What is the rationale for new treatment strategies in Alzheimer's disease?
Alzheimer's disease (AD) is characterized by the abnormal extracellular accumulation of amyloid beta-peptide (Abeta) into neuritic plaques and the intraneuronal aggregation of the microtubule-associated protein tau to form neurofibrillary tangles. These molecular events are implicated in the selective damage to neural systems critical for the brain functions that are impaired in AD. Impairment of cholinergic neurotransmission may be an important factor underlying the defects in cognition and memory that characterize AD. Cholinesterase (ChE) inhibitors, such as donepezil, rivastigmine, and galantamine, cause symptomatic improvement by inhibiting the breakdown of the neurotransmitter acetylcholine to increase its synaptic availability and, in the case of galantamine, by also allosterically potentiating nicotinic cholinergic receptors. Other agents, including vitamin E, monoamine oxidase inhibitors, and statins, have shown some benefit in epidemiological studies and clinical trials although compelling evidence of their efficacy is lacking. Memantine, shown to cause cognitive and functional improvement, is not an ChE inhibitor and does not interact with marketed ChE inhibitors. While the mechanism of action of memantine in AD is not known, the principal pharmacologic actions at therapeutic dose are inhibition of ionotropic neurotransmitter receptors, specifically N-methyl-D-aspartate (NMDA), 5-HT3, and nicotinic receptors. Like other NMDA antagonists, memantine causes behavioral activation associated with enhanced cerebral glucose utilization. Studies have shown that memantine can reverse the decreased metabolic activity associated with AD, possibly accounting for its beneficial effects on cognition and global functioning. Memantine also has neuroprotective properties and can inhibit Abeta-induced neurodegeneration.
Rogawski
Michael A
MA
Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 49 Convent Drive, Bethesda, MD 20892, USA. michael.rogawski@nih.gov
D000109:Acetylcholine / Q000502:physiology; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002799:Cholinergic Fibers / Q000187:drug effects / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D003072:Cognition Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D008559:Memantine / Q000009:adverse effects / Q000627:therapeutic use; D018697:Nootropic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology
D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018697:Nootropic Agents; D016194:Receptors, N-Methyl-D-Aspartate; D000109:Acetylcholine; D008559:Memantine