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

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.

The GLP-1 receptor agonist liraglutide reverses mania-like alterations and memory deficits induced by D-amphetamine and augments lithium effects in mice: Relevance for bipolar disorder.

Metabolic and psychiatric disorders present a bidirectional relationship. GLP-1 system, known for its insulinotropic effects, has also been associated with numerous regulatory effects in cognitive and emotional processing. GLP-1 receptors (GLP-1R) agonists present neuroprotective and antidepressant/anxiolytic properties. However, the effects of GLP-1R agonism in bipolar disorder (BD) mania and the related cognitive disturbances remains unknown. Here, we investigated the effects of the GLP-1R agonist liraglutide (LIRA) at monotherapy or combined with lithium (Li) against D-amphetamine (AMPH)-induced mania-like symptoms, brain oxidative and BDNF alterations in mice. Swiss mice received AMPH 2 mg/kg or saline for 14 days. Between days 8-14, they received LIRA 120 or 240 µg/kg, Li 47.5 mg/kg or the combination Li + LIRA, on both doses. After behavioral evaluation the brain areas prefrontal cortex (PFC), hippocampus and amygdala were collected. AMPH induced hyperlocomotion, risk-taking behavior and multiple cognitive deficits which resemble mania. LIRA reversed AMPH-induced hyperlocomotion, working and recognition memory impairments, while Li + LIRA240 rescued all behavioral changes induced by AMPH. LIRA reversed AMPH-induced hippocampal oxidative and neurotrophic changes. Li + LIRA240 augmented Li antioxidant effects and greatly reversed AMPH-induced BDNF changes in PFC and hippocampus. LIRA rescued the weight gain induced by Li in the course of mania model. Therefore, LIRA can reverse some mania-like behavioral alterations and combined with Li augmented the mood stabilizing and neuroprotective properties of Li. This study points to LIRA as a promising adjunctive tool for BD treatment and provides the first rationale for the design of clinical trials investigating its possible antimanic effect.