neurological or psychiatric disorders associated with excitotoxic cell death, including Parkinson's disease and vascular dementia [7,8,9]. The therapeutic effect of this compound is due primarily to its ability to bind to N -methyl-D-asparatate (NMDA) receptor-operated cation channels [10,11].…”

“…Despite the fact that NMDA receptors constitute the main target of MEM, recent studies have shown that it could inhibit ATP-sensitive K + (K ATP ) channels in substantia nigra neurons [12] and suppress electroporation-induced inward currents [13]. MEM has been reported to exert anti-inflammatory actions [7,8,14,15]; however, such mechanisms remain unclear. Additionally, little information is available concerning the mechanisms involved in effect of MEM or structurally similar compounds on Kir channels, while amantidine was reported to block viral K + channels [16].…”