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Prevention of paclitaxel-induced allodynia by minocycline: Effect on loss of peripheral nerve fibers and infiltration of macrophages in rats.

Liu CC, Lu N, Cui Y, Yang T, Zhao ZQ, Xin WJ, Liu XG - Mol Pain (2010)

Bottom Line: Moreover, we observe the effect of minocycline on the IENF, macrophages and ATF3.More importantly, we observed that pretreatment of minocycline at dose of 30 mg/kg or 50 mg/kg, but not 5 mg/kg, prevented paclitaxel-evoked allodynia.The finding might provide potential target for preventing paclitaxel-induced neuropathic pain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd, 2, Guangzhou, 510080, PR China.

ABSTRACT

Background: Although paclitaxel is a frontline antineoplastic agent for treatment of solid tumors, the paclitaxel-evoked pain syndrome is a serious problem for patients. There is currently no valid drug to prevent or treat the paclitaxel-induced allodynia, partly due to lack of understanding regarding the cellular mechanism. Studies have shown that minocycline, an inhibitor of microglia/macrophage, prevented neuropathic pain and promoted neuronal survival in animal models of neurodegenerative disease. Recently, Cata et al also reported that minocycline inhibited allodynia induced by low-dose paclitaxel (2 mg/kg) in rats, but the mechanism is still unclear.

Results: Here, we investigate by immunohistochemistry the change of intraepidermal nerve fiber (IENF) in the hind paw glabrous skin, expression of macrophage and activating transcription factor 3 (ATF3) in DRG at different time points after moderate-dose paclitaxel treatment (cumulative dose 24 mg/kg; 3 × 8 mg/kg) in rats. Moreover, we observe the effect of minocycline on the IENF, macrophages and ATF3. The results showed that moderate-dose paclitaxel induced a persisted, gradual mechanical allodynia, which was accompanied by the loss of IENF in the hind paw glabrous skin and up-regulation of macrophages and ATF3 in DRG in rats. The expressions of ATF3 mainly focus on the NF200-positive cells. More importantly, we observed that pretreatment of minocycline at dose of 30 mg/kg or 50 mg/kg, but not 5 mg/kg, prevented paclitaxel-evoked allodynia. The evidence from immunohistochemistry showed that 30 mg/kg minocycline rescued the degeneration of IENF, attenuated infiltration of macrophages and up-regulation of ATF3 induced by paclitaxel treatment in rats.

Conclusions: Minocycline prevents paclitaxel-evoked allodynia, likely due to its inhibition on loss of IENF, infiltration of macrophages and up-regulation of ATF3 in rats. The finding might provide potential target for preventing paclitaxel-induced neuropathic pain.

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Double immunofluorescence staining showed colocalization of activating transcription factor 3 (ATF3) with neurofilament 200 (NF200). Upregulated ATF3 induced by paclitaxel was co-localized with NF200-labeled cells (A-C), but not with IB4-labeled cells (D-F) or GFAP-labeled cells (G-I).
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Figure 4: Double immunofluorescence staining showed colocalization of activating transcription factor 3 (ATF3) with neurofilament 200 (NF200). Upregulated ATF3 induced by paclitaxel was co-localized with NF200-labeled cells (A-C), but not with IB4-labeled cells (D-F) or GFAP-labeled cells (G-I).

Mentions: To assess whether the loss of IENF is accompanied by the sensory cell injury. We examined the levels of ATF3 in DRG at various time points. The result showed that paclitaxel treatment significantly increased the number of ATF3-immunoreactivity (IR) positive cells in L4 DRG (Figure 3B-E and 3H) compared with vehicle-treated rats in that ATF3-IR positive cells were hardly found (Figure 3A). Meanwhile, double immunofluorescence staining showed that ATF3 was co-localized with NF200-labeled cells (A fiber neuronal marker), but not with IB4-labeled cells (C fiber neuronal marker) or GFAP-labeled cells (satellite cell marker) (Figure 4). Furthermore, pretreatment with minocycline inhibited the increase of ATF3 (0.44 ± 0.18 and 1.33 ± 0.50 in minocycline/paclitaxel group versus 12.44 ± 1.68 and 24.33 ± 2.12 in paclitaxel group on day 4 and 12, respectively) (Figure 3F and 3G).


