On the paradox of ion channel blockade and its benefits in the treatment of Alzheimer disease

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Summary

The surprisingly beneficial effects in Alzheimer disease (AD) of ion channel blockers (ICB) like memantine that act on NMDA- and other aminergic transmitter receptors are yet poorly understood. NMDA receptor levels and binding were shown to be significantly decreased in AD, in which highly NMDA receptor and Ca2+ dependent synaptic plasticity and re-modelling are severely compromised. Thus, how could one expect to improve AD by further suppressing NMDA channels with antagonists. Nevertheless, clinical trials with NMDA blockers revealed in moderate to advanced AD surprisingly positive effects. The present paper tries to provides a hypothetical explanation of that paradoxical success of ICBs. Based on evidence from current data, emphasis is put on a profound impairment in the AD brain of the inhibition–excitation balance in the neuronal circuitry to the advantage of excitation. This imbalance is conceived to result from a degeneration of four modulatory aminiergic transmitter systems (serotonin, noradrenalin, acetylcholine, histamine) and related peptidergic systems, the decline of which causes a profound loss of inhibitory impact in the forebrain neuronal circuitry leading to disinhibition of principal neurones (“aminergic disinhibition”). Subsequent Ca2+ excito-toxicity and its sequelae are suggested to be the basic promotors of the neuro-degeneration and the related mental decline in AD. Re-adjustment of the inhibition–excitation imbalance by decreasing excitation is conceived to be the mechanism that renders ion channel blockade therapeutically successful. Putatively, attempts to increase inhibition, e.g., by application of GABA mimetics that stimulate the production GABA from preserved but “lazy” GABA neurones lacking aminergic facilitation, might be an even better way to achieve the re-balance.

Introduction

Alzheimer disease (AD) is an incessant mental disorder characterized by progressive neuro-degeneration and dementia, leading to complete destruction of the personality. Up to now, there is no specific treatment that might halt this devastating disorder. However, various strategies for symptomatic treatment have been suggested or developed in the recent past [1], [2] including the use of ion channel blockers (ICBs) like memantine [3], [4] or the NMDA receptor (NMDA-R) antagonist N20C, which is still under development and promises to be even more effective in AD than memantine [5]. Up to now, the mechanism(s) by which ICBs yield their effects in AD is (are) unknown.

Section snippets

NMDA receptors are down in AD

As a theoretical basis for the use of the NMDA-R blocker memantine in AD, over-stimulation in the AD brain of NMDA receptors (NMDA-R) by glutamate was postulated [3].

However, but little evidence from the current literature supports this concept. NMDA-R levels and/or ligand binding to NMDA-Rs were shown to be significantly decreased in AD cortex, i.e., up to almost 90% in limbic regions [6], [7]. Glutamate levels were found to be reduced [8] rather than increased.

Of note, Farber et al. [9] based

NMDA receptor function is pivotal for synaptic plasticity and re-modelling which are severely compromised in AD

Compelling evidence has been provided that NMDA receptor-mediated glutamatergic neuro-transmission is of fundamental importance for functional and structural synaptic plasticity, i.e., the initiation and consolidation of long-term potentiation (LTP) in learning and memory [10], [11]. This is true not only because the NMDA-R functions as a highly Ca2+ permeable cationic ion channel that regulates Ca2+ influx and signalling, but also since it serves additional functions such as signalling to the

Effective cognitive processing requires neuro-modulation by aminergic neuro-transmitters

Neuro-modulation by aminergic transmitters is pivotally involved in cognitive processing. This includes arousal and attention as well as neural plasticity in learning, memory, and emotional behavior [18].

Five aminergic neuro-transmitter systems projecting to the forebrain exert significant modulatory impact on virtually all steps of cognitive and emotional processing. These are the cholinergic (ACh), the serotoninergic (SE), the noradrenergic (NA), the dopaminergic (DA), and the histaminergic

Hypothesis

The progressive decline of the MAT systems, accompanied by the likely secondary loss of some related inhibitory peptidergic systems such as somatostatin, NPY, neurotensin, galanin, and opioids [44], [45], [46], [47] means a fundamental loss of inhibitory impact in the neuronal circuitry to the advantage of excitation. The declining MAT facilitation of local GABA-ergic (inter-) neurones both in the cerebral cortex and the deep brain, including the aminergic nuclei, causes an additional

Increasing the inhibitory impact might be the better way to re-adjust the inhibition–excitation imbalance

NMDA blockade may have the disadvantage of further suppressing a most important mediator of glutamatergic impact on neural plasticity which is already severely hampered in AD.

Trying to re-adjust the inhibition–excitation balance through increasing the inhibitory impact, e.g., by enhancing the GABA transmission might be superior to strategies aimed at the suppression of excitation.

The fact that previous attempts employing various GABA receptor ligands yielded limited results is not surprising in

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    Presented in parts as a poster (No. P3-282) at the 9th International Conference on Alzheimer’s Disease and Related Disorders, July 17–22, 2004, Philadelphia, PA, USA.

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