Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzhei
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Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer’s Disease Martina Stazi 1 & Oliver Wirths 1 Received: 13 May 2020 / Accepted: 5 September 2020 # The Author(s) 2020
Abstract Memantine, a non-competitive NMDA receptor antagonist possessing neuroprotective properties, belongs to the small group of drugs which have been approved for the treatment of Alzheimer’s disease (AD). While several preclinical studies employing different transgenic AD mouse models have described beneficial effects with regard to rescued behavioral deficits or reduced amyloid plaque pathology, it is largely unknown whether memantine might have beneficial effects on neurodegeneration. In the current study, we assessed whether memantine treatment has an impact on hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. We demonstrate that a chronic oral memantine treatment for 4 months diminishes hippocampal CA1 neuron loss and rescues learning and memory performance in different behavioral paradigms, such as Morris water maze or a novel object recognition task. Cognitive benefits of chronic memantine treatment were accompanied by an amelioration of impaired adult hippocampal neurogenesis. Taken together, our results demonstrate that memantine successfully counteracts pathological alterations in a preclinical mouse model of AD. Keywords Alzheimer . Memantine . Neuron loss . Transgenic mice . Amyloid . Behavior
Introduction Alzheimer’s disease (AD) is an irreversible, chronic, and progressive neurodegenerative disorder representing the most common cause of dementia [1]. AD is associated with a gradual decline in memory and cognition, linked to neuronal death in the cerebral cortex and limbic system of the brain [2]. Until now, no disease-modifying treatments are available, and current pharmacotherapeutic strategies are based on symptom relief, preservation of mental abilities, and potential delay in the progression of neurodegeneration. A limited number of drugs are approved by the regulatory authorities which can be classified into two main categories: (1) acetylcholinesterase inhibitors, which prevent the break-down of the Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02120-z) contains supplementary material, which is available to authorized users. * Oliver Wirths [email protected] 1
Department of Psychiatry and Psychotherapy, Molecular Psychiatry, University Medical Center (UMG), Georg-August University, Von-Siebold-Str. 5, 37075 Göttingen, Germany
neurotransmitter acetylcholine into choline and acetate and are approved to treat mild to moderate dementia, and (2) glutamatergic antagonists, which are intended to protect nervous tissue against glutamate-mediated excitotoxicity [3]. Glutamate is the major excitatory neurotransmitter in the brain, and glutamatergic overstimulation might result in neuronal damage and ultimate cognitive decline. Memantine, a non-competitive N-methyl-
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