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Authors: Hummel, Regina
Lang, Manuel
Walderbach, Simona
Wang, Yong
Tegeder, Irmgard
Gölz, Christina
Schäfer, Michael K. E.
Title: Single intracerebroventricular progranulin injection adversely affects the blood–brain barrier in experimental traumatic brain injury
Online publication date: 12-Sep-2022
Year of first publication: 2021
Language: english
Abstract: Progranulin (PGRN) is a neurotrophic and anti-inflammatory factor with protective effects in animal models of ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury (TBI). Administration of recombinant (r) PGRN prevents exaggerated brain pathology after TBI in Grn-deficient mice, suggesting that local injection of recombinant progranulin (rPGRN) provides therapeutic benefit in the acute phase of TBI. To test this hypothesis, we subjected adult male C57Bl/6N mice to the controlled cortical impact model of TBI, administered a single dose of rPGRN intracerebroventricularly (ICV) shortly before the injury, and examined behavioral and biological effects up to 5 days post injury (dpi). The anti-inflammatory bioactivity of rPGRN was confirmed by its capability to inhibit the inflammation-induced hypertrophy of murine primary microglia and astrocytes in vitro. In C57Bl/6N mice, however, ICV administration of rPGRN failed to attenuate behavioral deficits over the 5-day observation period. (Immuno)histological gene and protein expression analyses at 5 dpi did not reveal a therapeutic benefit in terms of brain injury size, brain inflammation, glia activation, cell numbers in neurogenic niches, and neuronal damage. Instead, we observed a failure of TBI-induced mRNA upregulation of the tight junction protein occludin and increased extravasation of serum immunoglobulin G into the brain parenchyma at 5 dpi. In conclusion, single ICV administration of rPGRN had not the expected protective effects in the acute phase of murine TBI, but appeared to cause an aggravation of blood–brain barrier disruption. The data raise questions about putative PGRN-boosting approaches in other types of brain injuries and disease.
DDC: 610 Medizin
610 Medical sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 04 Medizin
Place: Mainz
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY-NC
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Journal: Journal of neurochemistry
Pages or article number: 342
Publisher: Wiley-Blackwell
Publisher place: Oxford
Issue date: 2021
ISSN: 1471-4159
Publisher DOI: 10.1111/jnc.15375
Appears in collections:JGU-Publikationen

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