Targeting Germinal Matrix Hemorrhage–Induced Overexpression of Sodium‐Coupled Bicarbonate Exchanger Reduces Posthemorrhagic Hydrocephalus Formation in Neonatal Rats

Autor: Paul R. Krafft, Yixin Zhang, Weifeng Wan, Qunling Zhan, Yan Ding, Feng Yan, Guangyong Wu, John H. Zhang, Qian Li
Rok vydání: 2018
Předmět:
0301 basic medicine
Pathology
Siderophores
Matrix (biology)
Ferric Compounds
Rats
Sprague-Dawley
chemistry.chemical_compound
Cognition
0302 clinical medicine
Posthemorrhagic hydrocephalus
Medicine
RNA
Small Interfering
slc4a10
Cerebrospinal Fluid
Original Research
Behavior
Animal
Stroke
germinal matrix hemorrhage
Germinal matrix hemorrhage
hemorrhage
Cardiology and Cardiovascular Medicine
Hydrocephalus
medicine.medical_specialty
iron‐responsive element‐binding protein 2
brain
Sodium
Bicarbonate
chemistry.chemical_element
Deferoxamine
Motor Activity
neonatal ischemia
03 medical and health sciences
Chlorides
Developmental biology
Animals
Iron Regulatory Protein 1
iron overload
Iron Regulatory Protein 2
Cerebral Hemorrhage
Injections
Intraventricular
business.industry
Sodium-Bicarbonate Symporters
medicine.disease
Disease Models
Animal
RNAi Therapeutics
030104 developmental biology
Animals
Newborn
Animal Models of Human Disease
chemistry
Choroid Plexus
Oxidant Stress
business
Complication
Basic Science Research
030217 neurology & neurosurgery
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
Popis: Background Germinal matrix hemorrhage ( GMH ) is a leading cause of mortality and lifelong morbidity in preterm infants. Posthemorrhagic hydrocephalus ( PHH ) is a common complication of GMH . A sodium‐coupled bicarbonate exchanger ( NCBE ) encoded by solute carrier family 4 member 10 gene is expressed on the choroid plexus basolateral membrane and may play a role in cerebrospinal fluid production and the development of PHH . Following GMH , iron degraded from hemoglobin has been linked to PHH . Choroid plexus epithelial cells also contain iron‐responsive element‐binding proteins ( IRP s), IRP 1, and IRP 2 that bind to mRNA iron‐responsive elements. The present study aims to resolve the following issues: (1) whether the expression of NCBE is regulated by IRP s; (2) whether NCBE regulates the formation of GMH ‐induced hydrocephalus; and (3) whether inhibition of NCBE reduces PHH development. Methods and Results GMH model was established in P7 rat pups by injecting bacterial collagenase into the right ganglionic eminence. Another group received iron trichloride injections instead of collagenase. Deferoxamine was administered intraperitoneally for 3 consecutive days after GMH /iron trichloride. Solute carrier family 4 member 10 small interfering RNA or scrambled small interfering RNA was administered by intracerebroventricular injection 24 hours before GMH and followed with an injection every 7 days over 21 days. NCBE expression increased while IRP 2 expression decreased after GMH /iron trichloride. Deferoxamine ameliorated both the GMH ‐induced and iron trichloride–induced decrease of IRP 2 and decreased NCBE expressions. Deferoxamine and solute carrier family 4 member 10 small interfering RNA improved cognitive and motor functions at 21 to 28 days post GMH and reduced cerebrospinal fluid production as well as the degree of hydrocephalus at 28 days after GMH . Conclusions Targeting iron‐induced overexpression of NCBE may be a translatable therapeutic strategy for the treatment of PHH following GMH .
Databáze: OpenAIRE
Externí odkaz: