Tetrahydrobiopterin modulates the behavioral neuroinflammatory response to an LPS challenge in mice

Vancassel, Sylvie; Fanet, Hortense; Castanon, Nathalie; Oliveira, C Moncheaux De; Cussotto, Sofia; Capuron, Lucile

doi:10.1016/j.bbi.2022.06.016

Cited by 9 publications

(11 citation statements)

References 80 publications

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“…The open-field test was performed according to previous reports [ 27 ]. Mice were allowed to explore freely for 10 min.…”

Section: Methodsmentioning

confidence: 99%

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Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)

Guan

et al. 2023

J Neuroinflammation

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Background Mutations in colony-stimulating factor 1 receptor (CSF1R) are known to cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), which has been recently demonstrated as a primary microgliopathy characterized by cognitive impairment. Although the molecular mechanism underlying CSF1R-mediated microgliopathy remains unclear, therapeutic strategies have generally targeted modulation of microglial function. In particular, the microglial inhibitor, minocycline, has been shown to attenuate learning and memory deficits in several neurodegenerative diseases. The objectives of this study were to investigate the pathogenic mechanisms underlying ALSP and to explore the therapeutic effects of minocycline in an in vivo model of ALSP. We hypothesized that inhibiting microglial activation via minocycline could reverse the behavior and pathological defects in ALSP model mice. Methods We generated a Csf1r haploinsufficiency mouse model of ALSP using CRISPR/Cas9 genome editing and conducted electrophysiological recordings of long-term potentiation (LTP) and behavioral tests to validate the recapitulation of clinical ALSP characteristics in 8- to 11-month-old mice. RNA-sequencing was used to explore enriched gene expression in the molecular pathogenesis of ALSP. Microglial activation was assessed by immunofluorescent detection of Iba1 and CD68 in brain sections of male ALSP mice and pro-inflammatory activation and phagocytosis were assessed in Csf1r+/− microglia. Therapeutic effects were assessed by behavioral tests, histological analysis, and morphological examination after four weeks of intraperitoneal injection with minocycline or vehicle control in Csf1r+/− mice and wild-type control littermates. Results We found that synaptic function was reduced in LTP recordings of neurons in the hippocampal CA1 region, while behavioral tests showed impaired spatial and cognitive memory specifically in male Csf1r+/− mice. Increased activation, pro-inflammatory cytokine production, and enhanced phagocytic capacity were also observed in Csf1r+/− microglia. Treatment with minocycline could suppress the activation of Csf1r+/− microglia both in vitro and in vivo. Notably, the behavioral and pathological deficits in Csf1r+/− mice were partially rescued by minocycline administration, potentially due to inhibition of microglial inflammation and phagocytosis in Csf1r+/− mice. Conclusions Our study shows that CSF1R deficiency results in aberrant microglial activation, characterized by a pro-inflammatory phenotype and enhanced phagocytosis of myelin. Our results also indicate that microglial inhibition by minocycline can ameliorate behavioral impairment and ALSP pathogenesis in CSF1R-deficient male mice, suggesting a potential therapeutic target for CSF1R-related leukoencephalopathy. Collectively, these data support that minocycline confers protective effects against CSF1R-related microgliopathy in male ALSP model mice.

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“…The open-field test was performed according to previous reports [ 27 ]. Mice were allowed to explore freely for 10 min.…”

Section: Methodsmentioning

confidence: 99%

“…SPT was used to assess depression-like behavior in mice. The experiment is performed as previously described [ 27 ]. The sucrose preference test lasted for 2 days and consisted of two processes: the training process and the testing process.…”

Section: Methodsmentioning

confidence: 99%

Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)

Guan

et al. 2023

J Neuroinflammation

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“…Moreover, the GCH1-BH4 pathway has been demonstrated as an endogenous antioxidant pathway independent of GSH-GPX4 (Kraft et al, 2020). BH4 serves as a cofactor in redox metabolism and regulates the metabolism of monoamines and aromatic compounds (Vancassel et al, 2022;Vasquez-Vivar et al, 2022). Aberrantly expressed BH4 is capable of trapping oxidative free radicals and preventing the production of lipid peroxides.…”

Section: Gch1-bh4 Pathwaymentioning

confidence: 99%

Current insights into the functional roles of ferroptosis in musculoskeletal diseases and therapeutic implications

Zhang

Yan

Cai

et al. 2023

Front. Cell Dev. Biol.

