|Fpr2: a novel drug target to tackle oxidative stress and inflammation in Alzheimer’s disease
Inflammation and oxidative stress both act as major contributors to Alzheimer’s disease [1,2]. Microglia, the resident immune cells of the central nervous system, are the first line of immunological defence, but can become toxic when chronically activated, leading to extensive neuronal damage . Attenuating or even reversing this may provide neuronal protection against chronic oxidative and inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced oxidative stress and inflammation could be reduced through activation of the Fpr2 receptor, known to have an important role in the resolution of peripheral inflammation. Immortalised murine microglia (BV2 cells) were stimulated with LPS (50ng/ml) for 1h prior to treatment with the Fpr2 ligand, Cpd43 (100nM). Cytokine (TNFα and IL-10) production was monitored at 24 and 48h. Reactive oxygen species (ROS) were monitored with carboxy-H2DCFDA. LPS was administered for 30 minutes prior to Cpd43, with ROS production analysed every 30 minutes between 1 and 3h.
Treatment with Cpd43 significantly suppressed LPS-induced production of TNFα at 24h and 48h post-exposure. Moreover, Cpd43 treatment significantly enhanced production of IL-10 48h post-LPS treatment. This was a result of the activation of p38 MAP kinase, as determined by western blot analysis. This aligns with previous data investigating Fpr2 activation and signaling . Interestingly however, Cpd43 also reduces LPS-induced ROS production back to baseline levels – something not previously recorded for Fpr2 agonists.
Combined, these data highlight Fpr2 as a novel target to exploit immunomodulatory strategies for the treatment of neurological diseases, but also indicates a combined action, involving the amelioration of oxidative stress.
1. Heppner et al. (2015). Nat Rev Neurosci 16: 358-372.
|Inflammation; Oxidative Stress; Fpr2; Alzheimer's
|Alzheimer's Research UK Conference