MANIC BEHAVIOR MAY BE ATTENUATED BY MATRIX METALLOPROTEINASE-8 INHIBITOR VIA DECREASING NEUROINFLAMMATION IN A MOUSE MODEL OF BIPOLAR DISORDER

Abstract Background Emergent evidence showed that neuroinflammation may be involved in the pathogenesis of bipolar disorder (BD). Ouabain, a Na+/K+-ATPase inhibitor, is used to induce BD in animal models [1] and is associated with neuroinflammation and glial cell activation [2]. Our previous study showed that ouabain treatment in astrocytes may increase matrix metalloproteinase (MMP)-8 expression. Aims & Objectives In the present study, we investigated whether the MMP-8 inhibitor, M8I, could control neuroinflammation and reduce manic-like behavior in an ouabain-induced BD animal model. Method Ouabain was intracerebroventricular (ICV) injected in mice to induce manic-like behavior in the open field test and tail suspension test. Pretreatment of M8I (5 mg/kg) or control medium was given before the 7th day of ouabain ICV injection. We then measured the behavior change and the activation pattern of astrocytes and microglia in the frontal cortex and hippocampus in ouabain-induced BD mice with M8I or control medium pretreatment. Results 0.625 nmol of ouabain ICV administration induced manic-like behavior in mice with increased locomotor activity both shown in the open field test and tail suspension test. Immunofluorescence in the hippocampal CA1 region showed an increased activation of astrocytes and microglia in ouabain-treated mice. Notably, pretreatment with M8I may reduce hyperactivity in the tail suspension test and attenuate the overactivation of astrocytes and microglia. Discussion & Conclusion Our study suggested neuroinflammation may have a key role in the pathogenesis of bipolar disorder, especially in the manic symptoms. The manic-like behavior may be attenuated by M8I via suppressing overactivated microglia and astrocytes in the hippocampus. Further studies to investigate the potential roles of M8I in treating depressive behavior in the ouabain-induced BD animal model may be warranted. References 1.Valvassori, S.S., et al., Validation of the animal model of bipolar disorder induced by Ouabain: face, construct and predictive perspectives. Transl Psychiatry, 2019. 9(1), 158. 2.Kurauchi, Y., et al., 2018. Na(+), K(+)-ATPase inhibition induces neuronal cell death in rat hippocampal slice cultures: Association with GLAST and glial cell abnormalities. J Pharmacol Sci, 2018. 138(3), 167- 175.