Doxycycline reverses cognitive impairment, neuroinflammation and oxidative imbalance induced by D-amphetamine mania model in mice: A promising drug repurposing for bipolar disorder treatment?

ABSTRACT

Immune-inflammatory mechanisms are involved in the pathophysiology of bipolar disorder. Tetracyclines present neuroprotective actions based on their anti-inflammatory and microglia suppressant effects. Doxycycline (DOXY) is a tetracycline that demonstrates a better usage profile with protective actions against inflammation and CNS injury. Here, we investigated the effects of DOXY against behavioral, neuroinflammatory, and pro-oxidative changes induced by the d-amphetamine mania model. Adult mice were given d-amphetamine 2.0 mg/kg or saline for 14 days. Between days 8 and 14, received lithium, DOXY (25 or 50 mg/kg), or their combination (lithium+DOXY) on both doses. We collected the brain areas prefrontal cortex (PFC), hippocampus, and amygdala to evaluate inflammatory and oxidative alterations. D-amphetamine induced hyperlocomotion and impairment in recognition and working memory. Lithium reversed hyperlocomotion but could not restore cognitive alterations. DOXY alone (at both doses) or combined with lithium reversed d-amphetamine-induced cognitive changes. DOXY, better than lithium, reversed the d-amphetamine-induced rise in TNFα, MPO, and lipid peroxidation. DOXY reduced the hippocampal expression of Iba1 (a marker of microglial activation), inducible nitric oxide synthase (iNOS), and nitrite. Combined with lithium, DOXY increased the phosphorylated (inactivated) form of GSK3ß (Ser9). Therefore, DOXY alone or combined with lithium reversed cognitive impairment and neuroinflammation induced by the mice's d-amphetamine model. This study points to DOXY as a promising adjunctive tool for bipolar disorder treatment focused on cognition and neuroimmune changes. Our data provide the first rationale for clinical trials investigating DOXY therapeutic actions in bipolar disorder mania.