Systemic Erythropoietin Has Neuroprotective Effects
Abstract & Commentary
Source: Brines ML, et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 2000;97:10526-10531.
Erythropoietin (epo) is a cytokine that in-creases red cell mass as part of the body’s response to hypoxia. Past studies have shown that intrathecally administered EPO can ameliorate the effects of various types of insults to the central nervous system. A new study provides compelling evidence that systemically administered EPO can exert neuroprotective effects on the rodent brain.
Brines and colleagues evaluated whether recombinent human EPO, which is 80% homologous to rodent EPO, crosses the blood-brain barrier (BBB) when administered systemically to mice. EPO is a large glycosylated protein that might be expected to be excluded by the BBB. Brines et al injected a labeled form of EPO into mice intraperitoneally, and examined the expression of the label in the brain after various time intervals. They found that EPO passed across brain capillaries into the brain parenchyma within hours, and later localized within neurons. The results strongly support an active translocation process for the EPO molecule across the BBB, and provides further evidence that neurons are one of the central targets of this molecule.
Having established that EPO crossed the BBB, Brines et al then examined the effects of systemically administed EPO in various experimental models of cerebral injury. They investigated middle cerebral artery occlusion as a model of focal ischemic injury, pneumatic percussion as a model of blunt trauma, experimental allergic encephalitis (EAE) as a model of demyelinating disease and kainate-induced seizures as a model of status-epilepticus induced brain injury.
In the focal ischemic model, animals receiving systemic EPO 24 hours before or up to six hours after the arterial occlusion exhibited significantly smaller volumes of necrosis compared to controls. Beneficial effects vanished at time intervals longer than six hours. Reductions in necrosis volume approached 60% in pretreated animals as well as those treated in the first three hours after occlusion. In the blunt trauma model, substantial reductions in the volume of necrotic tissue resulted from preadministration of EPO one day prior to the injury, followed by daily administrations for the following four days. Administration of EPO within the first six hours after brain injury had a comparable beneficial effect. Of note, no mononuclear cell infiltrate was seen at the site of injury in EPO-treated animals, in contrast to marked inflammatory infiltration in sham-injected animals. In the EAE model, EPO administration within three days of myelin basic protein innoculation produced a delayed onset of symptoms and a reduction in the severity of symptoms compared to controls. When animals were followed for up to three weeks after discontinuation of EPO, no relapse of symptoms was observed. In the kainate seizure model, onset of seizures and extent of motor manifestations was reduced by EPO injection 24 hours prior to kainate injection, but no protection was afforded by EPO injection 30 minutes before or anytime after seizure induction.
Brines et al speculate that EPO is acting by mechanisms distinct from those of conventional antiepileptic medications. They concluded that systemically administered EPO exerts neuroprotective effects in rodent brains in the context of a variety of cerebral insults. They suggest that these effects are sufficiently compelling to warrant initiation of clinical trials in humans for various neurologic indications.
Commentary
EPO is widely used and FDA approved for the treatment of anemia and is generally well tolerated at the doses and intervals used for that purpose. If EPO readily crosses the human BBB as it was demonstrated to do in rodents, this would greatly facilitate its administration for neurologic therapeutics. The effects described in this study were evident after single doses or small numbers of repeated doses of EPO, which would not be expected to raise the hemotocrit excessively or cause other unacceptable side effects in patients.
The dramatic neuroprotective effects of EPO on rodent brain demonstrated in this study, as well as the neurotrophic effects of this molecule revealed in other studies, were favorable. They provide encouraging evidence that this non-inflammatory cytokine may prove useful for the treatment of several types of neurologic disorders, including (but not necessarily limited to) cerebrovascular disease, epilepsy, demyelinating disease, and head trauma. These observations certainly bear further investigation, both in animal studies and human clinical trials —Norman R. Relkin
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