Resveratrol inhibits paclitaxel-induced neuropathic pain by the activation of PI3K/Akt and SIRT1/PGC1α pathway

Figures & data

Figure 1 Schematic of the experimental process. i.p. stands for injected intraperitoneally; i.t. stands for intrathecally.

Abbreviations: i.p., intraperitoneally; i.t., intrathecally; PWT, paw withdrawal mechanical threshold; TWL, thermal withdrawal latency.

Figure 2 Paclitaxel-induced mechanical and heat hypersensitivity.

Notes: (A) Paw withdrawal mechanical threshold of five groups (ten for each) at T0, T1, and T2. *P<0.05 compared to control animals, ^#P<0.05 compared to paclitaxel-treated rats. (B) Thermal withdrawal latency of five groups (ten for each) at T0, T1, and T2. *P<0.05 compared to control animals, ^#P<0.05 compared to paclitaxel-treated rats.
Abbreviations: C, control group; R, resveratrol group; P, paclitaxel-treated group; R+P, resveratrol + paclitaxel-treated group: LY, LY294002 group.

Figure 3 Mitochondrial histomorphology in the corpus striatums of five groups at day 14 by transmission electron microscopy.

Notes: (A) Control group (n=5); (B) resveratrol group (n=5); (C) paclitaxel-treated group (n=5); (D) resveratrol + paclitaxel-treated group (n=5); (E) LY294002 + resveratrol + paclitaxel-treated group (n=5).

Figure 4 The expressions of p-Akt, PI3K, and t-Akt in five groups (five for each) were detected by immunohistochemistry.

Abbreviations: C, control group; R, resveratrol group; P, paclitaxel-treated group; R+P, resveratrol + paclitaxel-treated group: R+P+LY, pretreated-resveratrol + pretreated-paclitaxel + LY294002; PI3K, phosphoinositide 3-kinase.

Table 1 The number of positive cells of p-Akt, t-Akt, and PI3K in striatum determined by immunohistochemistry (%, n=5, $\overline{x}\pm s$)

Group	p-Akt	t-Akt	PI3K
C	26.3±1.5	33.0±3.0	26.3±3.1
P	16.7±2.1#	30.7±1.5	12.2±2.1#
R	36±1.7	32.3±1.3	34.7±3.2
P+R	19.3±2.0&	32.3±2.0	20.7±2.1&
LY + R+P	8.4±1.4*	33.0±1.5	9.0±2.0*

Note: Compared with C group,

# P<0.05; compared with P group,

& P<0.05; compared with P+R group,

* P <0.05.

Abbreviations: C, control group; R, resveratrol group; P, paclitaxel-treated group; R+P, resveratrol + paclitaxel-treated group; LY, LY294002 group; PI3K, phosphoinositide 3-kinase.

Figure 5 Protein levels of t-Akt and p-Akt in corpus striatum (A-a). Three rats in each group. *P<0.05 compared to control animals, ^#P<0.05 compared to paclitaxel-treated rats. Protein levels of SIRT1 and PGC1α in corpus striatum (A, B). Protein levels of SIRT1and PGC1α in spinal dorsal horn (B). Protein levels of SIRT1and PGC1α in spinal dorsal horns (C). Protein levels of SIRT1and PGC1α in dorsal root ganglions (D). Paclitaxel reduced the expression levels of SIRT1 and PGC1α (*P<0.05), while resveratrol increased the expression of SIRT1 and PGC1α (*P<0.05); the protein levels of SIRT1 and PGC1α were suppressed by EX527 (*P<0.05).

Abbreviations: C, control group; R, resveratrol group; P, paclitaxel-treated group; R+P, resveratrol + paclitaxel-treated group; R+P+LY, pretreated-resveratrol + pretreated-paclitaxel + LY294002; E, pretreated-resveratrol + pretreated-paclitaxel + EX-527 group SIRT1, sirtuin 1.

Figure 6 Apoptosis in the corpus striatum, SDH, and DRG of rats with neuralgia induced by paclitaxel.

Notes: Compared to the control, the number of apoptosis in group P was increased, and group R has no significant change in apoptosis. In the resveratrol treatment group P+R, the apoptosis was decreased compared to group P. In the inhibitor treatment group E, the apoptosis was increased compared to group P.
Abbreviations: C, control group; R, resveratrol group; P, paclitaxel-treated group; R+P, resveratrol + paclitaxel-treated group; DRG, dorsal root ganglions; SDH, spinal dorsal horns; E, pretreated-resveratrol + pretreated-paclitaxel + EX-527 group.

Table 2 The apoptotic rate of corpus striatum, SDH, and DRG

Groups	Apoptotic rate (%)
	Corpus striatum	SDH	DRG
C	12%	8%	11%
P	44%	49%	45%
R	7%	7%	9%
R+P	31%	33%	28%
E	42%	45%	41%

Notes: Group C was the control rats; Group P was paclitaxel-treated rats; Group R received RES treatment; Group R+P was treated with paclitaxel with the pretreatment of RES; Group E underwent paclitaxel treatment with the pretreatment of RES and EX-527.

Abbreviations: C, control group; R, resveratrol group; P, paclitaxel-treated group; R+P, resveratrol + paclitaxel-treated group; DRG, dorsal root ganglions; RES, resveratrol; SDH, spinal dorsal horns; E, pretreated-resveratrol + pretreated-paclitaxel + EX-527 group.

Figure 7 The expression of IL-1β, IL-10, MDA, and SOD in the corpus striatum, SDH, and DRG tissues.

Notes: Five rats in each group. *P<0.05 compared to control animals, ^#P<0.05 compared to paclitaxel-treated rats, ^&P<0.05 compared to rats treated with paclitaxel with the pretreatment of resveratrol.
Abbreviations: C, control group; R, resveratrol group; P, paclitaxel-treated group; R+P, resveratrol + paclitaxel-treated group; DRG, dorsal root ganglions; MDA, malondialdehyde; SDH, spinal dorsal horns; SOD, superoxide dismutase.