Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose-and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P 450 -epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxeltreated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity. In a drug repurposing screen targeting CYP2J2, the human ortholog of murine CYP2J6, we identified telmisartan, a widely used angiotensin II receptor antagonist, as a potent inhibitor. In a translational approach, administration of telmisartan reduces EpOME concentrations in DRGs and in plasma and reverses mechanical hypersensitivity in paclitaxeltreated mice. We therefore suggest inhibition of CYP2J isoforms with telmisartan as a treatment option for paclitaxel-induced neuropathic pain.chemotherapy-induced neuropathy | neuropathic pain | TRPV1 | telmisartan | oxidized lipids R ecent studies identified members of the transient receptor potential-family of ion channels (TRPV1, TRPA1, and TRPV4) as contributors to both mechanical and cold allodynia during oxaliplatin and paclitaxel-induced neuropathy (1-5). Activation or sensitization of TRPV1 and TRPA1 can lead to enhanced release of CGRP and substance P, both of which can cause neurogenic inflammation and recruitment of T cells (6, 7).However, it remains unclear which endogenous mediators are involved in paclitaxel-dependent activation or sensitization of TRP channels, as paclitaxel cannot directly activate TRP channels (4,5,8). Interestingly, paclitaxel is an inducer of some Cytochrome-P 450 epoxygenases (e.g., CYP2C8, CYP2C9) (9). CYP epoxygenases can metabolize ω-6 fatty acids, such as arachidonic acid (AA) and linoleic acid (LA), generating either lipid epoxides such as EETs (epoxyeicosatrienoid acids) or ω-hydroxides such as 20-hydroxyeicosatetraenoic acid (20-HETE) (10, 11).Although therapeutic alternatives exist, paclitaxel is still the preferred first line of therapy for metastatic breast cancer (12), causing severe CIPNP in many treated patients. Here, we performed liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipid profiling of sciatic nerve, dorsal root ganglion (DRG), and dorsal horn tissue from paclitaxel-treated mice.We identified 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid), a CYP metabolite of LA, to be strongly synthesized in DRGs 24 h and 8 d after paclitaxel injection in mice. 9,10-EpOME is capable of sensitizing TRPV1 at submicromolar concentrations via a cAMP-PKA-dependent mechanism, causing enhanced frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina II neurons of the spin...
Bioactive lipids contribute to the pathophysiology of multiple sclerosis. Here, we show that lysophosphatidic acids (LPAs) are dysregulated in multiple sclerosis (MS) and are functionally relevant in this disease. LPAs and autotaxin, the major enzyme producing extracellular LPAs, were analyzed in serum and cerebrospinal fluid in a cross-sectional population of MS patients and were compared with respective data from mice in the experimental autoimmune encephalomyelitis (EAE) model, spontaneous EAE in TCR1640 mice, and EAE in Lpar2 -/- mice. Serum LPAs were reduced in MS and EAE whereas spinal cord LPAs in TCR1640 mice increased during the ‘symptom-free’ intervals, i.e. on resolution of inflammation during recovery hence possibly pointing to positive effects of brain LPAs during remyelination as suggested in previous studies. Peripheral LPAs mildly re-raised during relapses but further dropped in refractory relapses. The peripheral loss led to a redistribution of immune cells from the spleen to the spinal cord, suggesting defects of lymphocyte homing. In support, LPAR2 positive T-cells were reduced in EAE and the disease was intensified in Lpar2 deficient mice. Further, treatment with an LPAR2 agonist reduced clinical signs of relapsing-remitting EAE suggesting that the LPAR2 agonist partially compensated the endogenous loss of LPAs and implicating LPA signaling as a novel treatment approach.Graphical abstractGraphical summary of lysophosphatidic signaling in multiple sclerosis Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0446-4) contains supplementary material, which is available to authorized users.
Schizophrenic patients suffer from deficits in information processing. Patients show both a decrease in P50 gating [assessed in the conditioning-testing (C-T) paradigm] and prepulse inhibition (PPI), two paradigms that assess gating. These two paradigms might have a related underlying neural substrate. Gating, as measured in both the C-T paradigm (the gating of a component of the auditory evoked potential (AEP)], and PPI can easily be measured in animals as well as in humans. This offers the opportunity to model these information processing paradigms in animals in order to investigate the effects of neurotransmitter manipulations in the brain. In order to validate the animal model for disturbances in AEP gating, d-amphetamine (0.5 and 1 mg/kg, i.p.) was administered. Gating of an AEP component was changed due to injection of d-amphetamine (1 mg/kg) in the same way as seen in schizophrenic patients: both the amplitude to the conditioning click and the gating were significantly reduced. Next, the effect of the N-methyl-D-aspartate (NMDA) antagonist ketamine (2.5 and 10 mg/kg, i.p.) was investigated to assess its effects in the two gating paradigms. It was found that ketamine (10 mg/kg) did not affect gating as measured with components of the AEP. However, ketamine (10 mg/kg) disrupted PPI of the startle response to the extent that prepulse facilitation occurred. Firstly, it is concluded that AEP gating was disrupted by d-amphetamine and not by ketamine. Secondly, PPI and the C-T paradigm reflect distinct inhibitory sensory processes, since both paradigms are differentially influenced by ketamine.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.