Meningeal dendritic cells drive neuropathic pain through elevation of the kynurenine metabolic pathway in mice.

Neuropathic pain is one of the most important clinical consequences of injury to the somatosensory system. Nevertheless, the critical pathophysiological mechanisms involved in neuropathic pain development are poorly understood. In this study, we found that neuropathic pain is abrogated when the kynurenine metabolic pathway (KYNPATH) initiated by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is ablated pharmacologically or genetically. Mechanistically, it was found that IDO1-expressing dendritic cells (DCs) accumulated in the dorsal root leptomeninges and led to an increase in kynurenine levels in the spinal cord. In the spinal cord, kynurenine was metabolized by kynurenine-3-monooxygenase-expressing astrocytes into the pronociceptive metabolite 3-hydroxykynurenine. Ultimately, 3-hydroxyanthranilate 3,4-dioxygenase-derived quinolinic acid formed in the final step of the canonical KYNPATH was also involved in neuropathic pain development through the activation of the glutamatergic N-methyl-D-aspartate receptor. In conclusion, these data revealed a role for DCs driving neuropathic pain development through elevation of the KYNPATH. This paradigm offers potential new targets for drug development against this type of chronic pain.

Detection of the Cytotoxic Penitrems A-F in Cheese from the European Single Market by HPLC-MS/MS.

Penitrems are fungal indole diterpene-derived tremorgenic secondary metabolites, which are mainly produced by Penicillium spp. Several cases of intoxications with penitrems and subsequent occurrences of penitrem A in foodstuff underline the need for reliable quantitation methods for the detection of these mycotoxins in food. In this study, a simple and fast high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the quantitative analysis of penitrems A-F in cheese was developed. Therefore, penitrems A-F were isolated from Penicillium crustosum as analytical reference standards. The analysis of 60 cheese samples from the European single market (EU) revealed the occurrence of penitrem A in 10% of the analyzed samples with an average concentration of 28.4 µg/kg and a maximum concentration of 429 µg/kg. In addition to penitrem A, other members of the group of penitrems, namely, penitrems B, C, D, E, and F, were for the first time quantitatively detected in food samples, although in lower concentrations and with lower incidence in comparison to penitrem A. Moreover, we report cytotoxic effects of all penitrems on two cell lines (HepG2 and CCF-STTG1). This clearly underlines their relevance and the importance to analyze food samples in order to get insights into the human exposure toward these mycotoxins.