Short-term effect of erythropoietin on brain lesions and aquaporin-4 expression in a hypoxic-ischemic neonatal rat model assessed by magnetic resonance diffusion weighted imaging and immunohistochemistry.
Erythropoietin (Epo) is an endogenous cytokine that regulates hematopoiesis and is widely used to treat anemia. In addition, it has recently increased interest in the neurosciences since the new concept of Epo as a neuroprotective agent has emerged. The potential protective effect of human recombinant Epo (r-hu-Epo) on a hypoxic-ischemic (HI) pup rat model was studied. Cerebral HI was obtained by permanent left carotid artery ligature of pups followed by a 2-h hypoxia. Three hours after carotid occlusion, brain lesions were assessed by magnetic resonance diffusion weighted imaging. Intraperitoneal administration of r-hu-Epo (30,000 U/kg dose) limited both the HI-induced brain lesion area and the decrease in apparent diffusion coefficient (ADC) in the lesion. To identify potential mechanisms underlying the effects of Epo, immunohistochemical detection of caspase-3 and water channel protein aquaporin-4 (AQP4) were performed. No early apoptosis was detected, but up-regulation of AQP4 expression was observed in HI pups that received r-hu-Epo compared with HI animals without treatment. This study demonstrates an early neuroprotective effect of Epo with regard to brain lesion area and ADC values. One possible mechanism of Epo for decreasing brain edema and cellular swelling could be a better clearance of water excess in brain tissue, a process possibly mediated by AQP4.
Brissaud
Olivier
O
Neonatal Intensive Care Unit, University Children's Hospital, Bordeaux 33076, France. olivier.brissaud@chu-bordeaux.fr
Villega
Frédéric
F
Pieter Konsman
Jan
J
Sanchez
Stéphane
S
Raffard
Gérard
G
Franconi
Jean-Michel
JM
Chateil
Jean-François
JF
Bouzier-Sore
Anne-Karine
AK
D000818:Animals; D000831:Animals, Newborn; D051401:Aquaporin 4 / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology
D051401:Aquaporin 4; D011994:Recombinant Proteins; D004921:Erythropoietin