MK-801, memantine and amantadine show neuroprotective activity in the nucleus basalis magnocellularis.
The activation of glutamate receptors by endogenuous glutamate has been implicated in the processes that underlie cell loss associated with ischemia and trauma and in the development of some neurodegenerative diseases. The antagonism of NMDA-sensitive glutamate receptors may therefore have therapeutic applications. The present study compared the side effects and neuroprotective potency of 1-aminoadamantane hydrochloride (amantadine), 1-amino-3,5-dimethyladamantane hydrochloride (memantine), and (+)-5-methyl-10,11-dihydro-5H-debenzocyclhepten-5,10-imine maleate ((+)-MK-801) against NMDA injected directly into the nucleus basalis magnocellularis of rats. Each drug significantly attenuated the loss of nucleus basalis magnocellularis cholinergic cells. The ED50s were respectively 0.077, 2.81 and 43.5 mg/kg for (+)-MK-801, memantine and amantadine, giving a relative potency ratio of 1:36:565. The ratio of the ED50 for the side effects observed, including ataxia, myorelaxation and stereotypy, and the ED50 for neuroprotective ability, was highest for memantine and the lowest for (+)-MK-801. The results suggest that a potential neuroprotective action of NMDA receptor antagonists, memantine and amantadine in particular, can be seen at low doses lacking side effects.
Wenk
G L
GL
Arizona Research Laboratories Division of Neural Systems, Memory & Aging, University of Arizona, Tucson 85724, USA.
Danysz
W
W
Mobley
S L
SL
D000547:Amantadine / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000201:enzymology; D002540:Cerebral Cortex / Q000201:enzymology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000009:adverse effects / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008559:Memantine / Q000009:adverse effects / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009422:Nervous System Diseases / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D000547:Amantadine; D002795:Choline O-Acetyltransferase; D008559:Memantine