Effects of prolonged treatment with memantine in the MRL model of central nervous system lupus
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AbstractNeuropsychiatric manifestations and brain atrophy of unknown etiology are common and severe complications of systemic lupus erythematosus (SLE). An autoantibody that binds to N‐methyl‐d‐aspartate (NMDA) receptor NR2 has been proposed as a key factor in the etiology of central nervous system (CNS) SLE. This hypothesis was supported by evidence suggesting memantine (MEM), an uncompetitive NMDA receptor antagonist, prevents behavioral dysfunction and brain pathology in healthy mice immunized with a peptide similar to an epitope on the NR2 receptor. Given that SLE is a chronic condition, we examined the effects of MEM in MRL/lpr mice, which develop behavioral deficits alongside SLE‐like disease. A broad behavioral battery and 7‐Tesla magnetic resonance imaging (MRI) were used to examine whether prolonged treatment with MEM (~25 mg/kg bodyweight in drinking water) prevents CNS involvement in this spontaneous model of SLE. Although MEM increased novel object exploration in MRL/lpr mice, it did not show other beneficial, substrain‐specific effects. Conversely, MEM was detrimental to spontaneous activity in control MRL+/+ mice and had a negative effect on body mass gain. Similarly, MRI showed comparable increases in the volume of periventricular structures in MEM‐treated groups. We conclude that sustained exposure to MEM affects body growth, brain morphology and behavior primarily by pharmacological, and not autoimmunity‐dependent, mechanisms. Substrain‐specific improvement in exploratory behavior of MEM‐treated MRL/lpr mice might indicate that the NMDA system is merely a constituent of a complex pathogenic cascade. However, it was evident that chronic administration of MEM is unable to completely prevent the development of a CNS SLE‐like syndrome.
