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.2012 May;114(5):1104-20.
doi: 10.1213/ANE.0b013e31824b0191. Epub 2012 Mar 5.

Prevention of paclitaxel-induced neuropathy through activation of the central cannabinoid type 2 receptor system

Affiliations

Prevention of paclitaxel-induced neuropathy through activation of the central cannabinoid type 2 receptor system

Mohamed Naguib et al. Anesth Analg.2012 May.

Abstract

Background: Peripheral neuropathy is a major dose-limiting toxicity of chemotherapy, especially after multiple courses of paclitaxel. The development of paclitaxel-induced neuropathy is associated with the activation of microglia followed by the activation and proliferation of astrocytes, and the expression and release of proinflammatory cytokines in the spinal dorsal horn. Cannabinoid type 2 (CB(2)) receptors are expressed in the microglia in neurodegenerative disease models.

Methods: To explore the potential of CB(2) agonists for preventing paclitaxel-induced neuropathy, we designed and synthesized a novel CB(2)-selective agonist, namely, MDA7. The effect of MDA7 in preventing paclitaxel-induced allodynia was assessed in rats and in CB(2)(+/+) and CB(2)(-/-) mice. We hypothesized that the CB(2) receptor functions in a negative-feedback loop and that early MDA7 administration can blunt the neuroinflammatory response to paclitaxel and prevent mechanical allodynia through interference with specific signaling pathways.

Results: We found that MDA7 prevents paclitaxel-induced mechanical allodynia in rats and mice in a dose- and time-dependent manner without compromising paclitaxel's antineoplastic effect. MDA7's neuroprotective effect was absent in CB(2)(-/-) mice and was blocked by CB(2) antagonists, suggesting that MDA7's action directly involves CB(2) receptor activation. MDA7 treatment was found to interfere with early events in the paclitaxel-induced neuroinflammatory response as evidenced by relatively reduced toll-like receptor and CB(2) expression in the lumbar spinal cord, reduced levels of extracellular signal-regulated kinase 1/2 activity, reduced numbers of activated microglia and astrocytes, and reduced secretion of proinflammatory mediators in vivo and in in vitro models.

Conclusions: Our findings suggest an innovative therapeutic approach to prevent chemotherapy-induced neuropathy and may permit more aggressive use of active chemotherapeutic regimens with reduced long-term sequelae.

