1. ¹Institute of Virology and Immunobiology, University of Wurzburg, Germany
2. ²IZKF (Interdisciplinary Center for Clinical Research), University of Wurzburg, Germany
3. ³German Primate Center, Göttingen, Germany
4. ⁴Institute of Neuropathology, University of Duesseldorf, Germany
5. ⁵Clinical Neurochemistry (National Parkinson Foundation Center of Excellence Research Laboratory), Psychiatry and Psychotherapy, University of Wurzburg, Germany

Correspondence: PD Dr Eleni Koutsilieri, Clinical Neurochemistry, Department of Psychiatry and Psychotherapy, University of Wurzburg, Füchsleinstr. 15, Wurzburg 97080, Germany, Tel: ++49 931 20149928; Fax: ++49 931 20149553; E-mail: eleni.koutsilieri@mail.uni-wuerzburg.de

Received 26 June 2007; Revised 18 September 2007; Accepted 1 October 2007; Published online 31 October 2007.

Abstract

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.