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https://www.arca.fiocruz.br/handle/icict/58025
DOXYCYCLINE REVERSES COGNITIVE IMPAIRMENT, NEUROINFLAMMATION AND OXIDATIVE IMBALANCE INDUCED BY D-AMPHETAMINE MANIA MODEL IN MICE: A PROMISING DRUG REPURPOSING FOR BIPOLAR DISORDER TREATMENT?
D-amphetamine
cognitive impairment
doxycycline
mania
microglial activation
neuroinflammation
oxidative stress
Author
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 combina-
tion (lithium+DOXY) on both doses. We collected the brain areas prefrontal cortex (PFC), hip-
pocampus, 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 GSK3β (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.
Keywords
Bipolar disorderD-amphetamine
cognitive impairment
doxycycline
mania
microglial activation
neuroinflammation
oxidative stress
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