Prevention of paclitaxel-induced allodynia by minocycline: Effect on loss of peripheral nerve fibers and infiltration of macrophages in rats.

Liu CC, Lu N, Cui Y, Yang T, Zhao ZQ, Xin WJ, Liu XG - Mol Pain (2010)

Double immunofluorescence staining showed colocalization of activating transcription factor 3 (ATF3) with neurofilament 200 (NF200). Upregulated ATF3 induced by paclitaxel was co-localized with NF200-labeled cells (A-C), but not with IB4-labeled cells (D-F) or GFAP-labeled cells (G-I).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2991291&req=5

Figure 4: Double immunofluorescence staining showed colocalization of activating transcription factor 3 (ATF3) with neurofilament 200 (NF200). Upregulated ATF3 induced by paclitaxel was co-localized with NF200-labeled cells (A-C), but not with IB4-labeled cells (D-F) or GFAP-labeled cells (G-I).
Mentions: To assess whether the loss of IENF is accompanied by the sensory cell injury. We examined the levels of ATF3 in DRG at various time points. The result showed that paclitaxel treatment significantly increased the number of ATF3-immunoreactivity (IR) positive cells in L4 DRG (Figure 3B-E and 3H) compared with vehicle-treated rats in that ATF3-IR positive cells were hardly found (Figure 3A). Meanwhile, double immunofluorescence staining showed that ATF3 was co-localized with NF200-labeled cells (A fiber neuronal marker), but not with IB4-labeled cells (C fiber neuronal marker) or GFAP-labeled cells (satellite cell marker) (Figure 4). Furthermore, pretreatment with minocycline inhibited the increase of ATF3 (0.44 ± 0.18 and 1.33 ± 0.50 in minocycline/paclitaxel group versus 12.44 ± 1.68 and 24.33 ± 2.12 in paclitaxel group on day 4 and 12, respectively) (Figure 3F and 3G).

Bottom Line: Moreover, we observe the effect of minocycline on the IENF, macrophages and ATF3.More importantly, we observed that pretreatment of minocycline at dose of 30 mg/kg or 50 mg/kg, but not 5 mg/kg, prevented paclitaxel-evoked allodynia.The finding might provide potential target for preventing paclitaxel-induced neuropathic pain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd, 2, Guangzhou, 510080, PR China.

ABSTRACT

Background: Although paclitaxel is a frontline antineoplastic agent for treatment of solid tumors, the paclitaxel-evoked pain syndrome is a serious problem for patients. There is currently no valid drug to prevent or treat the paclitaxel-induced allodynia, partly due to lack of understanding regarding the cellular mechanism. Studies have shown that minocycline, an inhibitor of microglia/macrophage, prevented neuropathic pain and promoted neuronal survival in animal models of neurodegenerative disease. Recently, Cata et al also reported that minocycline inhibited allodynia induced by low-dose paclitaxel (2 mg/kg) in rats, but the mechanism is still unclear.

Results: Here, we investigate by immunohistochemistry the change of intraepidermal nerve fiber (IENF) in the hind paw glabrous skin, expression of macrophage and activating transcription factor 3 (ATF3) in DRG at different time points after moderate-dose paclitaxel treatment (cumulative dose 24 mg/kg; 3 × 8 mg/kg) in rats. Moreover, we observe the effect of minocycline on the IENF, macrophages and ATF3. The results showed that moderate-dose paclitaxel induced a persisted, gradual mechanical allodynia, which was accompanied by the loss of IENF in the hind paw glabrous skin and up-regulation of macrophages and ATF3 in DRG in rats. The expressions of ATF3 mainly focus on the NF200-positive cells. More importantly, we observed that pretreatment of minocycline at dose of 30 mg/kg or 50 mg/kg, but not 5 mg/kg, prevented paclitaxel-evoked allodynia. The evidence from immunohistochemistry showed that 30 mg/kg minocycline rescued the degeneration of IENF, attenuated infiltration of macrophages and up-regulation of ATF3 induced by paclitaxel treatment in rats.

Conclusions: Minocycline prevents paclitaxel-evoked allodynia, likely due to its inhibition on loss of IENF, infiltration of macrophages and up-regulation of ATF3 in rats. The finding might provide potential target for preventing paclitaxel-induced neuropathic pain.

Show MeSH
Related in: MedlinePlus