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

被引：16
|
作者：
Maia Chaves Filho, Adriano Jose [1 ,2 ]
Cunha, Natassia Lopes [1 ]
Rodrigues, Patricia de Araujo [1 ]
de Souza, Alana Gomes [1 ]
Soares, Michele Verde-Ramo [1 ]
Juca, Paloma Marinho [1 ]
de Queiroz, Tatiana [1 ]
da Silva Clemente, Dino Cesar [1 ]
Mottin, Melina [2 ]
Andrade, Carolina Horta [2 ]
Peixoto, Christina Alves [3 ,4 ]
Macedo, Danielle S. [1 ,5 ]
机构：
[1] Univ Fed Ceara, Fac Med, Drug Res & Dev Ctr, Dept Physiol & Pharmacol,Neuropharmacol Lab, Fortaleza, Ceara, Brazil
[2] Univ Fed Goias, Fac Pharm, LabMol Lab Mol Modeling & Drug Design, Goiania, Go, Brazil
[3] Inst Aggeu Magalhaes FIOCRUZ, Lab Ultraestrutura, Recife, PE, Brazil
[4] Inst Nacl Ciencia & Tecnol Neuroimunomodulacao NI, Rio De Janeiro, Brazil
[5] CNPq, Natl Inst Translat Med INCT TM, Ribeirao Preto, SP, Brazil
来源：
EUROPEAN NEUROPSYCHOPHARMACOLOGY | 2021年 / 42卷
关键词：
Bipolar disorder; mania; doxycycline; D-amphetamine; cognitive impairment; neuroinflammation; microglial activation; oxidative stress; GLYCOGEN-SYNTHASE KINASE-3; ANIMAL-MODEL; DOPAMINERGIC-NEURONS; NITRIC-OXIDE; LITHIUM; MYELOPEROXIDASE; MINOCYCLINE; RATS; NEUROPROTECTION; SCHIZOPHRENIA;
D O I：
10.1016/j.euroneuro.2020.11.007
中图分类号：
R74 [神经病学与精神病学];
学科分类号：
摘要：
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 TNF alpha, 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 GSK3 /3 (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. (c) 2020 Elsevier B.V. and ECNP. All rights reserved.
引用
收藏
页码：57 / 74
页数：18
相关论文
共 1 条
  • [1] 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
    Chaves Filho, Adriano Jose Maia
    Cunha, Natassia Lopes
    de Souza, Alana Gomes
    Soares, Michele Verde-Ramo
    Juca, Paloma Marinho
    de Queiroz, Tatiana
    Souza Oliveira, Joao Victor
    Valvassori, Samira S.
    Barichello, Tatiana
    Quevedo, Joao
    de Lucena, David
    Macedo, Danielle S.
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, 2020, 99
1