Novel neuroprotective mechanisms of memantine: increase in neurotrophic factor release from astroglia and anti-inflammation by preventing microglial activation.
Memantine shows clinically relevant efficacy in patients with Alzheimer's disease and Parkinson's disease. Most in vivo and in vitro studies attribute the neuroprotective effects of memantine to the blockade of N-methyl-D-aspartate (NMDA) receptor on neurons. However, it cannot be excluded that mechanisms other than NMDA receptor blockade may contribute to the neuroprotective effects of this compound. To address this question, primary midbrain neuron-glia cultures and reconstituted cultures were used, and lipopolysaccharide (LPS), an endotoxin from bacteria, was used to produce inflammation-mediated dopaminergic (DA) neuronal death. Here, we show that memantine exerted both potent neurotrophic and neuroprotective effects on DA neurons in rat neuron-glia cultures. The neurotrophic effect of memantine was glia dependent, as memantine failed to show any positive effect on DA neurons in neuron-enriched cultures. More specifically, it seems to be that astroglia, not microglia, are the source of the memantine-elicited neurotrophic effects through the increased production of glial cell line-derived neurotrophic factor (GDNF). Mechanistic studies showed that GDNF upregulation was associated with histone hyperacetylation by inhibiting the cellular histone deacetylase activity. In addition, memantine also displays neuroprotective effects against LPS-induced DA neuronal damage through its inhibition of microglia activation showed by both OX-42 immunostaining and reduction of pro-inflammatory factor production, such as extracellular superoxide anion, intracellular reactive oxygen species, nitric oxide, prostaglandin E(2), and tumor necrosis factor-alpha. These results suggest that the neuroprotective effects of memantine shown in our cell culture studies are mediated in part through alternative novel mechanisms by reducing microglia-associated inflammation and by stimulating neurotrophic factor release from astroglia.
Wu
Hung-Ming
HM
College of Medicine, Institute of Behavioral Medicine, National Cheng-Kung University, Tainan, Taiwan.
Tzeng
Nian-Sheng
NS
Qian
Li
L
Wei
Sung-Jen
SJ
Hu
Xiaoming
X
Chen
Shih-Heng
SH
Rawls
Scott M
SM
Flood
Patrick
P
Hong
Jau-Shyong
JS
Lu
Ru-Band
RB
D000818:Animals; D000831:Animals, Newborn; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D015232:Dinoprostone / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D008559:Memantine / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D018709:Statistics, Nonparametric; D013481:Superoxides / Q000378:metabolism; D014316:Tritium / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D039481:CD11b Antigen; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D014316:Tritium; D013481:Superoxides; D009569:Nitric Oxide; D006655:Histone Deacetylases; D015232:Dinoprostone; D004298:Dopamine; D008559:Memantine