Maraviroc reduces neuropathic pain through polarization of microglia and astroglia - Evidence from in vivo and in vitro studies.
Recent studies suggest that CCR5 and its ligands are important regulators for the development of neuropathic pain and that their modulation can have some beneficial properties. Therefore, the aim of our study was to investigate the influence of maraviroc (MVC, a CCR5 antagonist) on glial polarization markers and intracellular signaling pathways in the spinal cord 7 days after chronic constriction injury (CCI) to the sciatic nerve and in primary glial cultures after LPS stimulation. Our results demonstrated that chronic intrathecal administration of MVC diminished neuropathic pain symptoms and nociceptive threshold ∼60 min after drug administration on days 3 and 7 post-CCI. MVC downregulated the levels of phosphorylated p38 MAPK, ERK1/2 and NF-κB proteins in the spinal cord and upregulated STAT3 in the dorsal root ganglia (DRG). Additionally, using Western blot analysis, we demonstrated that MVC effectively diminished "classical" activation markers: IL-1β, IL-18, IL-6 and NOS2 in the spinal cord. In contrast, MVC upregulated "alternative" antinociceptive activation markers: IL-1RA, IL-18BP and IL-10 in the spinal cord. In parallel, MVC downregulated the levels of phosphorylated p38 MAPK, ERK1/2 and NF-κB proteins and upregulated STAT3 in microglial and astroglial cell cultures. Similarly, MVC reduced pronociceptive (IL-1β, IL-18, IL-6, NOS2) and enhanced the antinociceptive (IL-1RA, IL-18BP, IL-10) factors after LPS stimulation. Our studies provide new evidence that MVC attenuates neuropathy symptoms, promotes spinal glial "alternative" polarization and restores the balance between pro- and antinociceptive factors. Our results suggest the modulation of CCR5 by MVC as a novel therapeutic approach for neuropathy.
Department of Pain Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Anna
A
Piotrowska
Department of Pain Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Klaudia
K
Kwiatkowski
Department of Pain Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Ewelina
E
Rojewska
Department of Pain Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Wioletta
W
Makuch
Department of Pain Pharmacology, Polish Academy of Sciences, Krakow, Poland. Electronic address: joamika@if-pan.krakow.pl.
Joanna
J
Mika
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D065100:CCR5 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D003510:Cyclohexanes / Q000494:pharmacology / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D000077592:Maraviroc; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*
D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D018836:Inflammation Mediators; D014230:Triazoles; D000077592:Maraviroc
CCR5 antagonist; Cytokines; Glial “alternative” polarization; Signaling pathways