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PO1-1-68

Memantine treatment improves hyperactivity induced by Na+, K+-ATPase dysfunction in mice

[Speaker] Taishi Yamada:1
[Co-author] Yuki Kurauchi:1, Akinori Hisatsune:2,3, Takahiro Seki:1, Hiroshi Katsuki:1
1:Chemico-Pharmacological Sciences, Kumamoto University, Japan, 2:Priority Organization for Innovation and Excellence, Kumamoto University, Japan, 3:Program for Leading Grad. Sch. HIGO Program, Kumamoto University, Japan

Dysfunction of Na+, K+-ATPase has been implicated in the pathophysiology of psychiatric disorders such as schizophrenia, bipolar disorder and attention deficit hyperactivity disorder. We have previously reported that intracerebroventricular (ICV) injection of ouabain, an inhibitor of Na+, K+-ATPase, induces hyperactivity in mice. Although excessive release of glutamate from neurons and glial cells is reported to be involved in the pathophysiology of psychiatrie disorders, it is poorly understood whether glutamatergic system contributes to hyperactivity induced by Na+, K+-ATPase dysfunction. In this study, we investigated the effect of memantine, a blocker of N-methyl-D-aspartate (NMDA) receptor, on hyperactivity and brain pathophysiology induced by pharmacological inhibition of Na+, K+-ATPase in mice.
Male C57BL/6J mice at 5 weeks old received oral administration of memantine (40 mg/kg/day) in drinking water for 7 days, and then received ICV injection of ouabain (0.625 nmol). Seven days after ouabain injection, open field test was performed to assess locomotor activity. After open field test, mice brain were removed and immunohistochemistry and western blotting were performed.
ICV injection of ouabain significantly increased the distance traveled within the open field arena, which was prevented by memantine. By immunohistochemistry, ICV injection of ouabain significantly decreased the number of NeuN-positive cells in hippocampal CA3 regions, which was prevented by memantine. Although we observed significant increase in the number of ionized calcium binding adapter molecule 1 (Iba1)-positive cells as well as glial fibrillary acidic protein (GFAP)-positive cells in hippocampal CA3 region, memantine had little effect on glial activation. Iba1 and GFAP were used as microglia and astrocyte marker. By western blotting, administration of memantine significantly increased the protein level of glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT1) in the hippocampus in ouabain-injected mice.
These results suggest that neuroprotective action via NMDA blockade and upregulation of glutamate transporter expression on astrocytes contribute to the inhibitory effect of memantine on hyperactivity induced by Na+, K+-ATPase dysfunction in mice.

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