A Novel Preclinical Model of Germinal Matrix Hemorrhage Using Neonatal Rats
Background: Germinal matrix hemorrhage (GMH) is a neurological disorder associated with very low birth weight premature infants. This event can lead to post-hemorrhagic hydrocephalus, cerebral palsy, and mental retardation. This study developed a novel an
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Abstract Background: Germinal matrix hemorrhage (GMH) is a neurological disorder associated with very low birth weight premature infants. This event can lead to post-hemorrhagic hydrocephalus, cerebral palsy, and mental retardation. This study developed a novel animal model for pre-clinical investigations. Methods: Neonatal rats underwent infusion of clostridial collagenase into the right germinal matrix (anterior caudate) region using stereotaxic techniques. Developmental milestones were evaluated over 10 days, cognitive function at 3 weeks, and sensorimotor function at 4 weeks after collagenase infusion. This was accomplished by anthropometric quantifications of cranial, cerebral, cardiac, and splenic growths. Results: Collagenase infusion led to delays in neonatal developmental milestones, followed by cognitive and sensorimotor dysfunctions in the juvenile animals. Cranial growth was accelerated during the first week after injury, and this was followed by significant brain atrophy, splenomegaly, and cardiac hypertrophy 3 weeks later. Conclusion: This study characterized the developmental delays, mental retardation, and cerebral palsy features resembling the long-term clinical course after germinal matrix hemorrhage in premature infants. Pre-clinical testing of therapeutics in this experimental model could lead to improved patient outcomes while expanding upon the pathophysiological understanding of this disease. Keywords Animal models · Neurological deficits · Stroke, experimental
T. Lekic, A. Manaenko, W. Rolland, and J. Tang Department of Physiology, Loma Linda University, School of Medicine, Loma Linda, CA 92354, USA J.H. Zhang (*) Department of Physiology, Loma Linda University, School of Medicine, Loma Linda, CA 92354, USA and Department of Neurosurgery, Loma Linda University, School of Medicine, Loma Linda, CA 92354, USA and Department of Physiology, Loma Linda University, School of Medicine, Risley Hall, Room 223, Loma Linda, CA, 92354, USA e-mail: [email protected]
Introduction Germinal matrix hemorrhage (GMH) is the rupture of immature blood vessels within the subventricular (anterior caudate) progenitor cell region of neonatal brains [1] during the first 7 days of life [2]. GMH occurs in 20–25% of very low birth weight (VLBW £ 1,500 g) premature infants [3–5] and affects 3.5/1,000 births in the United States each year [6]. This is an important clinical problem, since the consequences are hydrocephalus (post-hemorrhagic ventricular dilation), cognitive and motor developmental delay, cerebral palsy, and mental retardation [4, 7]. However, available animal models to study the pathophysiological basis of these outcomes are lacking [8]. An important research priority is the development and validation of experimental models of brain hemorrhage for translational studies of human conditions [9]. Elevated MMP-2 and MMP-9 are associated with GMH induction in humans [10, 11]. Stereotaxic collagenase infusion is one of the most commonly used methods in adult experimental intracerebral hemorrhage (ICH) s
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