title: Parthenolide Relieves Pain and Promotes M2 Microglia/Macrophage Polarization in Rat Model of Neuropathy.
abstract: Neuropathic pain treatment remains a challenge because pathomechanism is not fully understood. It is believed that glial activation and increased spinal nociceptive factors are crucial for neuropathy. We investigated the effect of parthenolide (PTL) on the chronic constriction injury to the sciatic nerve (CCI)-induced neuropathy in rat. We analyzed spinal changes in glial markers and M1 and M2 polarization factors, as well as intracellular signaling pathways. PTL (5 µg; i.t.) was preemptively and then daily administered for 7 days after CCI. PTL attenuated the allodynia and hyperalgesia and increased the protein level of IBA1 (a microglial/macrophage marker) but did not change GFAP (an astrocyte marker) on day 7 after CCI. PTL reduced the protein level of M1 (IL-1β, IL-18, and iNOS) and enhanced M2 (IL-10, TIMP1) factors. In addition, it downregulated the phosphorylated form of NF-κB, p38MAPK, and ERK1/2 protein level and upregulated STAT3. In primary microglial cell culture we have shown that IL-1β, IL-18, iNOS, IL-6, IL-10, and TIMP1 are of microglial origin. Summing up, PTL directly or indirectly attenuates neuropathy symptoms and promotes M2 microglia/macrophages polarization. We suggest that neuropathic pain therapies should be shifted from blanketed microglia/macrophage suppression toward maintenance of the balance between neuroprotective and neurotoxic microglia/macrophage phenotypes.
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Popiolek-Barczyk
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Kolosowska
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
authors.forename: Anna
authors.identifier: 0000-0001-6187-1406
authors.initials: A
authors.lastname: Piotrowska
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
authors.forename: Wioletta
authors.initials: W
authors.lastname: Makuch
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Rojewska
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
authors.forename: Agnieszka M
authors.initials: AM
authors.lastname: Jurga
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Pilat
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
authors.forename: Joanna
authors.identifier: 0000-0003-1986-7205
authors.initials: J
authors.lastname: Mika
mesh_terms: D000700:Analgesics / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000378:metabolism*; D012717:Sesquiterpenes / Q000008:administration & dosage* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000700:Analgesics; D012717:Sesquiterpenes; C002669:parthenolide