[Curcumin prevents the arsenic-induced neuroimmune injury through JAK2/STAT3 pathway].

Abstract

Objective To investigate the protective effect of curcumin (Cur) against arsenic-induced neuroimmune toxicity and the underlying molecular mechanisms in vivo. Methods Eighty SPF female C57BL/6 mice were randomly assigned to four groups: a control group, an arsenic-treated group, a Cur-treated group and an arsenic+Cur group, with 20 mice in each group. The control group received distilled water; the arsenic-treated group was given 50 mg/L NaAsO₂ in the drinking water; the Cur-treated group was gavaged with 200 mg/kg of curcumin for 45 days; and the arsenic+Cur group received distilled water and was gavaged with 200 mg/kg of curcumin. Y-maze and Morris water maze experiments were conducted to assess the learning and memory ability of the mice. Western blot analysis was used to detect protein levels of blood-brain barrier tight junction proteins zonula occludens protein 1(ZO-1) and claudin 5, T lymphocyte subpopulation CD4 and CD8, Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway-related molecules JAK2 and STAT3. Real-time PCR was used to assess the mRNA levels of CD4⁺ T lymphocyte subsets type 1 T helper (Th1), Th2, Th17 and regulatory T cells (Treg) transcription factors and cytokines in hippocampus. Results Compared with the control group, the arsenic-treated group showed a significantly decreased correct rate, increased latency to reach the platform on the third and fifth days, and reduced times of crossing the platform. The expression of ZO-1 and claudin 5 protein decreased significantly, and the protein levels of CD4 and CD8 were up-regulated. The mRNA levels of Th1, Th17, and Treg transcription factor T-box expressed in T cell(T-bet), retinoid-related orphan receptor gamma t(RORγt), and forkhead box protein 3(FOXP3) in the arsenic-treated group were decreased. Th1 and Th17 cytokines interferon γ(IFN-γ) and interleukin 17(IL-17) were markedly decreased. In contrast, the mRNA levels of the Th2 transcription factor GATA binding protein 3(GATA3) and cytokine IL-4 in arsenic-treated group were higher than those in the control group. Furthermore, the protein levels of phosphorylated JAK2 (p-JAK2) and phosphorylated STAT3 (p-STAT3) increased. Compared with the arsenic-treated group, the arsenic+Cur group demonstrated a significantly increased correct rate, decreased latency to reach the platform on the third and fifth days, and increased times of crossing the platform. The protein expression levels of ZO-1 and claudin 5 increased significantly, and the protein levels of CD4 and CD8 were down-regulated. The mRNA levels of Th2 transcription factor GATA3 and cytokine IL-4 were decreased. The mRNA levels of Th17 transcription factor RORγt and cytokine IL-17 were markedly increased. Furthermore, the protein levels of p-JAK2 and p-STAT3 decreased. Conclusion Through inhibiting the JAK2/STAT3 signaling pathway, curcumin could improve arsenic-induced decline in learning and memory abilities in mice, reverse the destruction of blood-brain barrier permeability of innate immune system components in arsenic-exposed mice, and antagonize arsenic-induced increase in the number of renal CD4 and CD8 molecule as well as the imbalance of CD4⁺ T lymphocyte subsets (Th1, Th2, Th17 and Treg), ultimately counteracting arsenic-induced neurotoxicity.