Erythropoietin Modulation in Neuroprotective Therapies

Erythropoietin (EPO), classically recognised for its role in red blood cell production, has emerged as a multifunctional neuroprotective agent. Beyond its erythropoietic actions, EPO interacts with distinct receptor complexes expressed on neural and endothelial cells to promote cell survival, inhibit apoptosis and dampen inflammation. In models of cerebral ischaemia and neurodegeneration, EPO signalling stimulates neurogenesis, enhances dendritic spine density and restores synaptic connectivity. The hormone’s ability to cross the blood–brain barrier and engage autocrine and paracrine loops confers adaptive responses to metabolic and hypoxic stress. Clinical translation has focused on optimising dosing regimens to maximise tissue protection while minimising haematopoietic side effects. Current strategies under investigation include non-erythropoietic EPO derivatives that selectively activate tissue-protective pathways, and combination approaches that pair EPO modulation with rehabilitative and metabolic support. Taken together, these advances illustrate the promise of EPO-based interventions in acute stroke, cognitive impairment and psychiatric disorders.

Research from Nature Portfolio

Functional hypoxia in hippocampal circuits has been shown to trigger endogenous upregulation of EPO and its receptor within neurons. Augmenting this auto/paracrine EPO–EpoR axis with exogenous high-dose EPO enhances generation of new CA1 neurons, increases dendritic spine densities and improves performance on complex motor tasks. This work establishes a feedback loop whereby cognitive challenge induces transient hypoxia, driving neuroplastic adaptations via EPO signalling.

Investigations into systemic roles of EPO reveal that EpoR expression extends into non-haematopoietic tissues, including white adipose and skeletal muscle, where an EPO–EpoR–RUNX1 pathway regulates energy metabolism. Although primarily metabolic, these findings underscore the hormone’s pleiotropy and suggest that optimising peripheral energy balance may bolster neuronal resilience under metabolic stress, providing an indirect route to support neuroprotective therapies.

Erythropoietin Modulation in Neuroprotective Therapies publication trend

The graph below shows the total number of articles in erythropoietin modulation in neuroprotective therapies across all publications each year (not limited to Nature Index journals).

Technical terms

Erythropoietin (EPO): A glycoprotein hormone that binds to cell-surface receptors to regulate erythropoiesis and tissue protection.

Erythropoietin receptor (EpoR): A transmembrane protein that mediates EPO’s signalling in both haematopoietic and non-haematopoietic cells.

Neuroplasticity: The brain’s ability to reorganise its structure, function and connections in response to experience or injury.

Synaptic plasticity: Activity-dependent modifications of synaptic strength that underlie learning and memory.

Hypoxia: A state of reduced oxygen availability that can trigger adaptive cellular responses.

GADD45b/p38 MAPK axis: A stress-responsive signalling pathway implicated in DNA repair, apoptosis and synaptic regulation.

Interneuron: A local circuit neuron that modulates excitatory output and shapes network activity.

References

1. Erythropoietin regulates energy metabolism through EPO-EpoR-RUNX1 axis. Nature Communications (2024).
2. EPO Deficiency Upregulates GADD45b/p38 MAPK Axis, Mediating Schizophrenia‐Related Synaptic and Cognitive Impairments. Advanced Science (2024).
3. Erythropoietin restrains the inhibitory potential of interneurons in the mouse hippocampus. Molecular Psychiatry (2024).
4. Erythropoietin Therapy for Acute Stroke Is Both Safe and Beneficial. Molecular Medicine (2002).
5. Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin. Nature Communications (2020).
6. Erythropoietin and its derivatives: from tissue protection to immune regulation. Cell Death & Disease (2020).