3.5 Fingolimod treatment decreased hippocampal levels of the inflammatory cytokines IL-1β and IL-6 while increasing BDNF and phosphorylated-extracellular signal-regulated kinase (ERK) expression
Since glial activation can produce pro-inflammatory cytokines, such as IL-6 and IL-1β, which are thought to be trait markers of schizophrenia (Momtazmanesh, Zare-Shahabadi et al., 2019), we further examined cytokine expression in the hippocampus. We found that PCP-treated rats showed significantly higher IL-6 and L-1β levels. Concurrently, fingolimod (0.5 mg/kg, 1 mg/kg, i.p.) partially attenuated the expressions of these pro-inflammatory cytokines in a dose-dependent manner (Figure 6A, B). The above results suggest that the BDNF/ERK pathway activation and inhibition of IL-1β and IL-6 cytokine expressions is involved in the treatment effect of fingolimod. The BDNF/ERK pathway is extensively involved in learning and memory processes and plays a crucial role in modulating synaptic plasticity and adult neurogenesis (Kowiański, Lietzau et al., 2018). To evaluate whether the treatment effect of fingolimod was due to activation of the BDNF/ERK pathway, we assessed the expressions of BDNF and phosphorylated ERK. The results indicated that BDNF protein expression and ERK1/2 phosphorylation in the PCP (10 mg/kg, i.p.)-treated group were decreased. In contrast, fingolimod treatment (0.5 mg/kg, 1 mg/kg, i.p.) increased BDNF expression (Figure 6C) and ERK1/2 phosphorylation (Figure 6D) in a dose-dependent manner.