Post‐ischemic treatment with erythropoietin or carbamylated erythropoietin reduces infarction and improves neurological outcome in a rat model of focal cerebral ischemia

Abstract

Background and purpose: Recombinant human erythropoietin (rhEPO; Epoetin-a; PROCRITt) has been shown to exert neuroprotective and restorative effects in a variety of CNS injury models. However, limited information is available regarding the dose levels required for these beneficial effects or the neuronal responses that may underlie them. Here we have investigated the dose-response to rhEPO and compared the effects of rhEPO with those of carbamylated rhEPO (CEPO) in a model of cerebral stroke in rats. Experimental approach: Rats subjected to embolic middle cerebral artery occlusion (MCAo) were treated with rhEPO or CEPO, starting at 6 h and repeated at 24 and 48 h, after MCAo. Cerebral infarct volumes were assessed at 28 days and neurological impairment at 7, 14, 21 and 28 days, post-MCAo. Key results: rhEPO at dose levels of 500, 1150 or 5000 IU kg À1 or CEPO at a dose level of 50 mg kg À1 significantly reduced cortical infarct volume and reduced neurologic impairment. All doses of rhEPO, but not CEPO, produced a transient increase in haematocrit, while rhEPO and CEPO substantially reduced the number of apoptotic cells and activated microglia in the ischemic boundary region. Conclusions and implications: These data indicate that rhEPO and CEPO have anti-inflammatory and anti-apoptotic effects, even with administration at 6 h following embolic MCAo in rats. Taken together, these actions of rhEPO and CEPO are likely to contribute to their reduction of neurologic impairment following cerebral ischemia.

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

“…58 The hematocrit was transiently increased at all dose levels of EPO with a peak at 14 days after the initial dose. 58 CEPO (50 g/kg) induced protective effects equal to the highest dose of EPO (5000 U/kg equivalent to 46 g/kg) without increasing hematocrit.…”

“…58 The hematocrit was transiently increased at all dose levels of EPO with a peak at 14 days after the initial dose. 58 CEPO (50 g/kg) induced protective effects equal to the highest dose of EPO (5000 U/kg equivalent to 46 g/kg) without increasing hematocrit. 58 As summarized in Table 1, neuroprotection in experimental stroke can be achieved with CEPO and other nonhematopoietic derivatives of EPO (asialo-EPO, Caranesp, EPO-S100E) at equipotent doses to that of rhEPO.…”

“…6,33,44,[55][56][57][58][59][60][61][62][63][64] Earlier studies used the direct intracerebroventricular route of administration of EPO to demonstrate its potent tissue protective activity in focal and global models of cerebral ischemia. [2][3][4] EPO, as a large, highly glycosylated negatively charged molecule, was not expected to penetrate the blood-brain barrier.…”

“…Intriguingly, EPO and its derivatives reduce histological damage and improve functional outcome when given as intraperitoneal or even intranasal post-treatment after experimental stroke and hypoxia-ischemia. 33,44,[55][56][57][58][59][60][61][62][63][64]73 A typical example of the functional improvement by EPO in sensorimotor deficits after a focal stroke is presented in Figure 2 (Sirén and Ehrenreich, unpublished own preclinical data in preparation of the "Göttingen EPO Stroke Study," see as follows).…”

Parsing Physiological Functions of Erythropoietin One Domain at a Time

“…Experimental autoimmune encephalomyelitis Although erythropoietin (EPO) is best known for its role in hematopoiesis, there are other functions that are instigated via this protein. EPO is effective as a neuroprotective molecule in various animal models of neuroinflammation and ischemia, including experimental autoimmune encephalomyelitis (EAE), brain trauma, and stroke [1][2][3][4][5][6]. Fortunately, proteins are often divided into discrete domains with different functional activities residing in different regions of the molecule.…”