Erythropoietin and its receptor were thought to be present in the central nervous system according to experiments with antibodies that were subsequently shown to be nonspecific.
While erythropoietin alpha is capable of crossing the blood brain barrier via active transport,[1] concentrations in the central nervous system are very low.
In contrast to these results, numerous studies have suggested that Epo had no neuroprotective benefit in animal models and EpoR was not detected in brain tissues using anti-EpoR antibodies that were shown to be sensitive and specific.
[5] Mice without EpoR demonstrated severe anemia, defective heart development, and eventually death around embryonic day 13.5 from apoptosis in the liver, endocardium, myocardium, and fetal brain.
A short peptide sequence from the erythropoietin molecule called JM4, has been found to be non-erythropoietic yet theoretically neuroprotective and is being readied for Stage 1 and 2 clinical studies.
Most importantly, experiments with immunostaining revealed that the distribution and concentration of EpoR on Schwann cells doesn’t change after peripheral nerve injury.
[11] After nerve injury, the increased production of Epo may induce activation of certain cellular pathways, while the concentration of EpoR doesn’t change.
Additionally to the anti-apoptotic effect, Epo reduces inflammatory response during different types of cerebral injury via the NF-κB pathway.
[16] The NF-κB pathway activated by Epo/EpoR phosphorylation plays a role in regulating inflammatory and immune response, in addition to preventing apoptosis due to cellular stress.
As a neuroprotective agent erythropoietin has many functions: antagonizing glutamate cytotoxic action, enhancing antioxidant enzyme expression, reducing free radical production rate, and affecting neurotransmitter release.
It exerts its neuroprotective effect indirectly through restoration of blood flow or directly by activating transmitter molecules in neurons that also play a role in erythrogenesis.
This RhEpo therapy increased JAK2 phosphorylation, which has been found to be a key signaling step in Epo-induced neuroprotection by an anti-apoptotic mechanism.
However, recent research has demonstrated that high doses of recombinant erythropoietin can reduce or prevent this type of neonatal brain injury if administered early.
Epo is able to reduce or eliminate the consequences of mechanical injury to the hippocampus but also demonstrates possible therapeutic effects in other cognitive domains.
Epo was shown to specifically protect dopaminergic neurons, which are closely tied into attention deficit hyperactivity disorder.
[19] Specifically in mice, Epo demonstrated protective effects on nigral dopaminergic neurons in a mouse model of Parkinson's disease.
[22] This recent experiment tested the hypothesis that RhEpo could protect dopaminergic neurons and improve the neurobehavioral outcome in a rat model of Parkinson's Disease.
The intrastriatal administration of RhEpo significantly reduced the degree of rotational asymmetry, and the RhEpo-treated rats demonstrated improvement in skilled forearm use.
These experiments demonstrated that intrastriatal administration of RhEpo can protect nigral dopaminergic neurons from 6-OHDA induced cell death and improve neurobehavioral outcome in a rat model of Parkinson's Disease.
If administered within a specific timeframe in experiments with erythropoietin in central nervous system, Epo has a favorable response in brain and spinal cord injuries like mechanical trauma or subarachnoid hemorrhages.
[23] Research also demonstrates a therapeutic role in modulating neuronal excitability and acting as a trophic factor both in vivo and in vitro.
[23] This administration of erythropoietin functions by inhibiting the apoptosis of sensor and motor neurons via stimulation of intracellular anti-apoptotic metabolic paths.
Epo administration during optic nerve transaction was used to assess the neuroprotective properties in vivo as well as demonstrate the neuroregenerative capabilities.