Highlights
- •MDA7 (1-([3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl] carbonyl) piperidine) modulated microglial expression of cytokines induced by paclitaxel.
- •MDA7 modulated epigenetic upregulation of microglial brain-derived neurotrophic factor (BDNF) induced by paclitaxel.
- •BDNF regulated glutamatergic and GABAergic transmission in dorsal horn.
- •MDA7 (cannabinoid type 2 [CB2] agonist) attenuated paclitaxel-induced molecular and behavioral changes.
Abstract
Paclitaxel induces microglial activation and production of proinflammatory mediators
in the dorsal horn, which contribute to the development and maintenance of central
sensitization and pain behavior. MDA7, 1-([3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl]carbonyl)
piperidine, is a novel highly selective cannabinoid type 2 (CB2) agonist. We tested
the hypothesis that activation of CB2 receptor by MDA7 modulates microglial dysregulation,
suppresses the overexpression of brain-derived neurotrophic factor (BDNF) in microglia
in the dorsal horn, and attenuates the central sensitization and pain behavior induced
by paclitaxel. For 4 consecutice days, groups of rats randomly received saline or
1.0 mg/kg of paclitaxel daily intraperitoneally for a total cumulative dose of 4 mg/kg.
MDA7 15 mg/kg intraperitoneally or vehicle were administered 15 min before administering
paclitaxel for 4 days and then continued for another 10 days. Behavioral and molecular
studies were performed. Paclitaxel induced the expression of CB2 receptors and production
of interleukin (IL)-6 in microglia in the dorsal horn. MDA7 attenuated the expression
of IL-6 and promoted the expression of IL-10. Paclitaxel induced epigenetic upregulation
of IRF8 and P2X purinoceptor 4 (P2X4) in microglia and subsequently increased the
expression of alpha isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIα),
transcriptional factors p-CREB and ΔFosB, leading to the overproduction of BDNF in
microglia. Paclitaxel also upregulated the expression of glutamate receptor subunits
GluR1 and NR2B, decreased the expression of K+-Cl− cotransporter, and induced mechanical allodynia in rats. All of the aforementioned
molecular changes were attenuated by MDA7. Our data show that MDA7 attenuated paclitaxel-induced
molecular and behavioral changes in rats.
Perspective: This study provides evidence that paclitaxel induced microglia dysregulation
and epigenetically upregulated the microglial expression of BDNF, which led to sensitization
of dorsal horn neurons and mechanical allodynia in rats. The CB2 agonist MDA7 alleviated
these pathological processes. MDA7 represents an innovative therapeutic approach for
treatment of chemotherapy-induced neuropathy.
Key words
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Article info
Publication history
Published online: November 08, 2018
Accepted:
October 24,
2018
Received in revised form:
September 12,
2018
Received:
June 18,
2018
Footnotes
Dr. Naguib is supported by the National Institute On Aging of the National Institutes of Health under Award Number R56AG051594. This research was supported by departmental funds.
M.N. and J.F.F. have intellectual property assigned to Cleveland Clinic and they are cofounders of NeuroTherapia™, a spinoff company created by Cleveland Clinic Innovations. M.N. and J.F.F. have not received payments from NeuroTherapia™. As inventors of the technology, they and Cleveland Clinic are entitled to future royalty payments. J.W., M.H., and B.B. declare no conflicts of interest.
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© 2018 by the American Pain Society
