Memantine reduces neuronal dysfunctions triggered by in vitro ischemia and 3-nitropropionic acid.
Memantine, a low-affinity uncompetitive NMDA receptor antagonist, has been widely utilized for the treatment of Alzheimer's disease. A possible neuroprotective role of this drug in pathophysiological conditions involving an altered energetic metabolism of the basal ganglia has never been addressed. Thus, we have characterized the electrophysiological effect of memantine on striatal spiny neurons recorded under control conditions and after in vitro ischemia (oxygen and glucose deprivation). Memantine reduced in a dose-dependent manner (EC(50)=5 microM) the irreversible loss of field potential amplitude induced by in vitro ischemia. The neuroprotective effect of memantine against in vitro ischemia was even more potent (EC(50)=3.2 microM) in the absence of external magnesium, a condition enhancing NMDA-mediated glutamatergic transmission. Memantine was also able to block long-term potentiation recorded from spiny neurons following a brief ischemic episode. Moreover, memantine showed protection against irreversible field potential loss induced by 3-nitropropionic acid (3-NP), an inhibitor of the mitochondrial complex II, without influencing toxicity induced by rotenone, a complex I inhibitor. Memantine could represent a potential neuroprotective agent in pathophysiological conditions involving an altered energy metabolism of basal ganglia.
Clinica Neurologica, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, Via S. Andrea delle Fratte, Perugia 06156, Italy.
A
A
Tozzi
C
C
Costa
M
M
Di Filippo
M
M
Tantucci
S
S
Siliquini
V
V
Belcastro
L
L
Parnetti
B
B
Picconi
P
P
Calabresi
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D003292:Convulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D007306:Insecticides / Q000494:pharmacology; D007511:Ischemia / Q000473:pathology*; D008274:Magnesium / Q000378:metabolism; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects*; D009574:Nitro Compounds / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000494:pharmacology; D013997:Time Factors
D003292:Convulsants; D018691:Excitatory Amino Acid Antagonists; D007306:Insecticides; D009574:Nitro Compounds; D011422:Propionates; D012402:Rotenone; D008274:Magnesium; C015392:3-nitropropionic acid; D008559:Memantine