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Figures

Fig. 1
Fig. 1
(A) Prevention of paclitaxel-induced mechanical allodynia in rats (n = 6 in all groups except vehicle control,n = 4). Treatment with paclitaxel + MDA7 for 14 days resulted in significant differences (P < 0.001) from paclitaxel alone on days 5-28, whereas treatment with paclitaxel + MDA7 for only 4 days resulted in significant differences (P < 0.01) on days 5-12 only.(B) Confocal images of CD11b immunoreactivity in various groups of rats.Top, immunofluorescence staining intensity patterns of each section.(C) Analysis of CD11b immunofluorescence intensity by Metamorph (5-6 sections) showed that the paclitaxel + MDA7 14 days group had significantly less immunofluorescence integrated intensity than did the paclitaxel only and paclitaxel + MDA7 4 days groups(D). Confocal images of glial fibrillary acidic protein (GFAP) immunoreactivity in various groups of rats.Top, immunofluorescence staining intensity patterns of each section.(E) Analysis of GFAP immunofluorescence integrated intensity by Metamorph (2-3 sections) showed that the paclitaxel + MDA7 14 days group had significantly less immunofluorescence intensity than the paclitaxel only and paclitaxel + MDA7 4 days groups had. Scale bar = 50μm.
Fig. 2
Fig. 2
The effect of MDA7 is mediated through the Cannabinoid type 2 (CB2) receptor. MDA7 prevented paclitaxel-induced mechanical allodynia in CB2+/+(A) but not in CB2-/- mice(B). *P ≤ 0.01 compared with other groups (n = 5 in all groups).+P ≤ 0.05 compared with paclitaxel 4 days group.
Fig. 3
Fig. 3
(A) Cannabinoid type 2 (CB2) staining and localization in the lumbar spinal cord dorsal horn laminae I and II. Representative confocal images of CB2 (green) and glial fibrillary acidic protein (GFAP) (red). The coregionalization of CB2 and GFAP in astrocytes is shown inyellow. No significant CB2 expression was observed in the control group, but marked CB2 expression was observed in the paclitaxel group. CB2 expression was markedly decreased with MDA7 treatment for 14 days. Scale bar = 50μm.(B and C) Paclitaxel treatment significantly increased the CB2 expression in the lumbar spinal cord, and treatment with MDA7 for 14 days significantly attenuated this upregulated CB2 expression in the rats treated with paclitaxel.
Fig. 4
Fig. 4
(A) Heatmap of the expression intensities in the individual samples of the most significant 384 genes detected on the basis of the threshold of false discovery rate cutoff of 0.005. Hierarchical clustering based on Pearson's correlation coefficient was conducted among the 384 genes. SC = spinal cord. Taxol = paclitaxel.(B) Quantitative real-time reverse transcriptase-polymerase chain reaction (qRT–PCR) analysis of total RNA performed in triplicates isolated from all 12 spinal cord samples used in a microarray study (6 from paclitaxel-treated rats and 6 from paclitaxel + MDA7 14 d–treated rats). Data were normalized relative toGapdh and expressed as fold change relative to paclitaxel treatment without MDA7. The RNA fold change matches the trend seen in microarray data. Further, Western blotting analysis revealed that MDA7 treatment for 14 days significantly attenuated the upsurge of phosphorylation of extracellular signal regulated kinase (ERK)1/2 (C, D) and IκBα (E, F), and down-regulated Toll-like receptors 2 (TLR2) expression (G,H) but did not affect TLR4 (G, H) expression in the spinal cord of the rats with paclitaxel treatment. * =P<0.05.
Fig. 5
Fig. 5
MDA7 inhibited lipopolysaccharide (LPS, a Toll-like receptors 4 [TLR4] ligand)- and zymosan (a TLR2 ligand)-induced increases in interleukin (IL)-1β and tumor necrosis factor (TNF)-α secretion. Primary cultured astroglial cells were treated with 5 μM dimethylsulfoxide (DMSO) (solvent), 1.0 μg/ml lipopolysaccharide (LPS), and 100 μg/ml zymosan with or without 10 μM MDA7. Pretreatment with MDA7 significantly inhibited LPS-induced increases in IL-1β (A) and TNF-α secretion (B). Similarly, it also suppressed zymosan-induced increases in IL-1β (A) and TNF-α secretion (B). Arrows indicate that the corresponding TNF-α secretion was below detection level.(C) MDA7 attenuated the paclitaxel-induced increase in TLR2 mRNA level in cultured primary astroglial cells. There was no change in TLR4 mRNA level among groups.
Fig. 6
Fig. 6
MDA7 decreased paclitaxel-induced phosphorylation of extracellular signal regulated kinase (ERK)1/2 in human Cannabinoid type 2 (CB2) (hCB2) or rat CB2 (rCB2) receptor-transfected Chinese hamster ovary (CHO) cells. Cells were treated with dimethylsulfoxide (DMSO) (vehicle) and 0.1 μM paclitaxel (15 min) with or without 1 and 10 μM MDA7 (1 h before paclitaxel). Antibodies to ERK1/2 and phosphorylated-ERK1/2 (1:1500, Cell Signaling) were used.Top, grouped results to show the suppressive effect of MDA7 on the paclitaxel-induced phosphorylation of ERK1/2 in human CB2 (hCB2) or rat CB2 (rCB2) receptor-transfected CHO cells. *P < 0.05, **P < 0.01, ***P < 0.001versus paclitaxel.
Fig. 7
Fig. 7
MDA7 decreased paclitaxel-induced phosphorylation of extracellular signal regulated kinase (ERK)1/2 in Toll-like receptors (TLR)2- or TLR4-transfected Human Embryonic Kidney (HEK)-293 cells. Cells were treated with dimethylsulfoxide (DMSO) (vehicle) and 0.1 μM paclitaxel (15 min) with or without 1 and 10 μM MDA7 (1 h before paclitaxel).Top, grouped results to show the suppressive effect of MDA7 on the paclitaxel-induced phosphorylation of ERK1/2 in TLR2- or TLR4-transfected HEK-293 cells. *P < 0.05, **P < 0.01versus paclitaxel.
Fig. 8
Fig. 8
Effects of MDA7 on paclitaxel-induced cytotoxicity. MCF7, H1299, and Jurkat cell cultures were treated with MDA7 alone (1, 5, or 10 μM), paclitaxel alone (0.1 or 0.2 μM) or their combination for 48h and then assayed for the degree of cytotoxicity using measures of apoptosis (Annexin V staining) and necrosis (propidium iodide uptake).
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