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FGF21 modulates hippocampal cold-shock proteins and CA2-subregion proteins in neonatal mice with hypoxia–ischemia

Pediatric Research volume 94, pages 1355–1364 (2023)Cite this article

Abstract

Background

Fibroblast growth factor 21 (FGF21) is a neuroprotectant with cognitive enhancing effects but with poorly characterized mechanism(s) of action, particularly in females. Prior studies suggest that FGF21 may regulate cold-shock proteins (CSPs) and CA2-marker proteins in the hippocampus but empirical evidence is lacking.

Methods

We assessed in normothermic postnatal day (PND) 10 female mice, if hypoxic–ischemic (HI) brain injury (25 min 8% O2/92% N2) altered endogenous levels of FGF21 in serum or in the hippocampus, or its receptor β-klotho. We also tested if systemic administration of FGF21 (1.5 mg/kg) modulated hippocampal CSPs or CA2 proteins. Finally, we measured if FGF21 therapy altered markers of acute hippocampal injury.

Results

HI increased endogenous serum FGF21 (24 h), hippocampal tissue FGF21 (4d), and decreased hippocampal β-klotho levels (4d). Exogenous FGF21 therapy modulated hippocampal CSP levels, and dynamically altered hippocampal CA2 marker expression (24 h and 4d). Finally, FGF21 ameliorated neuronal damage markers at 24 h but did not affect GFAP (astrogliosis) or Iba1 (microgliosis) levels at 4d.

Conclusions

FGF21 therapy modulates CSP and CA2 protein levels in the injured hippocampus. These proteins serve different biological functions, but our findings suggest that FGF21 administration modulates them in a homeostatic manner after HI.

Impact

  • Hypoxic–ischemic (HI) injury in female post-natal day (PND) 10 mice decreases hippocampal RNA binding motif 3 (RBM3) levels in the normothermic newborn brain.

  • HI injury in normothermic newborn female mice alters serum and hippocampal fibroblast growth factor 21 (FGF21) levels 24 h post-injury.

  • HI injury in normothermic newborn female mice alters hippocampal levels of N-terminal EF-hand calcium binding protein 2 (NECAB2) in a time-dependent manner.

  • Exogenous FGF21 therapy ameliorates the HI-mediated loss of hippocampal cold-induced RNA-binding protein (CIRBP).

  • Exogenous FGF21 therapy modulates hippocampal levels of CA2-marker proteins after HI.

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Fig. 1: The effect of HI on endogenous FGF21 and hippocampal β-klotho levels.
Fig. 2: Validation of CSP detecting antibodies and the effect of HI on neurodevelopmental expression of hippocampal CSP proteins.
Fig. 3: The effect of FGF21 administration in HI-injured pups on hippocampal CSPs.
Fig. 4: The effect of FGF21 administration in HI-injured pups on hippocampal CA2 marker proteins.
Fig. 5: Acute brain injury markers in normothermic PND10 female mice subjected to HI.
Fig. 6: The effect of FGF21 administration on acute brain injury markers.

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Data availability

All data generated or analyzed during this study are included in this published article and its Supplementary Files.

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Funding

This work was supported by NIH/NINDS grant R01NS105721 to T.C.J., by the University of South Florida Morsani College of Medicine start-up funds to T.C.J., by a Lloyd Reback Family Gift, Laerdal Foundation for Acute Medicine grant, Zoll Foundation grant, and T32 (2T32HD040686) to J.R.H., and by the Ake N. Grenvik Chair in Critical Care Medicine to P.M.K.

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Authors and Affiliations

  1. Department of Critical Care Medicine, Safar Center for Resuscitation Research, UPMC Children’s Hospital of Pittsburgh, Rangos Research Center – 6th floor, Pittsburgh, PA, 15224, USA

    Jeremy R. Herrmann, Patrick M. Kochanek, Vincent A. Vagni, Keri Janesko-Feldman & Jason Stezoski

  2. USF Health Heart Institute, University of South Florida Morsani College of Medicine, MDD 0630, 560 Channelside Drive, Tampa, FL, 33602, USA

    Kiersten Gorse & Travis C. Jackson

  3. Department of Molecular Pharmacology & Physiology, University of South Florida Morsani College of Medicine, 12901 Bruce B Downs Boulevard, Tampa, FL, 33612-4799, USA

    Kiersten Gorse & Travis C. Jackson

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  1. Jeremy R. Herrmann
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Contributions

T.C.J. conceived the study. T.C.J., J.R.H., and P.M.K. contributed to the study design. J.R.H. and T.C.J. drafted the manuscript. V.A.V., K.G., K.J.-F., and J.S. contributed to experiments and data acquisition. T.C.J., P.M.K., and J.R.H. contributed to data analysis. P.M.K., V.A.V., K.G., and K.J.-F. edited the draft and contributed to the final submitted version.

Corresponding author

Correspondence to Travis C. Jackson.

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Competing interests

T.C.J. and P.M.K. are co-inventors on USPTO patent No. 11,638, 745 and on USPTO patent application No. 18/166,290 titled: “Method to Improve Neurologic Outcomes in Temperature Managed Patients”.

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Herrmann, J.R., Kochanek, P.M., Vagni, V.A. et al. FGF21 modulates hippocampal cold-shock proteins and CA2-subregion proteins in neonatal mice with hypoxia–ischemia. Pediatr Res 94, 1355–1364 (2023). https://doi.org/10.1038/s41390-023-02652-9

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