@phdthesis{Mohammadi2019,
  author    = {Mohammadi, Milad},
  title     = {Role of oxidized phospholipids in inflammatory pain},
  doi       = {10.25972/OPUS-19240},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-192402},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Introduction: During inflammation, reactive oxygen species (ROS) such as Hydrogen peroxide accumulate at the inflammation site and by oxidizing lipids, they produce metabolites such as 4-hydroxynonenal (4-HNE) and oxidized phospholipids (OxPLs). Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are ligand gated ion channels that are expressed on nociceptors and their activation elicits pain. Hydrogen peroxide and 4-HNE are endogenous ligands for TRPA1 and their role in inflammatory pain conditions has been shown. OxPLs play a major pro-inflammatory role in many pathologies including atherosclerosis and multiple sclerosis. E06/T15 is a mouse IgM mAb that specifically binds oxidized phosphatidylcholine. D-4F is an apolipoprotein A-I mimetic peptide with a very high affinity for OxPLs and possess anti-inflammatory properties. E06 mAb and D-4F peptide protect against OxPLs-induced damage in atherosclerosis in vivo. Methods: To investigate the role of ROS and their metabolites in inflammatory pain, I utilized a combination of diverse and complex behavioral pain measurements and binding assays. I examined E06 mAb and D-4F as local treatment options for hypersensitivity evoked by endogenous and exogenous activators of TRPA1 and TRPV1 as well as in inflammatory and OxPL-induced pain models in vivo. 4-HNE, hydrogen peroxide as ROS source and mustard oil (AITC) were used to activate TRPA1, while capsaicin was used to activate TRPV1. Results: Intraplantar injection of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) into rats' hind paw elicited thermal and mechanical hypersensitivity. Genetic and pharmacological evidence in vivo confirmed the role of TRPA1 in OxPLs-induced hypersensitivity. OxPLs formation increased in complete Freund's adjuvant (CFA)-induced inflamed rats' paw. E06 mAb and D-4F prevented OxPAPC-induced mechanical and thermal hypersensitivity (hyperalgesia) as well as CFA-induced mechanical hypersensitivity. Also, all irritants induced thermal and mechanical hypersensitivity as well as affective-emotional responses and spontaneous nocifensive behaviors. E06 mAb blocked prolonged mechanical hypersensitivity by all but hydrogen peroxide. In parallel, D-4F prevented mechanical hypersensitivity induced by all irritants as well as thermal hypersensitivity induced by capsaicin and 4-HNE. In addition, competitive binding assays showed that all TRPA1/V1 agonists induced prolonged formation of OxPLs in the paw tissue explaining the anti-nociceptive properties of E06 mAb and D-4F. Finally, the potential of gait analysis as a readout for non-provoked pain behavioral measurements were examined. Conclusion and implications: OxPLs were characterized as novel targets in inflammatory pain. Treatment with the monoclonal antibody E06 or apolipoprotein A-I mimetic peptide D-4F are suggested as potential inflammatory pain medications. OxPLs' role in neuropathic pain is yet to be investigated.},
  language  = {en}
}
@article{OehlerMohammadiPerpinaVicianoetal.2017,
  author    = {Oehler, Beatrice and Mohammadi, Milad and Perpina Viciano, Cristina and Hackel, Dagmar and Hoffmann, Carsten and Brack, Alexander and Rittner, Heike L.},
  title     = {Peripheral interaction of Resolvin D1 and E1 with opioid receptor antagonists for antinociception in inflammatory pain in rats},
  series = {Frontiers in Molecular Neuroscience},
  volume    = {10},
  journal   = {Frontiers in Molecular Neuroscience},
  number    = {242},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158642},
  year      = {2017},
  abstract  = {Antinociceptive pathways are activated in the periphery in inflammatory pain, for instance resolvins and opioid peptides. Resolvins are biosynthesized from omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid. Resolvin D1 (RvD1) and resolvin E1 (RvE1) initiate the resolution of inflammation and control of hypersensitivity via induction of anti-inflammatory signaling cascades. RvD1 binds to lipoxin A4/annexin-A1 receptor/formyl-peptide receptor 2 (ALX/FPR2), RvE1 to chemerin receptor 23 (ChemR23). Antinociception of RvD1 is mediated by interaction with transient receptor potential channels ankyrin 1 (TRPA1). Endogenous opioid peptides are synthesized and released from leukocytes in the tissue and bind to opioid receptors on nociceptor terminals. Here, we further explored peripheral mechanisms of RvD1 and chemerin (Chem), the ligand of ChemR23, in complete Freund's adjuvant (CFA)-induced hindpaw inflammation in male Wistar rats. RvD1 and Chem ameliorated CFA-induced hypersensitivity in early and late inflammatory phases. This was prevented by peripheral blockade of the μ-opioid peptide receptor (MOR) using low dose local