Inhibition of Transforming Growth Factor-β Attenuates Brain Injury and Neurological Deficits in a Rat Model of Germinal Matrix Hemorrhage

• Published in: Stroke (1970) Vol. 45; no. 3; pp. 828 - 834
• Main Authors: Manaenko, Anatol, Lekic, Tim, Barnhart, Margaret, Hartman, Richard, Zhang, John H.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.03.2014
• Subjects: Adult; Animals; Atrophy; Biological and medical sciences; Blotting, Western; Brain Injuries - drug therapy; Brain Injuries - physiopathology; Cerebral Ventricles - pathology; Extracellular Matrix Proteins - metabolism; Female; Glial Fibrillary Acidic Protein - metabolism; Humans; Hydrocephalus - etiology; Hydrocephalus - pathology; Immunohistochemistry; Intracranial Hemorrhages - drug therapy; Intracranial Hemorrhages - physiopathology; Medical sciences; Nervous System Diseases - drug therapy; Nervous System Diseases - etiology; Nervous System Diseases - physiopathology; Neurologic Examination; Neurology; Neuropharmacology; Neuroprotective agent; Pharmacology. Drug treatments; Pregnancy; Pteridines - pharmacology; Pteridines - therapeutic use; Rats; Rats, Sprague-Dawley; Signal Transduction - physiology; Survival; Transforming Growth Factor beta - antagonists & inhibitors; Vascular diseases and vascular malformations of the nervous system; Vitronectin - metabolism; Weight Loss - drug effects; Stroke; Nervous system diseases; Rat; Transforming growth factor β; transforming growth factor beta; Transforming growth factor; Rodentia; Cardiovascular disease; Hemorrhage; Cerebral disorder; Vascular disease; Vertebrata; Growth factor receptor; Mammalia; Animal; Central nervous system disease; receptors, transforming growth factor beta; Cerebrovascular disease
• ISSN: 0039-2499; 1524-4628; 1524-4628
• DOI: 10.1161/STROKEAHA.113.003754

Transforming growth factor-β (TGF-β) overproduction and activation of the TGF-β pathway are associated with the development of brain injury following germinal matrix hemorrhage (GMH) in premature infants. We examined the effects of GMH on the level of TGF-β1 in a novel rat collagenase-induced GMH model and determined the effect of inhibition of the TGF receptor I. In total, 92 seven-day old (P7) rats were used. Time-dependent effects of GMH on the level of TGF-β1 and TGF receptor I were evaluated by Western blot. A TGF receptor I inhibitor (SD208) was administered daily for 3 days, starting either 1 hour or 3 days after GMH induction. The effects of GMH and SD208 on the TGF-β pathway were evaluated by Western blot at day 3. The effects of GMH and SD208 on cognitive and motor function were also assessed. The effects of TGF receptor I inhibition by SD208 on GMH-induced brain injury and underlying molecular pathways were investigated by Western blot, immunofluorescence, and morphology studies 24 days after GMH. GMH induced significant delay in development, caused impairment in both cognitive and motor functions, and resulted in brain atrophy in rat subjects. GMH also caused deposition of both vitronectin (an extracellular matrix protein) and glial fibrillary acidic protein in perilesion areas, associated with development of hydrocephalus. SD208 ameliorated GMH-induced developmental delay, improved cognitive and motor functions, and attenuated body weight loss. SD208 also decreased vitronectin and glial fibrillary acidic protein deposition and decreased GMH-induced brain injury. Increased level of TGF-β1 and activation of the TGF-β pathway associate with the development of brain injury after GMH. SD208 inhibits GMH-induced activation of the TGF-β pathway and leads to an improved developmental profile, partial recovery of cognitive and motor functions, and attenuation of GMH-induced brain atrophy and hydrocephalus.