Anti-inflammatory effects of minocycline are mediated by retinoid signaling

Abstract

BackgroundMinocycline is a lipophilic tetracycline of increasing appeal in neuroscience as it inhibits microglial activation, a mechanism involved in numerous neuropsychiatric disorders. Own data point towards retinoid-mediated effects of minocycline in murine brain and skin, and towards a vicious cycle of neuroinflammation which is driven by microglial activation-induced breakdown of local retinoids such as retinoic acid (RA). We therefore sought to study minocycline’s anti-inflammatory effects on human microglial-like monocyte-derived cells in the context of retinoid signaling.ResultsAs hypothesized, minocycline exposure resulted in a substantial increase of RA levels in the human monocytic cell line THP-1. While pro-inflammatory stimulation with lipopolysaccharides resulted in increased tryptophane-degrading indoleamine-2,3-dioxygenase IDO-expression and TNF-α levels in primary human monocyte-derived microglial-like cells, this effect was attenuated by minocycline only in the presence of retinoids. The anti-inflammatory effects of minocycline on TNF-α expression were completely abolished by a pharmacological blockage of retinoic acid receptors (RARs) using BMS-493 and unaffected by selectively blocking retinoid-X-receptors using UVI-3003.ConclusionsOur data indicate for the first time a RA-dependent, anti-inflammatory effect for minocycline in human microglial-like cells via inhibition of local RA turnover. The RA-dependent mode of action for minocycline appears to be predominantly mediated through RAR-signaling.

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

“…Another interesting compound, which might target IDO, is the antibiotic minocycline, which was demonstrated to reduce IDO activation and thus prevent depressive-like behavior in animal studies (232)(233)(234). Minocycline was also able to decrease IDO expression and the formation of pro-inflammatory cytokines in LPS-treated monocytic human microglial cells (235)(236)(237), suggesting that IDO inhibition might be responsible for the anti-depressive effects of minocycline. Also, in humans a large and statistically significant antidepressant effect of minocycline has been observed when comparing to placebo [see review and metaanalysis by Rosenblat and McIntyre (238)].…”

Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia

“…To overcome this problem, it may be an option to enhance retinoid signaling by means of blocking RA degradation, which is a pivotal step in controlling local RA levels [28,65,66]. We previously identified this mechanism for pleiotropic minocycline [46,48,67], a tetracycline antibiotic and modulator of microglial activity discussed for use in SZ [68][69][70]. Out of all antipsychotics available, clozapine is still considered the most effective drug in treatmentrefractory SZ.…”

“…We hypothesized that clozapine might modulate RA homeostasis via direct interactions with local brain at-RA catabolism, which is highly prevalent in the human brain and the most relevant regulatory step in brain at-RA signaling [43][44][45]. To identify possible effects of clozapine and its metabolites on retinoid homeostasis, we used a previously established methodology to assess tissue-specific catabolism of RA in murine tissues, human postmortem brain tissue and human peripheral blood-derived mononuclear cells (PBMC) in vitro [46][47][48]. Furthermore, we assessed various RA homeostasis-related parameters in an observatory clinical study of patients with SZ with and without clozapine medication and matched healthy controls.…”

Minocycline for the treatment of mental health and neurological conditions: study protocol of a systematic review and meta-analysis

“…3 Minocycline has been proposed as a novel intervention for psychiatric and neurological disorders due to its anti-inflammatory, antioxidant and anti-apoptotic properties, in addition to its ability to promote neurogenesis. [4][5][6] Several neuropsychiatric and neurologic disorders have been associated with neuroinflammation. [7][8][9][10][11][12] Minocycline is known to have inhibitory effects on microglial activation.…”

“…[7][8][9][10][11][12] Minocycline is known to have inhibitory effects on microglial activation. 4 This inhibition aids to attenuate neuroinflammation and may be beneficial in preventing cognitive and behavioural impairments. In addition, the antioxidant properties of minocycline, including freeradical scavenging activity and inhibition of lipid peroxidation, have been described in several studies.…”