When more is less: magnesium attenuates the efficacy of memantine in an aged rat model of multiple sclerosis

Introduction

Ageing modulates both the pathophysiological mechanisms of multiple sclerosis and the efficacy of therapeutic interventions. The population of older patients with multiple sclerosis is increasing, reflecting the long-term disease course and a rising incidence of late-onset multiple sclerosis (onset after age 50). In our previous work, we demonstrated that N-methyl-D-aspartate receptors (NMDARs), expressed on both neuronal and immune cells, contribute significantly to the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, in aged rats. On the other hand, magnesium is known to play an important role in the regulation of neuronal excitability, largely through its interaction with NMDARs, and in the modulation of oxidative stress. Experimental data on the concomitant use of memantine, a non-competitive NMDAR antagonist, and magnesium are limited and partly contradictory, especially in in vivo models.

The Aim: To investigate the effects of combined memantine and magnesium treatment on immune cell populations and oxidative stress parameters in aged rats with EAE.

Methods

EAE was induced in female Dark Agouti rats aged 24 months. The animals were divided into four groups: EAE, EAE+memantine, EAE+magnesium, and EAE+memantine+magnesium. Memantine and/or magnesium were administered by oral gavage for 7 consecutive days from the first day post-immunisation. The animals were sacrificed on the 8th day after immunisation. Mononuclear cells were isolated from draining lymph nodes and analysed by flow cytometry, and superoxide anion radical, malondialdehyde, and superoxide dismutase (SOD) activity were assessed in brain tissue. For flow cytometric analysis, 50 000 events per sample were acquired using a flow cytometer, and compensation was applied using single-stained control samples. Data were analyzed with FlowJo software, version 7.8. Appropriate fluorescence minus one or isotype controls were used to define gating strategies and to determine marker-specific positivity. One-way analysis of variance followed by Bonferroni post hoc tests was performed for statistical analysis.

Results

Memantine significantly reduced (p < 0.001) the proportions of CD4⁺ and CD8⁺ T lymphocytes, NK cells and OX62⁺ dendritic cells in the draining lymph nodes of aged EAE rats compared with untreated EAE controls, indicating a marked suppression of peripheral immune activation. In parallel, memantine decreased oxidative stress in the brain, as reflected by lower levels of superoxide anion radical (p < 0.05) and malondialdehyde (p < 0.001), and increased superoxide dismutase (SOD) activity (p < 0.05), suggesting an improved antioxidant defence status. However, when magnesium was co‑administered with memantine, the reductions in the proportions of the immune cell subsets in the draining lymph nodes and the improvements in brain oxidative stress parameters were diminished, indicating that magnesium attenuated these immunomodulatory and antioxidant effects of memantine.

Conclusions

The combined administration of memantine and magnesium may attenuate the beneficial effects of memantine in an aged rat model of multiple sclerosis, and suggests a potential pharmacological interaction between these agents. These results underscore the importance of carefully evaluating drug–nutrient combinations in the context of ageing and neuroinflammation before translating them into clinical practice.

References

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