Glutamatergic Dysfunctioning in Alzheimer's Disease and Related Therapeutic Targets

Issue title: 2013 International Congress on Vascular Dementia

Guest editors: Amos D. Korczyn

Article type: Review Article

Authors: Zádori, Dénes^a | Veres, Gábor^a | Szalárdy, Levente^a | Klivényi, Péter^a | Toldi, József^{b; c} | Vécsei, László^{a; c; *}

Affiliations: [a] Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Szeged, Hungary | [b] Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary | [c] MTA-SZTE Neuroscience Research Group, Szeged, Hungary

Correspondence: [*] Correspondence to: László Vécsei MD, PhD, DSc, Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary. Tel.: +36 62 545351; Fax: +36 62 545597; E-mail: [email protected].

Abstract: The impairment of glutamatergic neurotransmission plays an important role in the development of Alzheimer's disease (AD). The pathological process, which involves the production of amyloid-β peptides and hyperphosphorylated tau proteins, spreads over well-delineated neuroanatomical circuits. The gradual deterioration of proper synaptic functioning (via GluN2A-containing N-methyl-D-aspartate receptors, NMDARs) and the development of excitotoxicity (via GluN2B-containing NMDARs) in these structures both accompany the disease pathogenesis. Although one of the most important therapeutic targets would be glutamate excitotoxicity, the application of conventional anti-glutamatergic agents could result in further deterioration of synaptic transmission and intolerable side-effects. With regard to NMDAR antagonists with tolerable side-effects, ion channel blockers with low affinity, glycine site agents, and specific antagonists of polyamine site and GluN2B subunit may come into play. However, in the mirror of experimental data, only the application of ion channel blockers with pronounced voltage dependency, low affinity, and rapid unblocking kinetics (e.g., memantine) and specific antagonists of the GluN2B subunit (e.g., ifenprodil and certain kynurenic acid amides) resulted in desirable symptom amelioration. Therefore we propose that these kinds of chemical agents may have therapeutic potential for present and future drug development.

Keywords: Alzheimer's disease, glutamate excitotoxicity, kynurenic acid amides, memantine, neurodegeneration, neuroprotection, therapy

DOI: 10.3233/JAD-132621

Journal: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S177-S187, 2014