Neuroprotective effects of dimethyl fumarate against depression-like behaviors via astrocytes and microglia modulation in mice: possible involvement of the HCAR2/Nrf2 signaling pathway

Souza, Alana Gomes de; Lopes, Iardja Stéfane; Filho, Adriano José Maia Chaves; Cavalcante, Talita Matias Barbosa; Oliveira, João Almir; Carvalho, Michelle Garcêz de; Lima, Klistenes Alves de; Jucá, Paloma Marinho; Mendonça, Sabrina Silva; Mottin, Melina; Andrade, Carolina Horta; Sousa, Francisca Cléa Florenço de; Macêdo, Danielle Silveira; Fonteles, Marta Maria de França

doi:10.1007/s00210-022-02247-x

Cited by 11 publications

(13 citation statements)

References 106 publications

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“…The studies included here were based on different animal depression paradigms, with many studies using stress-induced DLB, mostly elicited by LPS [ 40 , 43 , 51 , 53 , 58 , 59 , 63 , 65 , 67 , 73 , 75 , 79 , 85 , 88 , 95 , 105 , 106 , 125 ], or through corticosterone or cortisol [ 44 , 46 , 80 , 87 , 98 ], while other studies used chronic unpredictable mild stress [ 61 , 72 , 76 , 83 , 93 , 96 , 97 , 99 , 100 , 101 , 106 , 108 , 111 , 122 , 124 ] or social defeat stress [ 50 , 52 , 88 , 102 , 107 , 120 ]. Two studies used tumour-related depression models [ 71 , 91 ], while just one study each used post-ovariectomised depression [ 121 ], pentylenetetrazol-induced seizures [ 116 ], maternal separation [ <...…”

Section: Discussionmentioning

confidence: 99%

“…Anti-inflammatory or anti-neuroinflammatory effects of employed antidepressants and putative antidepressant substances, such as the many plant extracts used in the studies we considered here, were shown to be related to various improvements in neurochemical indexes and behavioural tests [ 43 , 48 , 59 , 71 , 76 , 81 , 85 , 91 , 95 , 108 , 111 , 123 , 125 ].…”

Section: Discussionmentioning

confidence: 99%

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The Nrf2 Pathway in Depressive Disorders: A Systematic Review of Animal and Human Studies

et al. 2023

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There is increasing interest in the involvement of antioxidative systems in protecting from depression. Among these, Nrf2 occupies a central place. We aimed to review the role of Nrf2 in depression. For this reason, we conducted a PubMed search using as search strategy (psychiatr*[ti] OR schizo*[ti] OR psychot*[ti] OR psychos*[ti] OR depress*[ti] OR MDD[ti] OR BD[ti] OR bipolar[ti] OR Anxiety[ti] OR antidepress*[ti] OR panic[ti] OR obsess*[ti] OR compulsio*[ti] OR “mood disord*”[ti] OR phobi*[ti] OR agoraphob*[ti] OR anorex*[ti] OR anorect*[ti] OR bulimi*[ti] OR “eating disorder*”[ti] OR neurodevelopm*[ti] OR retardation[ti] OR autism[ti] OR autistic[ti] OR ASM[ti] OR adhd[ti] OR “attention-deficit”[ti]) AND nrf2, which on the 9th of March produced 208 results of which 89 were eligible for our purposes. Eligible articles were studies reporting data of Nrf2 manipulations or content by any treatment in human patients or animals with any animal model of depression. Most studies were on mice only (N = 58), 20 on rats only, and three on both rats and mice. There were two studies on cell lines (in vitro) and one each on nematodes and fish. Only four studies were conducted in humans, one of which was post mortem. Most studies were conducted on male animals; however, human studies were carried out on both men and women. The results indicate that Nrf2 is lower in depression and that antidepressant methods (drugs or other methods) increase it. Antioxidant systems and plasticity-promoting molecules, such as those in the Nrf2–HO-1, BDNF–TrkB, and cyclic AMP–CREB pathways, could protect from depression, while glycogen synthase kinase-3β and nuclear factor κB oppose these actions, thus increasing depressive-like behaviours. Since Nrf2 is also endowed with tumorigenic and atherogenic potential, the balance between benefits and harms must be taken into account in designing novel drugs aiming at increasing the intracellular content of Nrf2.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Nrf2 Pathway in Depressive Disorders: A Systematic Review of Animal and Human Studies

