Protective effect of lappaconitine on Freund's complete adjuvant-induced arthritis exerted through P2X7 receptor-mediated regulation of M1/M2 balance in rats

doi:10.19852/j.cnki.jtcm.2025.01.004

Abstract

Abstract:

OBJECTIVE: to investigate the anti-arthritic effects of lappaconitine (LA) on adjuvant-induced arthritis in Sprague-Dawley rats and its possible involvement in the regulation of M1/M2 macrophage balance through the P2X7 receptor (P2X7r).

METHODS: Rats were immunized with complete Freund’s adjuvant and then intraperitoneally administered LA (2, 4, or 8 mg·kg^-1·d^-1) or methotrexate (0.5 mg/kg per 3 d) for 14 d. The anti-arthritic effects of LA were evaluated through arthritis index (AI) assessment, ankle diameter measurement, and histopathological staining analysis. The analgesic effect of LA on arthritis was measured using mechanical withdrawal threshold testing and gait scoring. The impacts of LA on macrophage polarization, the expression of pro-/anti-inflammatory cytokines and P2X7r were analyzed using quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting.

RESULTS: LA treatment significantly reduced AI scores, paw swelling, joint destruction, and inflammatory cell infiltration, and alleviated arthritis pain. Additionally, LA promoted a balanced M1/M2 ratio by increasing the mRNA expression level of M2 marker arginase 1 and decreasing those of M1 markers inducible nitric oxide synthase and interleukin (IL)-1β in synovial tissues. Furthermore, LA lowered the levels of three M1-related cytokines, namely tumor necrosis factor-α, IL-1β and IL-18, and raised the level of the M2-related cytokine IL-10. Further research showed that treatment with LA inhibited the expression of P2X7r.

CONCLUSION: Our findings indicate that the notable therapeutic and analgesic effects of LA on AIA rats are exerted through balancing the M1/M2 ratio, probably via P2X7r.

Key words: arthritis, experimental, macrophage polarization, receptors, purinergic P2X7, anti-inflammatory agents, analgesics, lappaconitine

ZHANG Pengqiang, FENG Qi, HUANG Weiyan, OU Shan. Protective effect of lappaconitine on Freund's complete adjuvant-induced arthritis exerted through P2X7 receptor-mediated regulation of M1/M2 balance in rats[J]. Journal of Traditional Chinese Medicine, 2025, 45(1): 39-48.

Figures/Tables 6

Figure 1 Effects of LA on macroscopic features of AIA rats A: body weight gain was observed every 3 d from days 14 to 28; B: ankle diameter was observed at day 0 and every 3 d from days 14 to 28; C: AI was observed every 3 d from days 14 to 28. Control: normal group and treated with 4 mL·kg-1·d-1 of NS for 14 d; AIA: treated with 4 mL·kg-1·d-1 of NS for 14 d; AIA + LA low-dose: treated with 2 mg·kg-1·d-1 of LA for 14 d; AIA + LA medium-dose: treated with 4 mg·kg-1·d-1 of LA for 14 d; AIA + LA high-dose: treated with 8 mg·kg-1·d-1 of LA for 14 d; AIA + MTX: treated with 0.5 mg/kg per 3 d of MTX for 14 d. LA: lappaconitine; AIA: adjuvant induced arthritis; MTX: methotrexate; AI: arthritis index; NS: normal saline. Data are represented as mean ± standard deviation (n = 8). The groups were compared using a one-way analysis of variance followed by Tukey's multiple comparisons test. aP < 0.01 and fP < 0.05, compared with the control group rats; bP < 0.05 and dP < 0.01, compared with the AIA group rats; cP < 0.05 and eP < 0.01, compared with the AIA + MTX group rats.

Figure 2 Effect of LA on the antinociceptive activity of AIA rats A: measurement of hyperalgesia in rats by mechanical withdrawal threshold; B: semi-quantitative assessment of arthritis pain in rats by gait soring. Control: normal group and treated with 4 mL·kg-1·d-1 of NS for 14 d; AIA: treated with 4 mL·kg-1·d-1 of NS for 14 d; AIA + LA low-dose: treated with 2 mg·kg-1·d-1 of LA for 14 d; AIA + LA medium-dose: treated with 4 mg·kg-1·d-1 of LA for 14 d; AIA + LA high-dose: treated with 8 mg·kg-1·d-1 of LA for 14 d; AIA + MTX: treated with 0.5 mg/kg per 3 d of MTX for 14 d. LA: lappaconitine; AIA: adjuvant induced arthritis; MTX: methotrexate; NS: normal saline. Data are represented as mean ± standard deviation (n = 8). The groups were compared using a one-way analysis of variance followed by Tukey's multiple comparisons test. aP < 0.01 and fP < 0.05, compared with the control group rats; bP < 0.01 and dP < 0.05, compared with the AIA group rats; cP < 0.01 and eP < 0.05, compared with the AIA + MTX group rats.

