Memantine upregulates BDNF and prevents dopamine deficits in SIV-infected macaques: a novel pharmacological action of memantine.
N-methyl-D-aspartate (NMDA) receptor activation is involved in the pathogenetic cascades of neurodegenerative disorders including human immunodeficiency virus (HIV) dementia. Memantine, an uncompetitive NMDA receptor antagonist, which has been recently approved for the treatment of Alzheimer's disease, is being discussed as a potential adjunctive therapeutic substance for HIV dementia. We used simian immunodeficiency virus-infected rhesus macaques to assess the effects of memantine on brain dysfunction and brain pathology within 3-5 months after initial infection during early asymptomatic stage of disease. We had shown previously that within this time frame, marked changes were evident in the dopaminergic systems. Memantine was administered two weeks post infection, at peak viremia, in order to prevent early NMDA receptor activation due to immune mediators. We found that memantine prevented onset of dopamine deficits in the brains of SIV-infected macaques, without affecting early brain pathology or peripheral course of infection. Memantine specifically upregulated mRNA and protein expression of the neurotrophic factor brain-derived neurotrophic factor (BDNF), suggesting that the protective effect of memantine on dopamine function may be mechanistically remote from NMDA receptor antagonism. This novel pharmacological action of memantine may also be relevant for other neurodegenerative disorders and supports the involvement of neurotrophic factors in adult brain neuroprotection.
Meisner
Falko
F
Institute of Virology and Immunobiology, University of Wurzburg, Germany.
Scheller
Carsten
C
Kneitz
Susanne
S
Sopper
Sieghart
S
Neuen-Jacob
Eva
E
Riederer
Peter
P
ter Meulen
Volker
V
Koutsilieri
Eleni
E
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D008253:Macaca mulatta; D008559:Memantine / Q000494:pharmacology* / Q000627:therapeutic use; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D015854:Up-Regulation / Q000187:drug effects*; D019562:Viral Load / Q000379:methods
D019208:Brain-Derived Neurotrophic Factor; D018691:Excitatory Amino Acid Antagonists; D012333:RNA, Messenger; D015102:3,4-Dihydroxyphenylacetic Acid; D004298:Dopamine; D008559:Memantine; D006719:Homovanillic Acid