Pharmacology of acetylcholinesterase inhibitors and N-methyl-D-aspartate receptors for combination therapy in the treatment of Alzheimer's disease.
The search for effective treatments of Alzheimer's disease (AD) is one of the major challenges facing modern medicine. Acetylcholinesterase (AChE) inhibitors (AChEIs) are effective for the treatment of mild to moderate AD, and memantine, an N-methyl-D-aspartate (NMDA) inhibitor, has been approved for moderate to severe AD. Galantamine is of particular interest because it has a dual mechanism of action: it is postulated to be both an AChEI and an allosteric modulator of nicotinic receptors. Modulation of NMDA and nicotinic receptors by memantine and galantamine may provide an optimal combination therapy for AD. The cholinergic and glutamatergic neurotransmitter systems, which share a close functional relationship, may play a role in the pathogenesis of AD. Close examination of the pharmacology of the 2 compounds suggests that galantamine can augment memantine's glutamatergic noise suppression while simultaneously enhancing the physiologic glutamatergic signal. The link between these systems suggests that AD therapies, which capitalize on this relationship, may be more effective in improving cognition than approaches focusing on a single system.
Geerts
Hugo
H
In Silico Biosciences Inc, Berwyn, PA 19312, USA. Hugo-Geerts@In-Silico-Biosciences.com
Grossberg
George T
GT
D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005702:Galantamine / Q000494:pharmacology / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008559:Memantine / Q000494:pharmacology / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D005702:Galantamine; D018698:Glutamic Acid; D000109:Acetylcholine; D008559:Memantine