Figure 3 Effects of LA on the histopathology of AIA joints by HE staining A-F: representative histological changes of hematoxylin and eosin-stained sections of the right hind ankle joints (scale bar: 200 μm). A: control group; B: AIA group; C: AIA + LA low-dose group; D: AIA + LA medium-dose group; E: AIA + LA high-dose group; F: AIA + MTX group. Red arrow: pannus formation; black arrow: bone erosion; golden arrow: inflammatory cell infiltration; blue arrow: cartilage destruction; JS: joint space; HP: synovial proliferation. G: histopathological scores of right hind ankle joints. Control: normal group and treated with 4 mL·kg-1·d-1 of NS for 14 d; AIA: treated with 4 mL·kg-1·d-1 of NS for 14 d; AIA + LA low-dose: treated with 2 mg·kg-1·d-1 of LA for 14 d; AIA + LA medium-dose: treated with 4 mg·kg-1·d-1 of LA for 14 d; AIA + LA high-dose: treated with 8 mg·kg-1·d-1 of LA for 14 d; AIA + MTX: treated with 0.5 mg/kg per 3 d of MTX for 14 d. LA: lappaconitine; AIA: adjuvant induced arthritis; MTX: methotrexate; NS: normal saline; HE: hematoxylin and eosin. Data are expressed as the mean ± standard deviation (n = 5). The groups were compared using a one-way analysis of variance followed by Tukey's multiple comparisons test. aP < 0.01, compared with the control group rats; bP < 0.01, compared with the AIA group rats.

Table 1 Effect of LA on the expression of macrophage M1 and M2 biomarkers in synovial tissues ($\bar{x}±s$)

Group	n	IL-1β mMRA relative expression	iNOS mMRA relative expression	Arg1mMRA relative expression
Control	5	1.27±0.92	1.72±1.32	1.41±1.22
AIA	5	15.78±4.06^a	15.85±4.25^a	1.94±0.68
AIA+LA low-dose	5	7.16±0.84^ab	4.29±1.76^b	2.21±0.39
AIA+LA medium-dose	5	5.16±1.18^ab	2.71±0.28^b	4.71±0.37^ab
AIA+LA high-dose	5	3.36±0.29^b	2.21±0.64^b	12.28±1.09^ab
AIA+MTX	5	1.93±0.14^b	1.55±0.50^b	24.96±0.96^ab

Table 2 Effects of LA on inflammatory cytokines in the serum of the rat AIA model (pg/mL, $\bar{x}±s$)

Group	n	Serum TNF-α	Serum IL-1β	Serum IL-10	Serum IL-18
Control	6	16.1±2.4	10.0±1.2	235.1±13.4	50.0±3.9
AIA	6	192.7±10.3^a	48.2±4.2^a	97.6±11.8^a	165.5±13.1^a
AIA+LA low-dose	6	146.7±9.9^abc	33.9±3.3^abc	141.3±10.12^abc	132.8±8.1^abc
AIA+LA medium-dose	6	126.6±10.8^abc	26.1±3.7^abc	162.5±12.7^abc	117.7±8.19^abc
AIA+LA high-dose	6	114.1±9.5^ab	21.97±2.43^ab	176.4±12.4^abc	105.3±7.7^ab
AIA+MTX	6	99.17±8.11^ab	21.01±2.52^ab	197.3±14.9^ab	100.9±8.5^ab

Figure 4 Effect of LA on the protein expression of P2X7r in synovial tissues by Western blotting A: Western blotting representative images of P2X7 in each group; B: relative protein expression levels of P2X7 in each group. 1: Control group; 2: AIA group; 3: AIA + LA low-dose group; 4: AIA + LA medium-dose group; 5: AIA + LA high-dose group; 6: AIA + MTX group. Control: normal group and treated with 4 mL·kg-1·d-1 of NS for 14 d; AIA: treated with 4 mL·kg-1·d-1 of NS for 14 d; AIA + LA low-dose: treated with 2 mg·kg-1·d-1 of LA for 14 d; AIA + LA medium-dose: treated with 4 mg·kg-1·d-1 of LA for 14 d; AIA + LA high-dose: treated with 8 mg·kg-1·d-1 of LA for 14 d; AIA + MTX: treated with 0.5 mg/kg per 3 d of MTX for 14 d. LA: lappaconitine; AIA: adjuvant induced arthritis; MTX: methotrexate; NS: normal saline; GAPDH: glyceraldehyde-3-phosphate dehydrogenase. Data are expressed as the mean ± standard deviation (n = 6). The groups were compared using a one-way analysis of variance followed by Tukey's multiple comparisons test. Compared with the control group, aP < 0.01; compared with the AIA group, bP < 0.01.

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