Purpose of Study Erythropoietin (Epo) is neuroprotective in neonatal animal models of brain injury at doses ranging from 1,000 to 30,000 U/kg intraperitoneal (IP) or subcutaneous (SC). At these high doses, it is not clear if route of administration affects either blood or brain Epo concentrations and/or if brain injury affects blood-brain barrier (BBB) permeability. We hypothesized that (1) serum Epo concentration (s[Epo]) depends on route of administration, (2) measured brain Epo correlates with s[Epo], and (3) brain injury will increase BBB permeability to Epo.
Methods P7 rats underwent right common carotid artery occlusion followed by 90 minutes of 8% oxygen exposure. Control and brain-injured rats received Epo (5,000 U/kg) IP or SC and were euthanized at timed intervals from 1 to 10 hours after injection (n = 3-6 per time point). Blood was collected, and brains were quickly removed and homogenized in cold buffer containing protease inhibitors. [Epo] was measured by ELISA (R&D) and normalized to protein concentration (BSA assay).
Results Three hours after dosing IP, s[Epo] is approximately double that achieved by SC (Figure). The timing of peak s[Epo] differed by route of administration. Control brain [Epo] is also time dependent, mean ± SD 2,037 ± 2,092 mU/g at 3 hours and 2,532 ± 490 mU/g at 10 hours following SC injection. Serum to brain [Epo] correlations were 0.88 IP and 0.57 SC (both p < .001). Data from additional time points, including brain-injured animals and controls, are in progress.
Conclusions We conclude that route of Epo administration affects both peak and steady state s[Epo] and that s[Epo] correlates with control brain Epo concentrations. Such pharmacokinetic profiles are necessary to determine optimal dosing regimens for experimental neuroprotection.
Supported by NIH R21 HD042213-01. The first author is a fellow in training.