The FKBP51 Inhibitor SAFit2 Restores the Pain-Relieving C16 Dihydroceramide after Nerve Injury

Abstract

Neuropathic pain is a pathological pain state with a broad symptom scope that affects patients after nerve injuries, but it can also arise after infections or exposure to toxic substances. Current treatment possibilities are still limited because of the low efficacy and severe adverse effects of available therapeutics, highlighting an emerging need for novel analgesics and for a detailed understanding of the pathophysiological alterations in the onset and maintenance of neuropathic pain. Here, we show that the novel and highly specific FKBP51 inhibitor SAFit2 restores lipid signaling and metabolism in nervous tissue after nerve injury. More specifically, we identify that SAFit2 restores the levels of the C16 dihydroceramide, which significantly reduces the sensitization of the pain-mediating TRPV1 channel and subsequently the secretion of the pro-inflammatory neuropeptide CGRP in primary sensory neurons. Furthermore, we show that the C16 dihydroceramide is capable of reducing acute thermal hypersensitivity in a capsaicin mouse model. In conclusion, we report for the first time the C16 dihydroceramide as a novel and crucial lipid mediator in the context of neuropathic pain as it has analgesic properties, contributing to the pain-relieving properties of SAFit2.

FKBP5 drives bone marrow stem cells senescence and suppresses osteogenic differentiation via canonical WNT/β-catenin signaling pathway

“…SAFit2 is a promising pharmacological agent that inhibits FKBP5 and modulates stress responses [36][37][38]. This small molecule selectively targets FKBP5 but not the closely related FKBP4 [13,39]. Using an animal model of senile osteoporosis, we showed that administration of SAFit2 enhanced bone density.…”

SAFit2 ameliorates paclitaxel-induced neuropathic pain by reducing spinal gliosis and elevating pro-resolving lipid mediators

“…The tissue samples were grinded for 30 to 60 s, with short breaks included to avoid overheating, in an ethanol:water (1:9, v/v) solution, using 119 µl ethanol for DRG samples and 1190 µl ethanol for spinal cord samples. Afterwards, lipid extraction and chromatographic separation was performed as well as the measurement settings and internal standards chosen as previously described [ 24 ]. Instrumental setup consisted of a Vanquish Horizon coupled to an Exploris 480 (both Thermo Fisher Scientific) with Zorbax RRHD Eclipse Plus C8 column (2.1 × 50 mm, 1.8 µm, Agilent) and a pre-column of the same type.…”

Analysis of the Selective Antagonist SAFit2 as a Chemical Probe for the FK506-Binding Protein 51

“…In particular, the levels of C16 dihydroceramide (d18:0/ 16:0), an antihyperalgesic lipid mediator, were restored upon treatment with SAFit2 in the lumbar DRG. 71 Overall, the collective studies with SAFit, together with results from FKBP51-deficient mice, suggest inhibition of FKBP51 with the current gold standard SAFit2 as a novel therapeutic strategy for treating chronic pain states.…”

“…administration of SAFit2 at the dose of 10 mg/kg impacts on the levels of lipids and lipid-oxidizing enzymes in the DRG and in the SC. In particular, the levels of C16 dihydroceramide (d18:0/16:0), an antihyperalgesic lipid mediator, were restored upon treatment with SAFit2 in the lumbar DRG …”

“…application of this formulation of SAFit2 (20 mg/kg), stable plasma levels of about 2 μg/mL were obtained. 40 Further improvements were made in the Hausch lab in order to reduce the EtOH content of the formulation to 0.7%, as published by Wedel et al 69,71 More details can be found in the Supporting Information.…”