Diazepam treatment reduces inflammatory cells and mediators in the central nervous system of rats with experimental autoimmune encephalomyelitis

Hurst, Nicolás Fernández; Zanetti, Samanta Romina; Baez, Natalia Soledad; Bibolini, Mario J.; Bouzat, Cecilia; Roth, German A.

doi:10.1016/j.jneuroim.2017.09.012

Cited by 21 publications

(11 citation statements)

References 32 publications

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“…Similarly, although islet ß-cells secrete GABA, it is insufficient to prevent T1D in NOD mice, but exogenous GABA or homotaurine administration can prevent and/or reverse the disease [2][3][4]27 . Consistent with our observations, the administration of the benzodiazepine diazepam has been shown to inhibit EAE (e.g., 42,43 ). However, many benzodiazepines such as diazepam also bind to the mitochondrial translocator protein (TSPO, previously referred to as a "peripheral benzodiazepine receptor"), making it difficult to discern effects mediated through TSPO versus those through GABA A -Rs.…”

Section: Discussionsupporting

confidence: 91%

Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis

Tian

Song

Kaufman

2021

Sci Rep

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Most multiple sclerosis (MS) patients given currently available disease-modifying drugs (DMDs) experience progressive disability. Accordingly, there is a need for new treatments that can limit the generation of new waves T cell autoreactivity that drive disease progression. Notably, immune cells express GABAA-receptors (GABAA-Rs) whose activation has anti-inflammatory effects such that GABA administration can ameliorate disease in models of type 1 diabetes, rheumatoid arthritis, and COVID-19. Here, we show that oral GABA, which cannot cross the blood–brain barrier (BBB), does not affect the course of murine experimental autoimmune encephalomyelitis (EAE). In contrast, oral administration of the BBB-permeable GABAA-R-specific agonist homotaurine ameliorates monophasic EAE, as well as advanced-stage relapsing–remitting EAE (RR-EAE). Homotaurine treatment beginning after the first peak of paralysis reduced the spreading of Th17 and Th1 responses from the priming immunogen to a new myelin T cell epitope within the CNS. Antigen-presenting cells (APC) isolated from homotaurine-treated mice displayed an attenuated ability to promote autoantigen-specific T cell proliferation. The ability of homotaurine treatment to limit epitope spreading within the CNS, along with its safety record, makes it an excellent candidate to help treat MS and other inflammatory disorders of the CNS.

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Section: Discussionsupporting

confidence: 91%

Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis

Tian

Song

Kaufman

2021

Sci Rep

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“…As shown in Figure 8J,K, the TSPO signal clearly co-localized to both, eGFP-expressing microglia and RFP-expressing monocyte-derived macrophages. Although not shown in this study, it has been reported that TSPO is as well expressed by CD4 + lymphocytes in EAE [72], as it is in humans [73] and in a model of rheumatoid arthritis [69]. Further studies have to demonstrate to what extent lymphocytes and other peripheral immune cells contribute to the increased TSPO ligand uptake observed in MS lesions.…”

Section: Discussionmentioning

confidence: 62%

Expression of Translocator Protein and [18F]-GE180 Ligand Uptake in Multiple Sclerosis Animal Models

Nack

Brendel

Nedelcu

et al. 2019

Cells

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Positron emission tomography (PET) ligands targeting the translocator protein (TSPO) represent promising tools to visualize neuroinflammation in multiple sclerosis (MS). Although it is known that TSPO is expressed in the outer mitochondria membrane, its cellular localization in the central nervous system under physiological and pathological conditions is not entirely clear. The purpose of this study was to assess the feasibility of utilizing PET imaging with the TSPO tracer, [18F]-GE180, to detect histopathological changes during experimental demyelination, and to determine which cell types express TSPO. C57BL/6 mice were fed with cuprizone for up to 5 weeks to induce demyelination. Groups of mice were investigated by [18F]-GE180 PET imaging at week 5. Recruitment of peripheral immune cells was triggered by combining cuprizone intoxication with MOG35–55 immunization (i.e., Cup/EAE). Immunofluorescence double-labelling and transgene mice were used to determine which cell types express TSPO. [18F]-GE180-PET reliably detected the cuprizone-induced pathology in various white and grey matter regions, including the corpus callosum, cortex, hippocampus, thalamus and caudoputamen. Cuprizone-induced demyelination was paralleled by an increase in TSPO expression, glia activation and axonal injury. Most of the microglia and around one-third of the astrocytes expressed TSPO. TSPO expression induction was more severe in the white matter corpus callosum compared to the grey matter cortex. Although mitochondria accumulate at sites of focal axonal injury, these mitochondria do not express TSPO. In Cup/EAE mice, both microglia and recruited monocytes contribute to the TSPO expressing cell populations. These findings support the notion that TSPO is a valuable marker for the in vivo visualization and quantification of neuropathological changes in the MS brain. The pathological substrate of an increase in TSPO-ligand binding might be diverse including microglia activation, peripheral monocyte recruitment, or astrocytosis, but not axonal injury.

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“…Overall, these results indicate a further enhancement of the anti-inflammatory activity by the performed molecular modification. It has been found that diazepam reduces the number of inflammatory cells in the central nervous system [11], treatment with high diazepam doses decreases paw oedema after carrageenan-induced injury [12] and that benzodiazepine derivatives with imide substitution at the C3 of the benzodiazepine ring reduced up to 80% carrageenan rat paw hyperalgesia, in a dose dependent manner, and this activity was at least partly attributed to bradykinin B 1 receptor antagonism [6].…”

Section: Resultsmentioning

confidence: 99%

Active Anti-Inflammatory and Hypolipidemic Derivatives of Lorazepam

et al. 2019

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Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%–93%). All the tested derivatives strongly decreased lipidemic indices in rat plasma after Triton induced hyperlipidaemia. They also reduced acute inflammation and a number of them demonstrated lipoxygenase inhibitory activity. Those compounds acquiring antioxidant moiety were inhibitors of lipid peroxidation and radical scavengers. Therefore, the synthesised compounds may add to the current knowledge about multifunctional agents acting against various disorders implicating inflammation, dyslipidaemia and oxidative stress.

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Diazepam treatment reduces inflammatory cells and mediators in the central nervous system of rats with experimental autoimmune encephalomyelitis

Cited by 21 publications

References 32 publications

Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis

Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis

Expression of Translocator Protein and [18F]-GE180 Ligand Uptake in Multiple Sclerosis Animal Models

Active Anti-Inflammatory and Hypolipidemic Derivatives of Lorazepam

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