On the paradox of ion channel blockade and its benefits in the treatment of Alzheimer disease☆
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
References (75)
A new NMDA-receptor blocker provides potential neuroprotection
Trends Neurosci (TINS)
(2002)- et al.
Decreased expression of N-methyl-d-aspartate receptor 1 messenger RNA in select regions of Alzheimer brain
Neuroscience
(1997) Neurochemical studies of Alzheimer’s disease
Neurodegeneration
(1996)- et al.
The glutamate synapse in neuropsychiatric disorders. Focus on schizophrenia and Alzheimer’s disease
Progr Brain Res
(1998) - et al.
Second messenger-mediated actions of norepinephrine on target neurons in central circuits: a new perspective on intracellular mechanisms and functional consequences
Progr Brain Res
(1991) The nucleus basalis and memory codes: auditory cortical plasticity and the induction of specific, associative behavioral memory
Neurobiol Learn Mem
(2003)- et al.
Neurotransmitters, peptides, and neural cell adhesion molecules in the cortices of normal elderly humans and Alzheimer patients: a comparison
Exp Gerontol
(1999) Neuroplasticity failure in Alzheimer’s disease: bridging the gap between plaques and tangles
Neuron
(1999)- et al.
Histamine excites GABAergic cells in the rat substantia nigra and ventral tegmental area in vitro
Neurosci Lett
(2002) - et al.
Reduction of neurotensin immunoreactivity in the amygdala in Alzheimer’s disease
Brain Res
(1990)
Widespread deficits in somatostatin but not neuropeptide Y concentrations in Alzheimer’s disease cerebral cortex
Neurosci Lett
First one in, last one out: the role of gabaergic transmission in generation and degeneration
Prog Neurobiol
Inhibitory neuronal activity can compensate for adverse effects of β-amyloid in hippocampal neurons
Brain Res
Regulation of ion channels by cAMP-dependent protein kinase and A-kinase anchoring proteins
Curr Opin Neurobiol
Quantitative assessment of nicotinic acetylcholine receptor proteins in the cerebral cortex of Alzheimer patients
Brain Res Mol Brain Res
The effects of ondansetron, a 5-HT3 receptor antagonist, on cognition in rodents and primates
Pharmacol Biochem Bahav
Modulation of 5-HT3 receptor-mediated response and trafficking by activation of protein kinase C
J Biol Chem
Approaches to the treatment of Alzheimer’s disease
Neurosci News
for the Donepezil Nordic Study Group. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD
Neurology
Memantine in moderate-to-severe Alzheimer’s disease
New Engl J Med
Memantine treatment in patients with moderate to severe Alzheimer’s disease already receiving donepezil
JAMA
Dementia of the Alzheimer type: Changes in hippocampal l-[3H]glutamate binding
J Neurochem
NMDA receptors ahead of the game
Nat Rev Neurosci
Differential contribution of NMDA receptors in hippocampal subregions to spatial memory
Nature Neurosci
Induction of immediate-early genes and the control of neurotransmitter-regulated gene expression within the nervous system
Pharmacol Rev
Regulated transcription of the immediate-early gene Zif268: mechanisms and gene dosage-dependent function in synaptic plasticity and memory formation
Hippocampus
Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity
Ann Neurol
Synaptophysin immunoreactivity of the cortical neuropil in vascular dementia of Binswanger type compared with the dementia of Alzheimer type and nondemented controls
Dementia
Synaptic plasticity in animal models of early Alzheimer’s disease
Memantine in severe dementia: Results of the 9M-best study benefit and efficacy in severely demented patients during treatment with memantine
Int J Geriat Psychiat
The anatomical organization of the central nervous system. Modulatory systems in the brain influence motivation, emotion, and memory
Neurophysiology of visual attention
Cortical map reorganization enabled by nucleus basalis activity
Change in bidirectional plasticity at CA1 synapses in hippocampal slices taken from 6-hydroxydopamine-treated rats: the role of endogenous norepinephrine
Eur J Neurosci
The molecular biology of memory storage: a dialog between genes and synapses
Biosci Rep
Synaptic plasticity and dynamic modulation of the postsynaptic membrane
Nat Neurosci
Characterization of serotonin receptor mediating contraction in the mouse thoracic aorta and signal pathway coupling
J Pharmacol Exp Ther
Cited by (31)
Neuronal chloride transporters in neurodegenerative diseases
2020, Neuronal Chloride Transporters in Health and DiseaseEffects of memantine on the excitation-inhibition balance in prefrontal cortex
2016, Neurobiology of DiseaseCitation Excerpt :However, there is evidence arguing against therapeutic effects of memantine based solely on neuroprotection, e.g. the lack of beneficial effects in early-stage AD, and the rapidity of memantine's effects (Johnson and Kotermanski, 2006). The ability of memantine to slow cognitive decline in AD patients has also been proposed to result from partial correction of an AD-induced alteration of cortical excitation/inhibition (E/I) balance (Schmitt, 2005). A delicate balance of excitatory and inhibitory elements in the cortex is essential to circuit function, and disturbances of this balance can lead to pathological conditions (Homayoun and Moghaddam, 2007, Haider and McCormick, 2009).
Recent insights into the mode of action of memantine and ketamine
2015, Current Opinion in PharmacologyDose-dependent folic acid and memantine treatments promote synergistic or additive protection against Aβ<inf>(25-35)</inf> peptide-induced apoptosis in SH-SY5Y cells mediated by mitochondria stress-associated death signals
2013, Food and Chemical ToxicologyCitation Excerpt :The Aβ peptide-induced death signaling and the neuronal apoptosis have been implicated in the molecular etiology, and have been identified as an early pathogenic feature of AD, which explains the early cognitive decline associated with AD (Takuma et al., 2005; Zhu et al., 2006; Klein, 2006). Memantine (Mn) is approved for use as a therapeutic drug in clinical AD treatment (Schmitt, 2005a,b). Mn is an uncompetitive NMDA receptor open channel blocker which prevents neuron excitotoxicity both in vitro and in vivo (Volbracht et al., 2006; Alley et al., 2010).
Targeting glutamate system for novel antipsychotic approaches: Relevance for residual psychotic symptoms and treatment resistant schizophrenia
2012, European Journal of Pharmacology
- ☆
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.