gms | German Medical Science

Objective: Recombinant Erythropoietin (rEPO) is neuroprotective in animal models of hypoxic ischemia and traumatic brain injury. Our objective was to determine the pharmacokinetics and neurological improvement after administration of rEPO in the double-SAH model of the rat simulating delayed cerebral vasospasm (CVS).

Methods: CVS was induced by injection of 0.25ml autologous blood twice in the cisterna magna of 48 Sprague-Dawley rats. Treatment with rEPO was started immediately after second SAH. rEPO was given intravenously in doses of 0, 500, 5000 and 50000 IU/kg. Plasma, cerebrospinal fluid (CSF) samples and brain tissue was collected at scheduled intervals. The animals were examined on days 2, 3, 4 and 5 and compared to the sham-operated control group (n=48). The functional deficits were graded between 0 and 3.

Results: Endogenous EPO was below detection level in the analysed samples - even after second SAH. rEPO crossed the blood-brain barrier (BBB) in a dose-dependent manner. Three hours after SAH rEPO serum concentrations were 3212±221, 39512±1706, and 413697±24882 mIU/ml respectively. CSF concentrations in sham-operated rats were 83±7, 525±24, and 17842±1388 mIU/ml. After second SAH, CSF concentrations were 8–11 fold higher. Brain tissue concentrations 3 hours after rEPO administration were 5,8±0,5, 62,3±2, and 703±66 mIU/ml. In rats with SAH, brain tissue concentrations were 3–7 fold higher, depending on the administered rEPO-dosage. 72 hours after second SAH, serum concentrations were 9,6±0,4, 72±4, and 4243±292 mIU/ml, CSF concentrations were 7,3±0,6, 69,6±3, and 348±14 mIU/ml. Brain tissue concentrations were 4,3±0,2, 6,4±0,4, and 71,5±6 mIU/ml. The neurological state of the rats with rEPO of any dosage between day 2 and 4 was significantly better than of the rats in the group without rEPO (Grade 1 vs. 2; p<0.05). At day 5 the neurological state in the group with the lowest rEPO-dosage was not different compared to the group without rEPO but were significantly worse compared to the groups with higher rEPO-doses (p<0.05 both).

Conclusions: rEPO passes the BBB in a dose-dependent manner and leads to a neurological improvement after a single systemic injection. SAH leads to an increase of permeability for rEPO. The improving effects of low dose rEPO seem to diminish on day 5 whereas the effect of high dose rEPO continuous.