Premium
Single intracerebroventricular progranulin injection adversely affects the blood–brain barrier in experimental traumatic brain injury
Author(s) -
Hummel Regina,
Lang Manuel,
Walderbach Simona,
Wang Yong,
Tegeder Irmgard,
Gölz Christina,
Schäfer Michael K. E.
Publication year - 2021
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.15375
Subject(s) - traumatic brain injury , medicine , microglia , occludin , neurotrophic factors , extravasation , blood–brain barrier , inflammation , parenchyma , brain damage , endocrinology , pathology , pharmacology , central nervous system , tight junction , biology , receptor , psychiatry , microbiology and biotechnology
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.