naloxone or by local injection of anti-β-endorphin and anti-met-enkephalin (anti-ENK) antibodies. Naloxone also hindered antinociception by the TRPA1 inhibitor HC-030031. RvD1 did not stimulate the release of β-endorphin from macrophages and neutrophils, nor did RvD1 itself activate G-proteins coupled MOR or initiate β-arrestin recruitment to the membrane. TRPA1 blockade by HC-030031 in inflammation in vivo as well as inhibition of the TRPA1-mediated calcium influx in dorsal root ganglia neurons in vitro was hampered by naloxone. Peripheral application of naloxone alone in vivo already lowered mechanical nociceptive thresholds. Therefore, either a perturbation of the balance of endogenous pro- and antinociceptive mechanisms in early and late inflammation, or an interaction of TRPA1 and opioid receptors weaken the antinociceptive potency of RvD1 and TRPA1 blockers.},
  language  = {en}
}
@article{OehlerKistnerMartinetal.2017,
  author    = {Oehler, Beatrice and Kistner, Katrin and Martin, Corinna and Schiller, J{\"u}rgen and Mayer, Rafaela and Mohammadi, Milad and Sauer, Reine-Solange and Filipovic, Milos R. and Nieto, Francisco R. and Kloka, Jan and Pfl{\"u}cke, Diana and Hill, Kerstin and Schaefer, Michael and Malcangio, Marzia and Reeh, Peter W. and Brack, Alexander and Blum, Robert and Rittner, Heike L.},
  title     = {Inflammatory pain control by blocking oxidized phospholipid-mediated TRP channel activation},
  series = {Scientific Reports},
  volume    = {7},
  journal   = {Scientific Reports},
  number    = {5447},
  doi       = {10.1038/s41598-017-05348-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158536},
  year      = {2017},
  abstract  = {Phospholipids occurring in cell membranes and lipoproteins are converted into oxidized phospholipids (OxPL) by oxidative stress promoting atherosclerotic plaque formation. Here, OxPL were characterized as novel targets in acute and chronic inflammatory pain. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) and its derivatives were identified in inflamed tissue by mass spectrometry and binding assays. They elicited calcium influx, hyperalgesia and induced pro-nociceptive peptide release. Genetic, pharmacological and mass spectrometric evidence in vivo as well as in vitro confirmed the role of transient receptor potential channels (TRPA1 and TRPV1) as OxPAPC targets. Treatment with the monoclonal antibody E06 or with apolipoprotein A-I mimetic peptide D-4F, capturing OxPAPC in atherosclerosis, prevented inflammatory hyperalgesia, and in vitro TRPA1 activation. Administration of D-4F or E06 to rats profoundly ameliorated mechanical hyperalgesia and inflammation in collagen-induced arthritis. These data reveal a clinically relevant role for OxPAPC in inflammation offering therapy for acute and chronic inflammatory pain treatment by scavenging OxPAPC.},
  language  = {en}
}
@article{OehlerKlokaMohammadietal.2020,
  author    = {Oehler, Beatrice and Kloka, Jan and Mohammadi, Milad and Ben-Kraiem, Adel and Rittner, Heike L.},
  title     = {D-4F, an ApoA-I mimetic peptide ameliorating TRPA1-mediated nocifensive behaviour in a model of neurogenic inflammation},
  series = {Molecular Pain},
  volume    = {16},
  journal   = {Molecular Pain},
  doi       = {10.1177/1744806920903848},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236061},
  pages     = {1-11},
  year      = {2020},
  abstract  = {Background High doses of capsaicin are recommended for the treatment of neuropathic pain. However, low doses evoke mechanical hypersensitivity. Activation of the capsaicin chemosensor transient receptor potential vanilloid 1 (TRPV1) induces neurogenic inflammation. In addition to the release of pro-inflammatory mediators, reactive oxygen species are produced. These highly reactive molecules generate oxidised phospholipids and 4-hydroxynonenal (4-HNE) which then directly activate TRP ankyrin 1 (TRPA1). The apolipoprotein A-I mimetic peptide D-4F neutralises oxidised phospholipids. Here, we asked whether D-4F ameliorates neurogenic hypersensitivity in rodents by targeting reactive oxygen species and 4-HNE in the capsaicin-evoked pain model. Results Co-application of D-4F ameliorated capsaicin-induced mechanical hypersensitivity and allodynia as well as persistent heat hypersensitivity measured by Randell-Selitto, von Frey and Hargreaves test, respectively. In addition, mechanical hypersensitivity was blocked after co-injection of D-4F with the reactive oxygen species analogue H2O2 or 4-HNE. In vitro studies on dorsal root ganglion neurons and stably transfected cell lines revealed a TRPA1-dependent inhibition of the calcium influx when agonists were pre-incubated with D-4F. The capsaicin-induced calcium influx in TRPV1-expressing cell lines and dorsal root ganglion neurons sustained in the presence of D-4F. Conclusions D-4F is a promising compound to ameliorate TRPA1-dependent hypersensitivity during neurogenic inflammation.},
  language  = {en}
}