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Ferroptosis is a novel type of cell death associated with iron accumulation and excessive lipid peroxidation. Elucidating the underlying molecular mechanisms of ferroptosis is intensively related to the development and treatment of multiple diseases, including musculoskeletal disorders. Moreover, in vitro and in vivo studies have shown the importance of oxidative stress in musculoskeletal conditions such as osteoporosis, osteoarthritis, rheumatoid arthritis, and osteosarcoma. Ferroptosis-derived clinical management of musculoskeletal diseases offers tremendous and attractive opportunities. Notably, ferroptosis agonists have been proven to enhance the sensitivity of osteosarcoma cells to conventional therapeutic strategies. In this review, we have mainly focused on the implications of ferroptosis regulation in the pathophysiology and therapeutic response of musculoskeletal disorders. Understanding roles of ferroptosis for controlling musculoskeletal diseases might provide directions for ferroptosis-driven therapies, which could be promising for the development of novel therapeutic strategies.

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“…In addition to interfering with 5-HT metabolism, proinflammatory cytokines have also been reported to disrupt the synthesis, release, and reuptake of DA. By suppressing striatal DA release, INF-α may contribute to multiple depressive symptoms ( 43 – 45 ). TNF-α can induce delayed and progressive loss of DA neurons in the substantia nigra (SN) ( 46 ).…”

Section: Graves' Disease As a Mechanistic Driver Of Depressionmentioning

confidence: 99%

“…As neurotransmitters play a critical role in the function of the central nervous system, the disrupted metabolism of monoamine neurotransmitters can increase the risk of depressive behaviors. On the one hand, disruption of these neurotransmitter metabolisms can result in the loss of innervation of monoamine neurons in the brain and induces depressive behaviors such as mood disorders ( 45 , 49 , 50 ). On the other hand, inflammation, as previously indicated, triggers an increase in QUIN, which binds to the N-methyl-D-aspartate receptor (NMDAR), inducing the release of glutamate ( 48 , 51 ).…”

Section: Graves' Disease As a Mechanistic Driver Of Depressionmentioning

confidence: 99%

Graves’ disease as a driver of depression: a mechanistic insight

Song

Wang

et al. 2023

Front. Endocrinol.

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Graves’ disease (GD) is characterized by diffuse enlargement and overactivity of the thyroid gland, which may be accompanied by other physical symptoms. Among them, depression can dramatically damage patients’ quality of life, yet its prevalence in GD has not received adequate attention. Some studies have established a strong correlation between GD and increased risk of depression, though the data from current study remains limited. The summary of mechanistic insights regarding GD and depression has underpinned possible pathways by which GD contributes to depression. In this review, we first summarized the clinical evidence that supported the increased prevalence of depression by GD. We then concentrated on the mechanistic findings related to the acceleration of depression in the context of GD, as mounting evidence has indicated that GD promotes the development of depression through various mechanisms, including triggering autoimmune responses, inducing hormonal disorders, and influencing the thyroid-gut-microbiome-brain axis. Finally, we briefly presented potential therapeutic approaches to decreasing the risk of depression among patients with GD.

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Tetrahydrobiopterin modulates the behavioral neuroinflammatory response to an LPS challenge in mice

Cited by 9 publications

References 80 publications

Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)

Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)

Current insights into the functional roles of ferroptosis in musculoskeletal diseases and therapeutic implications

Graves’ disease as a driver of depression: a mechanistic insight

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