JNK inhibition suppresses microglial NLRP3 activation and oxidative stress but unexpectedly worsens pain in diabetic neuropathy: insights from a combined in vitro and in vivo pharmacological study
Neurochem Int. 2026 May 4:106167. doi: 10.1016/j.neuint.2026.106167. Online ahead of print.
ABSTRACT
Diabetic neuropathy (DN) is driven by neuroinflammation and oxidative stress, with c-Jun N-terminal kinase (JNK) as a key mediator; however, the effects of JNK inhibition on neuropathic pain remain unclear. Therefore, we investigated the therapeutic potential of the JNK inhibitor SP600125 in a type 2 diabetic mouse model using combined in vitro and in vivo approaches. BV2 microglia were exposed to high glucose, lipopolysaccharide, palmitic acid, or hydrogen peroxide (H2O2) with or without SP600125 (10 nM). The PPARγ antagonist GW9662 was used for mechanistic dissection. Diabetic mice received SP600125 (15 mg/kg/day) or vehicle for 7 weeks. In vitro, SP600125 attenuated JNK phosphorylation and suppressed pro-inflammatory activation via NF-κB and NLRP3 in a PPARγ-dependent manner. SP600125 reduced palmitate-induced oxidative stress but exacerbated H2O2-induced injury (p < 0.0001), revealing context-dependent redox modulation. In vivo, SP600125 reduced diabetes-induced lipid accumulation and microglial reactivity while shifting microglia to an anti-inflammatory phenotype; however, it did not alter NLRP3, ASC, IKKα, or PPARγ expression. Despite these effects, SP600125 paradoxically worsened mechanical allodynia and thermal hyperalgesia. Together, these findings indicate that JNK inhibition provides anti-inflammatory and anti-lipid effects but paradoxically exacerbates pain, revealing a critical dissociation between neuroprotection and pain modulation in diabetic neuropathy.
PMID:42092483 | DOI:10.1016/j.neuint.2026.106167