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

Filho, Adriano José Maia Chaves; Cunha, Natássia Lopes; Rodrigues, Patrícia; Souza, Alana Gomes de; Soares, Michele Verde-Ramo; Jucá, Paloma Marinho; Queiroz, Tatiana de; Clemente, Dino César da Silva; Mottin, Melina; Andrade, Carolina Horta; Peixoto, Christina Alves; Macêdo, Danielle Silveira

doi:10.1016/j.euroneuro.2020.11.007

Cited by 16 publications

(7 citation statements)

References 78 publications

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“…Likewise, the use of minocycline can be particularly effective for the therapy of bipolar depression in patients with high glutathione (GSH) levels [ 318 ]. Similar roles have been given to another tetracycline, doxycycline, which appears to be a promising adjunctive therapy with lithium for treating BD, according to preclinical models [ 319 ]. Other studies and systematic reviews, however, did not find any benefits from using minocycline as adjunctive therapy in patients with BD [ 320 , 321 ], and contrary to some proposals, doxycycline exposure in the adolescence did not report any causal relationship between this tetracycline and BD development [ 322 ].…”

Section: Translational Approaches Modulating Gut Microbiotamentioning

confidence: 99%

Microbiota–gut–brain axis mechanisms in the complex network of bipolar disorders: potential clinical implications and translational opportunities

et al. 2023

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Bipolar disorders (BD) represent a severe leading disabling mental condition worldwide characterized by episodic and often progressive mood fluctuations with manic and depressive stages. The biological mechanisms underlying the pathophysiology of BD remain incompletely understood, but it seems that there is a complex picture of genetic and environmental factors implicated. Nowadays, gut microbiota is in the spotlight of new research related to this kind of psychiatric disorder, as it can be consistently related to several pathophysiological events observed in BD. In the context of the so-called microbiota–gut–brain (MGB) axis, it is shown to have a strong influence on host neuromodulation and endocrine functions (i.e., controlling the synthesis of neurotransmitters like serotonin or mediating the activation of the hypothalamic–pituitary–adrenal axis), as well as in modulation of host immune responses, critically regulating intestinal, systemic and brain inflammation (neuroinflammation). The present review aims to elucidate pathophysiological mechanisms derived from the MGB axis disruption and possible therapeutic approaches mainly focusing on gut microbiota in the complex network of BD. Understanding the mechanisms of gut microbiota and its bidirectional communication with the immune and other systems can shed light on the discovery of new therapies for improving the clinical management of these patients. Besides, the effect of psychiatric drugs on gut microbiota currently used in BD patients, together with new therapeutical approaches targeting this ecosystem (dietary patterns, probiotics, prebiotics, and other novelties) will also be contemplated.

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Section: Translational Approaches Modulating Gut Microbiotamentioning

confidence: 99%

Microbiota–gut–brain axis mechanisms in the complex network of bipolar disorders: potential clinical implications and translational opportunities

et al. 2023

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“…An alternative is drug repurposing, which is strongly supported by governments and funding bodies as an efficient and effective option [ 108 ] (see [ 109 ] for detailed benefits). In addition, drug repurposing may be particularly appropriate in conditions with high oxidative stress and comorbidities [ 110 , 111 ]. We propose that trimetazidine is a promising drug that can be repurposed to target mitochondrial dysfunction, inflammation and oxidative stress to treat bipolar depression.…”

Section: Trimetazidinementioning

confidence: 99%

Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine

et al. 2023

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Bipolar disorder’s core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression–mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine’s potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine’s demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.

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“…The observation that mood stabilizing agents such as lithium and sodium valproate also exert antioxidant effects, reinforces the idea that oxidative stress is involved in the pathophysiology and treatment of mania (Andreazza et al, 2007;Banerjee et al, 2012;Brown et al, 2014;Kanazawa et al, 2016;Valvassori et al, 2017;de Queiroz et al, 2018). However, the antioxidant effects of lithium may be specific to certain brain regions and these can vary depending on experimental variables including type of drug and age of animals (Chaves Filho et al, 2020;Schmitz et al, 2012). Particularly to LDX, it increased LPO in rat PFC, hippocampus and striatum, and lithium and valproate prevented and reversed the effects of repeated LDX administration on LPO in these brain areas (Macêdo et al, 2013;de Souza et al, 2015).…”

Section: Discussionmentioning

confidence: 57%

“…Oxidative stress in the brain was observed in different models of mania such as psychostimulants (Frey et al, 2006;Sharma et al, 2016;Hodes et al, 2018;Valvassori et al, 2019;Chaves Filho et al, 2020), ouabain (Valvassori et al, 2017;Dal Pont et al, 2019), sleep deprivation Fig. 3.…”

Section: Discussionmentioning

confidence: 99%

Andrographolide blocks 50-kHz ultrasonic vocalizations, hyperlocomotion and oxidative stress in an animal model of mania

Kanazawa

Radulski

Pereira

et al. 2021

Journal of Psychiatric Research

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

Cited by 16 publications

References 78 publications

Microbiota–gut–brain axis mechanisms in the complex network of bipolar disorders: potential clinical implications and translational opportunities

Microbiota–gut–brain axis mechanisms in the complex network of bipolar disorders: potential clinical implications and translational opportunities

Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine

Andrographolide blocks 50-kHz ultrasonic vocalizations, hyperlocomotion and oxidative stress in an animal model of mania

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