Dementia of Alzheimer's disease and other neurodegenerative disorders--memantine, a new hope.
Alzheimer's disease is the fourth largest cause of death for people over 65 years of age. Dementia of Alzheimer's type is the commonest form of dementia, the other two forms being vascular dementia and mixed dementia. At present, the therapy of Alzheimer's disease is aimed at improving both, cognitive and behavioural symptoms and thereby, quality of life for the patients. Since the discovery of Alzheimer's disease by Alois Alzheimer, many pathological mechanisms have been proposed which led to the testing of various new treatments. Until recently the available drugs for the treatment of Alzheimer's disease are cholinesterase inhibitors, which have limited success because these drugs improve cognitive functions only in mild dementia and cannot stop the process of neurodegeneration. Moreover, drugs of this category show gastrointestinal side effects. As the cells of central and peripheral nervous system cannot regenerate, newer strategies are aimed at preserving the surviving neurons by preventing their degeneration. NMDA-receptor-mediated glutamate excitotoxicity plays a major role in Abeta-induced neuronal death. Hence, it was thought that NMDA receptors could be a promising target for preventing the progression of Alzheimer's disease. All the compounds synthesized initially in this category showed toxicity mainly because of their high affinity for NMDA receptors. Memantine (1-amino adamantane derivative), NMDA-receptor antagonist was reported to be effective therapeutically in Alzheimer's disease. It was available in Germany as well as European Union and has been approved for moderate to severe dementia in United States of America recently. It is an uncompetitive, moderate affinity antagonist of NMDA receptors that inhibits the pathological functions of NMDA receptors while physiological processes in learning and memory are unaffected. Memantine is also reported to have beneficial effects in other CNS disorders viz., Parkinson's disease (PD), stroke, epilepsy, CNS trauma, amyotrophic lateral sclerosis (ALS), drug dependence and chronic pain. Mechanisms of neuroprotection, preclinical and clinical evidence for effectiveness of memantine have been provided. Pharmacology and pharmacokinetics of memantine and other NMDA-receptor antagonists in comparison with currently approved drugs for dementia treatment have been discussed. The focus is on 'glutamate excitotoxicity' and glutamate receptors as drug target. Various other novel strategies for the treatment of dementia of neurodegenerative disorders have also been discussed.
Sonkusare
S K
SK
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali 160 062, India.
Kaul
C L
CL
Ramarao
P
P
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D006801:Humans; D008559:Memantine / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use
D018696:Neuroprotective Agents; D008559:Memantine