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Effects of TGMXD-208, a Novel PI3K Inhibitor, on Adjuvant-induced Arthritis Rats by Suppressing PI3K/AKT Signaling
Jiahua Yin1,2, Jiayu Wang1,2, Wenrui Su1,2
1School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China.
Background:
The PI3K/AKT signaling pathway is critical for immune cell proliferation, differentiation, survival, and inflammatory cytokine release. TGMXD-208, a novel dual PI3K inhibitor, selectively targets both PI3Kδ and PI3Kγ, positioning it as a potential therapeutic agent for Rheumatoid Arthritis (RA).
Methods:
This study evaluated ankle joint swelling and arthritis index and employed HE staining, X-ray imaging, and small animal ultrasonography to assess rat joint tissues. Serum antibodies for IL-1β, IL-6, and TNF-α were determined, as well as organ indices for the spleen and thymus. Western blotting and immunohistochemistry were used to measure the expression and phosphorylation of key enzymes in the PI3K/AKT pathway. The study also examined the impact of TGMXD- 208 on hematological parameters and organs.
Results:
Our investigation found that TGMXD-208 dramatically reduced ankle redness and swelling, as well as the arthritis index, in rats in the model group. Additionally, TGMXD-208 reduced arthralgia, deformity, and synovial hyperplasia of the knee joint and accelerated blood flow signals, vascular opacities, accumulation of inflammatory cells, and cartilage erosion of the rats' ankle joints to varying degrees. TGMXD-208 therapy markedly reduced serum levels of IL-1β, IL-6, and TNF-α compared to the model group. Besides, it also reduced organ indices. Furthermore, TGMXD-208 diminished the protein levels of p-PI3K and p-AKT. However, hematological parameters were not considerably impacted by TGMXD-208, and no appreciable aberrant alterations were noted in the organs.
Discussion:
TGMXD-208 alleviates RA pathology by suppressing PI3K/AKT pathway activation and reducing the levels of pro-inflammatory cytokines. Its dual PI3Kδ/γ targeting mitigates synovial hyperplasia and cartilage erosion in AA rats. Notably, 5 mg/kg TGMXD-208 demonstrated safety with no hematological or organ toxicity, supporting its therapeutic potential for RA
Conclusion:
TGMXD-208 cuts down arthritic symptoms in AA rats by blocking the PI3K/AKT pathway, making it a potential treatment option for RA.
