16: FGF21 THERAPY ATTENUATES ISCHEMIA-MEDIATED DOWNREGULATION OF NEUROPROTECTIVE RBM3 IN NEWBORN MICE

Abstract

Introduction: Fibroblast Growth Factor 21 (FGF21) is a neuroprotective cold stress hormone – i.e., a hormone upregulated by cold exposure. The mechanisms underlying FGF21-mediated neuroprotection remain to be fully elucidated. A key clue comes from studies in cultured immature neurons which revealed that FGF21 administration augments the ability of cold-stress to increase the potent neuroprotective cold-shock protein (CSP) RNA-Binding Motif 3 (RBM3). Furthermore, Beta-klotho, the obligatory FGF21 co-receptor, is uniquely abundant in the infant brain suggesting that newborns may benefit most from FGF21 therapy. Here we tested in a mouse model of neonatal encephalopathy (NE) if FGF21 bolus increased RBM3 levels in the normothermic (non-cooled) brain. We also tested if it affected the levels of a related CSP termed cold-inducible RNA-binding protein (CIRBP). Methods: Post-natal day 10 C57BL/6 female pups (n = 8/group) underwent right common carotid artery ligation followed by 25 min of 8% hypoxia (the Rice-Vannucci model of NE). Post-injury, mice were randomized to FGF21 (1.5mg/kg) or vehicle via subcutaneous bolus. Shams were also studied. RBM3 and CIRBP levels were measured (western blot) 24h later in the ipsilateral hippocampus. Levels were analyzed by Kruskal-Wallis (KW) with post-hoc Dunn’s test. Results: Median RBM3 densitometry differed between sham (0.309, IQR: 0.269-0.356), vehicle (0.133, IQR: 0.077-0.191) and FGF21 (0.160, IQR: 0.125-0.341) treated mice (KW, p=0.0135). Post-hoc Dunn’s test revealed significant decreases in RBM3 in vehicle treated NE vs. sham mice (p=0.010), but not in FGF21 treated NE vs. sham mice (p=0.385). Median CIRBP densitometry differed between sham (0.672, IQR: 0.608-0.695), vehicle (0.470, IQR: 0.418-0.591) and FGF21 (0.659, IQR: 0.511-0.731) treated mice (KW, p=0.031). There were no significant differences in CIRBP for individual group comparisons. Conclusions: Bolus administration of FGF21 attenuates the loss of the powerful neuroprotectant RBM3 in the normothermic hippocampus at 24h post-insult. Future studies of FGF21 treatment in RBM3 knockout mice are warranted to determine the contribution of this pathway to FGF21-mediated neuroprotection in NE.