Erythropoietin (EPO) functions as a tissue-protective cytokine in addition to its crucial hormonal role in red cell production. In the brain, for example, EPO and its receptor are locally produced, are modulated by metabolic stressors, and provide neuroprotective and antiinflammatory functions. We have previously shown that recombinant human EPO (rhEPO) administered within the systemic circulation enters the brain and is neuroprotective. At present, it is unknown whether rhEPO can also improve recovery after traumatic injury of the spinal cord. To evaluate whether rhEPO improves functional outcome if administered after cord injury, two rodent models were evaluated. First, a moderate compression of 0.6 N was produced by application of an aneursym clip at level T3 for 1 min. RhEPO (1,000 units per kg of body weight i.p.) administered immediately after release of compression was associated with partial recovery of motor function within 12 h after injury, which was nearly complete by 28 days. In contrast, saline-treated animals exhibited only poor recovery. In the second model used, rhEPO administration (5,000 units per kg of body weight i.p. given once 1 h after injury) also produced a superior recovery of function compared with saline-treated controls after a contusion of 1 N at level T9. In this model of more severe spinal cord injury, secondary inflammation was also markedly attenuated by rhEPO administration and associated with reduced cavitation within the cord. These observations suggest that rhEPO provides early recovery of function, especially after spinal cord compression, as well as longerlatency neuroprotective, antiinflammatory and antiapoptotic functions.T raumatic spinal cord injury (TSCI) occurs frequently and is devastating for the individual patient and costly to society by requiring substantial long-term health care expenditures. Currently, methylprednisolone administered at high dose within 8 h after injury is the only therapy with any recognized benefit (1), which, unfortunately, is relatively minor. Any new treatment of TSCI that allows for major recovery of function would be a significant advance in clinical care.Injury of the nervous system provokes a complex cascade of proinflammatory cytokines and other molecules that ultimately result in apoptosis and necrosis of neurons, oligodendrocytes, and endothelial cells (2-4). Recent studies have demonstrated that one general response of the brain to injury is the increased local production of the erythropoietin (EPO) and its receptor (5, 6). These proteins are members of the cytokine type I superfamily that provide beneficial effects including inhibition of apoptosis, reduction of inflammation, modulation of excitability (7-11), and mobilization and proliferation of neuronal stem cells (12). Prior study has shown that recombinant human EPO (rhEPO) administered directly into the brain dramatically reduces hypoxic or ischemic injury and conversely, that neutralization of endogenous EPO amplifies injury (8). We have extended these observations by sho...