Table 1.
Animal models evaluating exogenously administered EPO
| Study | Model | Method | Findings |
|---|---|---|---|
| King et al. [48] | Hemisection injury (rats) | SC hemisection extending from the midline to the lateral edge of SC at T10/T11 level | Three days post-injury: both EPO and CEPO reduced the size of lesion, the number of apoptotic nuclei around lesion, the number of axons expressing the injury marker β-amyloid precursor protein |
| Administration of EPO and CEPO intraperitoneally 30 min and 24 h after injury | Both compounds increased Schwann cell infiltration into the lesion site | ||
| None of them had any effect on macrophage infiltration within either the lesion site or surrounding intact tissue | |||
| Gorio et al. [36] | Compression—contusion injury (rodents) | Employment of modified aneurysm clip | At 28 days treated animals exhibited substantially superior clinical outcome |
| Impaction with a steel rod | Compression model: improvement 12 h after treatment | ||
| Administration of rhEPO via an intraperitoneal injection immediately after injury | Contusion model: myelinated axons appeared histologically normal—no apoptotic oligodendrocytes in the region of the fasciculus cuneatus—reduction in the number of inflammatory cells in and around the site of injury | ||
| Arishima et al. [4] | Compression injury (rats) | Induction of injury by the static load technique | Decrease of apoptotic neurons and oligodendrocytes as early as 6 h after SCI |
| Administration of EPO intraperitoneally 15 min and 24 h after compression | Decrease of active caspase-3 immunoreactive cells | ||
| Cetin et al. [19] | Compression injury (rats) | Employment of aneurysm clip at T3 level | Significant decrease of ischemic damage |
| Administration of rhEPO intraperitoneally 5 min after injury | Best neurological, functional and histopathological recovery was documented with the combined administration of rhEPO and MPSS | ||
| Comparison with MPSS | |||
| Fumagalli et al. [33] | Contusion injury (rats) | Impaction with a steel rod at T9 level | Three days after injury: only EPO up-regulated the NGF gene expression both caudally and rostrally to the lesion site enhancing the regenerative process |
| Administration of rhEPO via an intraperitoneal injection within 30 min after injury | |||
| Investigation of NGF expression | Seven days after injury: both EPO and MPSS enhanced NGF mRNA levels at the epicenter of the lesion | ||
| Comparison with MPSS | |||
| Okutan et al. [62] | Contusion injury (rats) | Impaction with a steel rod | Increase of MPO and caspase-3 activity after SCI |
| Administration of rhEPO via an intraperitoneal injection immediately after injury | Decrease of MPO and caspase-3 activity in animals treated either by rhEPO or MPSS | ||
| Significant early functional recovery | |||
| Determination of MPO and caspase-3 activity | EPO presented substantial anti-apoptotic and anti-inflammatory effects | ||
| Comparison with MPSS | |||
| Vitellaro-Zuccarello et al. [75] | Contusion injury (rats) | Impaction with a steel rod | Attenuation of astrogliosis |
| Administration of rhEPO via an intraperitoneal injection 30 min after injury | Influence on the expression of aquaporin 4 (astrocytic water channel) with beneficial effect for the resolution of edema | ||
| Investigation of chronic (1 month) EPO-mediated effects | |||
| Vitellaro-Zuccarello et al. [74] | Contusion injury (rats) | Impaction with a steel rod | Better preservation of myelin in the ventral white matter |
| Administration of rhEPO via an intraperitoneal injection 30 min after injury | Generation of new myelinating oligodendrocytes | ||
| Increased density of the serotonergic plexus around motor neurons (sparing of fiber tracts) | |||
| Investigation of: myelin preservation, activation of oligodendrocyte progenitors, ventral horn density of serotonergic plexus | |||
| Boran et al. [11] | Contusion injury (rats) | Steel bullet dropped through a tube onto the dorsal surface of SC | Enhancement of neurological recovery |
| Administration of rhEPO intraperitoneally within 60 min after SCI | EPO provided better results than MPSS | ||
| Comparison with MPSS | |||
| Gorio et al. [37] | Contusion injury (rats) | Impaction with steel rod | Both EPO and MPSS suppressed proinflammatory cytokines |
| Administration of EPO intravenously | Only EPO was associated with reduced microglial infiltration, attenuated scar formation and sustained neurological improvement in 1 month | ||
| Comparison with MPSS | Co-administration of MPSS antagonized the protective effects of EPO | ||
| Kaptanoglu et al. [43] | Contusion injury (rodents) | Impaction with a steel rod | Preservation of the SC ultrastructure as determined by electron microscope |
| Intraperitoneal administration of rhEPO | RhEPO and MPSS gave similar results | ||
| Comparison with MPSS | EPO was more effective than MPSS in inhibiting SCI-induced lipid peroxidation | ||
| Sekiguchi et al. [66] | Nerve root crush injury (rats) | L5 dorsal root ganglia exposed and the nerves crushed with forceps | Although EPO was not initially protective, it significantly increased the recovery rate from mechanical allodynia after 7 days |
| Administration of rhEPO subcutaneously 1 day before injury and daily after that | 50% of ipsilateral hindpaws in untreated animals demonstrated allodynia, but only 12.5% of animals treated with rhEPO | ||
| Sönmez et al. [68] | Transient ischemia (rats) | Inflation of balloon below the branching point of left subsclavian artery | Attenuation of neuronal injury |
| Administration of rhEPO intravenously immediately after the onset of reperfusion | Potentiation of the expression of transcription factor pCREB in anterior horn of SC | ||
| Celik et al. [18] | Transient ischemia (rabbits) | Infrarenal aorta exposed and non-traumatically occluded | Significant amelioration in neurological damage within 1 h of treatment |
| Lack of histological evidence of injury | |||
| Treatment with rhEPO intravenously immediately after the release of occlusion | Motor neurons negative for TUNEL labeling (a marker of apoptosis) | ||
| Agnello et al. [1] | Inflammation in EAE (rats) | Induction of the disease by immunization with MBP | Delay of onset of EAE |
| Administration of rhEPO intraperitoneally daily from day 3 after immunization with MBP | Reduced inflammation and glial activation/proliferation | ||
| Clinical effects maintained without further EPO administration for at least 2 months |
NGF nerve growth factor, MPO myeloperoxidase, MBP myelin basic protein