Anemoside B4 alleviates arthritis pain via suppressing ferroptosis-mediated inflammation.

Chronic pain is the key manifestations of rheumatoid arthritis. Neuroinflammation in the spinal cord drives central sensitization and chronic pain. Ferroptosis has potentially important roles in the occurrence of neuroinflammation and chronic pain. In the current study, mouse model of collagen-induced arthritis was established by intradermal injection of type II collagen in complete Freund's adjuvant (CFA) solution. CFA inducement resulted in swollen paw and ankle, mechanical and spontaneous pain, and impaired motor coordination. The spinal inflammation was triggered, astrocytes were activated, and increased NLRP3-mediated inflammatory signal was found in CFA spinal cord. Oxidative stress and ferroptosis in the spinal cord were manifested. Meanwhile, enhancive spinal GSK-3ß activity and abnormal phosphorylated Drp1 were observed. To investigate the potential therapeutic options for arthritic pain, mice were intraperitoneally injected with AB4 for three consecutive days. AB4 treatment reduced pain sensitivity and increased the motor coordination. In the spinal cord, AB4 treatment inhibited NLRP3 inflammasome-mediated inflammatory response, increased antioxidation, decreased mitochondrial reactive oxygen species and ferroptosis. Furthermore, AB4 decreased GSK-3ß activity by binding with GSK-3ß through five electrovalent bonds. Our findings indicated that AB treatment relieves arthritis pain by inhibiting GSK-3ß activation, increasing antioxidant capability, reducing Drp1-mediated mitochondrial dysfunction and suppressing neuroinflammation.

Emodin alleviates arthritis pain through reducing spinal inflammation and oxidative stress.

Chronic pain is the predominant problem for rheumatoid arthritis patients, and negatively affects quality of life. Arthritis pain management remains largely inadequate, and developing new treatment strategies are urgently needed. Spinal inflammation and oxidative stress contribute to arthritis pain and represent ideal targets for the treatment of arthritis pain. In the present study, collagen-induced arthritis (CIA) mouse model was established by intradermally injection of type II collagen (CII) in complete Freund's adjuvant (CFA) solution, and exhibited as paw and ankle swelling, pain hypersensitivity and motor disability. In spinal cord, CIA inducement triggered spinal inflammatory reaction presenting with inflammatory cells infiltration, increased Interleukin-1ß (IL-1ß) expression, and up-regulated NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and cleaved caspase-1 levels, elevated spinal oxidative level presenting as decreased nuclear factor E2-related factor 2 (Nrf2) expression and Superoxide dismutase (SOD) activity. To explore potential therapeutic options for arthritis pain, emodin was intraperitoneally injected for 3 days on CIA mice. Emodin treatment statistically elevated mechanical pain sensitivity, suppressed spontaneous pain, recovered motor coordination, decreased spinal inflammation score and IL-1ß expression, increased spinal Nrf2 expression and SOD activity. Further, AutoDock data showed that emodin bind to Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) through two electrovalent bonds. And emodin treatment increased the phosphorylated AMPK at threonine 172. In summary, emodin treatment activates AMPK, suppresses NLRP3 inflammasome response, elevates antioxidant response, inhibits spinal inflammatory reaction and alleviates arthritis pain.

Alleviating effect of lycorine on CFA­induced arthritic pain via inhibition of spinal inflammation and oxidative stress.

Chronic pain is the primary symptom of osteoarthritis affecting a patient's quality of life. Neuroinflammation and oxidative stress in the spinal cord contribute to arthritic pain and represent ideal targets for pain management. In the present study, a model of arthritis was established by intra-articular injection of complete Freund's adjuvant (CFA) into the left knee joint in mice. After CFA inducement, knee width and pain hypersensitivity in the mice were increased, motor disability was impaired, spinal inflammatory reaction was induced, spinal astrocytes were activated, antioxidant responses were decreased, and glycogen synthase kinase 3ß (GSK-3ß) activity was inhibited. To explore the potential therapeutic options for arthritic pain, lycorine was intraperitoneally injected for 3 days in the CFA mice. Lycorine treatment significantly reduced mechanical pain sensitivity, suppressed spontaneous pain, and recovered motor coordination in the CFA-induced mice. Additionally, in the spinal cord, lycorine treatment decreased the inflammatory score, reduced NOD-like receptor protein 3 inflammasome (NLRP3) activity and IL-1ß expression, suppressed astrocytic activation, downregulated NF-κB levels, increased nuclear factor erythroid 2-related factor 2 expression and superoxide dismutase activity. Furthermore, lycorine was shown to bind to GSK-3ß through three electrovalent bonds, to inhibit GSK-3ß activity. In summary, lycorine treatment inhibited GSK-3ß activity, suppressed NLRP3 inflammasome activation, increased the antioxidant response, reduced spinal inflammation, and relieved arthritic pain.