Abstract
Erythropoietin (EPO) has been recognized as a neuroprotective agent. In animal models of neonatal brain injury, exogenous EPO has been shown to reduce lesion size, improve structure and function. Experimental studies have focused on short course treatment after injury. Timing, dose and length of treatment in preterm brain damage remain to be defined. We have evaluated the effects of high dose and long-term EPO treatment in hypoxic-ischemic (HI) injury in 3 days old (P3) rat pups using histopathology, magnetic resonance imaging (MRI) and spectroscopy (MRS) as well as functional assessment with somatosensory-evoked potentials (SEP). After HI, rat pups were assessed by MRI for initial damage and were randomized to receive EPO or vehicle. At the end of treatment period (P25) the size of resulting cortical damage and white matter (WM) microstructure integrity were assessed by MRI and cortical metabolism by MRS. Whisker elicited SEP were recorded to evaluate somatosensory function. Brains were collected for neuropathological assessment. The EPO treated animals did not show significant decrease of the HI induced cortical loss at P25. WM microstructure measured by diffusion tensor imaging was improved and SEP response in the injured cortex was recovered in the EPO treated animals compared to vehicle treated animals. In addition, the metabolic profile was less altered in the EPO group. Long-term treatment with high dose EPO after HI injury in the very immature rat brain induced recovery of WM microstructure and connectivity as well as somatosensory cortical function despite no effects on volume of cortical damage. This indicates that long-term high-dose EPO induces recovery of structural and functional connectivity despite persisting gross anatomical cortical alteration resulting from HI.
Highlights
Neonatal hypoxic-ischemic (HI) brain injuries involve both primary destructive events including neuronal death, gliotic reaction and secondary maturational disturbances leading to subsequent abnormal development of cerebral white and gray matter [1,2]
We investigated the neuroprotective effects, including damage reduction and neurotrophic action, of long-term high dose EPO administration in the postnatal day 3 (P3)-HI model using a multi-modal strategy that combine histological, macro-structural (MRI), micro-structural (DTI), neurochemical (MRS) as well as functional (SEP) assessments
No significant score difference was found between NaCl and EPO groups
Summary
Neonatal hypoxic-ischemic (HI) brain injuries involve both primary destructive events including neuronal death, gliotic reaction and secondary maturational disturbances leading to subsequent abnormal development of cerebral white and gray matter [1,2]. P3-HI injury damages specific brain regions and is characterized by diffuse intracortical white matter loss, zones of patchy neuronal degeneration, altered oligodendrocyte progenitors maturation and subsequent myelination, and hypertrophic astrocytes with formation of gliotic scares [4,5,6,7]. These neuropathological features are mainly found in the somatosensory cortex. In the first 3 weeks after birth, partial recovery processes take place in the establishment of the sensorimotor cortical networks during the cortical functional maturation period [8]
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