1. ¹College of Medicine, Institute of Behavioral Medicine, National Cheng-Kung University, Tainan, Taiwan
2. ²Department of Psychiatry, National Cheng-Kung University Hospital, Tainan, Taiwan
3. ³Laboratory of Pharmacology, Neuropharmacology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, USA
4. ⁴Department of Psychiatry, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan
5. ⁵Comprehensive Center for Inflammatory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
6. ⁶Cancer Biology Group, Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, USA
7. ⁷Medical Research Division, Department of Pharmacology, Edinburg Regional Academic Health Center, The University of Texas Health Science Center at San Antonio, Edinburg, TX, USA
8. ⁸Department of Pharmaceutical Sciences and Center for Substance Abuse Research, Temple University School of Pharmacy, Philadelphia, PA, USA

Correspondence: Professor R-B Lu, Department of Psychiatry, College of Medicine & Hospital, National Cheng Kung University, No. 138, Sheng-Li Road, 70428 Tainan, Taiwan, ROC. Tel: +886 6 235 3535 ext. 5108, Fax: +886 6 302 8012, E-mails: rblu@mail.ncku.edu.tw or rubandlu@gmail.com

⁹These authors contributed equally to this work.

Received 26 December 2008; Revised 11 May 2009; Accepted 11 May 2009; Published online 17 June 2009.

Abstract

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 E₂, and tumor necrosis factor-. 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.