Dócs, KlaudiaKhalil, Mohamed Mounir Hassan Mohamed2025-06-162025-06-162025-03-02https://hdl.handle.net/2437/391836Chronic polyneuropathy is one of the most common consequences of type 2 diabetes, leading to the development of neuropathic pain (DNP) in more than 30% of patients. First-line drugs used to treat DNP are often completely ineffective, indicating that the mechanism of DNP development is not fully understood. One of the hallmarks of central sensitization inducing chronic pain is reactive gliosis, which leads to an interleukin-1 beta (IL-1β)-dependent neuroinflammation. Here, using behavioral and immunocytochemical methods, we investigated if methylglyoxal (MGO), a cytotoxic metabolite accumulating in diabetic patients, induces reactive astrocytes and microglia and an increased IL-1β production in the spinal dorsal horn (SDH) of mice, where primary pain processing takes place. MGO at a concentration of 1 μM induced a 5-fold increase in mechanical pain sensitivity in males and a 6-fold increase in female mice. In both sexes, the TRPA1 antagonist HC030031 partially, and the integrated stress response inhibitor ISRIB almost completely prevented the development of MGO-induced pain hypersensitivity. Double immunohistochemistry revealed that MGO induces a 3-fold increase of astrocytic IL-1β production in the SDH of female mice, which was only partially inhibited by HC030031 and almost completely abolished by ISRIB. Microglia in female mice showed a 14-fold increase in IL-1β expression following MGO administration. Inhibition of TRPA1 or the integrated stress response reduced this effect by 28% and 87%, respectively. In contrast, male mice exhibited a 1.5-fold and 3.7-fold increase in the expression of IL-1β in SDH astrocytes and microglia, respectively, in response to the application of MGO. In astrocytes, both HC030031 and ISRIB attenuated but did not fully prevent the effect of MGO. In microglia, ISRIB prevented, whereas TRPA1 inhibition did not show any effect on the MGO-induced elevation of IL-1β production. Our results suggest that in diabetic patients, accumulation of MGO can lead to the development of neuropathic pain. Effects of MGO were mediated by TRPA1 and the integrated stress response. However, the roles of these transduction mechanisms are different in astrocytes and microglia. The increased production of IL-1β may play a more pronounced role in the development of diabetic neuropathic pain in female mice.40endiabetic neuropathic painAstrocytesmicroglianeuroinflammationIL-1bmethylglyoxalBiology::NeurobiologyHozzáférhető a 2022 decemberi felsőoktatási törvénymódosítás értelmében.