et al. 2023

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“…The DMF vehicle was DMSO and PEG300 in a 19:1 v/v ratio. The dose of DMF was at the high end of the range used in previous mouse studies [ 18 , 19 ] to ensure the MMF plasma concentrations could be quantified over a reasonable time frame, and the alcohol dose of 3 g/kg is the same dose as used in a previous mouse study of alcohol’s interaction with methylphenidate, a CES1-substrate drug [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

Alcohol inhibits the metabolism of dimethyl fumarate to the active metabolite responsible for decreasing relapse frequency in the treatment of multiple sclerosis

et al. 2022

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Dimethyl fumarate (DMF) is a first-line prodrug for the treatment of relapsing-remitting multiple sclerosis (RRMS) that is completely metabolized to monomethyl fumarate (MMF), the active metabolite, before reaching the systemic circulation. Its metabolism has been proposed to be due to ubiquitous esterases in the intestines and other tissues, but the specific enzymes involved are unknown. We hypothesized based on its structure and extensive presystemic metabolism that DMF would be a carboxylesterase substrate subject to interaction with alcohol. We sought to determine the enzymes(s) responsible for the extensive presystemic metabolism of DMF to MMF and the effect of alcohol on its disposition by conducting metabolic incubation studies in human recombinant carboxylesterase-1 (CES1), carboxylesterase-2 (CES2) and human intestinal microsomes (HIM), and by performing a follow-up study in an in vivo mouse model. The in vitro incubation studies demonstrated that DMF was only metabolized to MMF by CES1. Consistent with the incubation studies, the mouse pharmacokinetic study demonstrated that alcohol decreased the maximum concentration and area-under-the-curve of MMF in the plasma and the brain after dosing with DMF. We conclude that alcohol may markedly decrease exposure to the active MMF metabolite in the plasma and brain potentially decreasing the effectiveness of DMF in the treatment of RRMS.

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“…The entry of any foreign pathogen activates glial cells (astrocytes and microglia) and the over-activation of these cells triggers the release of various neuroinflammatory markers (NM), such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-10 (IL-10), nitric oxide (NO), COX-2, etc. Various studies have shown the importance of neuroinflammatory markers in the development, diagnosis and treatment of depression (9)(10)(11).…”

Section: Cyclo-oxygen-ase-2 Roles In the Pathogenesis Of Depression N...mentioning

confidence: 99%

Biology of cyclooxygenase-2: An application in depression therapeutics

Han

Liao

et al. 2022

Front. Psychiatry

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Depressive Disorder is a common mood disorder or affective disorder that is dominated by depressed mood. It is characterized by a high incidence and recurrence. The onset of depression is related to genetic, biological and psychosocial factors. However, the pathogenesis is still unclear. In recent years, there has been an increasing amount of research on the inflammatory hypothesis of depression, in which cyclo-oxygen-ase 2 (COX-2), a pro-inflammatory cytokine, is closely associated with depression. A variety of chemical drugs and natural products have been found to exert therapeutic effects by modulating COX-2 levels. This paper summarizes the relationship between COX-2 and depression in terms of neuroinflammation, intestinal flora, neurotransmitters, HPA axis, mitochondrial dysfunction and hippocampal neuronal damage, which can provide a reference for further preventive control, clinical treatment and scientific research on depression.

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Neuroprotective effects of dimethyl fumarate against depression-like behaviors via astrocytes and microglia modulation in mice: possible involvement of the HCAR2/Nrf2 signaling pathway

Cited by 11 publications

References 106 publications

The Nrf2 Pathway in Depressive Disorders: A Systematic Review of Animal and Human Studies

The Nrf2 Pathway in Depressive Disorders: A Systematic Review of Animal and Human Studies

Alcohol inhibits the metabolism of dimethyl fumarate to the active metabolite responsible for decreasing relapse frequency in the treatment of multiple sclerosis

Biology of cyclooxygenase-2: An application in depression therapeutics

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