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Optimized lactoferrin as a highly promising treatment for intracerebral hemorrhage: Pre-clinical experience
- Source :
- J Cereb Blood Flow Metab
- Publication Year :
- 2020
-
Abstract
- Intracerebral hemorrhage (ICH) is the deadliest form of stroke for which there is no effective treatment, despite an endless number of pre-clinical studies and clinical trials. The obvious therapeutic target is the neutralization of toxic products of red blood cell (RBC) lysis that lead to cytotoxicity, inflammation, and oxidative damage. We used rigorous approaches and translationally relevant experimental ICH models to show that lactoferrin-(LTF)-based monotherapy is uniquely robust in reducing brain damage after ICH. Specifically, we designed, produced, and pharmacokinetically/toxicologically characterized an optimized LTF, a fusion of human LTF and the Fc domain of human IgG (FcLTF) that has a 5.8-fold longer half-life in the circulation than native LTF. Following dose-optimization studies, we showed that FcLTF reduces neurological injury caused by ICH in aged male/female mice, and in young male Sprague Dawley (SD) and spontaneously hypertensive rats (SHR). FcLTF showed a remarkably long 24-h therapeutic window. In tissue culture systems, FcLTF protected neurons from the toxic effects of RBCs and promoted microglia toward phagocytosis of RBCs and dead neurons, documenting its pleotropic effect. Our findings indicate that FcLTF is safe and effective in reducing ICH-induced damage in animal models used in this study.
- Subjects :
- Male
Inflammation
Brain damage
Pharmacology
Neuroprotection
Rats, Sprague-Dawley
03 medical and health sciences
Mice
0302 clinical medicine
Anti-Infective Agents
Medicine
Animals
Humans
Cytotoxicity
Stroke
030304 developmental biology
Cerebral Hemorrhage
Intracerebral hemorrhage
0303 health sciences
Microglia
biology
business.industry
Lactoferrin
Original Articles
medicine.disease
Rats
medicine.anatomical_structure
Neurology
biology.protein
Female
Neurology (clinical)
medicine.symptom
Cardiology and Cardiovascular Medicine
business
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15597016
- Volume :
- 41
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
- Accession number :
- edsair.doi.dedup.....2aee9e91e65da3f3ba78bb3d78d7a2cb