Intranasal erythropoietin ameliorates neurological function impairments and neural pathology in mice with chronic alcoholism by regulating autophagy-related Nrf2 degradation

The neurological disorders and neural pathology brought about by chronic alcoholism are difficult to be reversed. Increasing evidence highlights the protective roles of erythropoietin (EPO) in neurodegenerative diseases and injuries of the central nervous system. In the present study, we investigated the therapeutic effects of EPO on the neurological function deficits and neural pathology caused by chronic alcoholism and the regulatory mechanisms. Using the canonical mouse model of chronic alcohol exposure designed to mimic the repeated cycles of heavy abuse typical of chronic alcoholism, it was found that EPO delivered via intranasal route effectively restored the alcohol-impaired motor cooperation in rotarod and beam walk tests, reversed alcoholic cognitive and emotional alterations in the novel location recognition task and open-filed test, and rescued alcohol-disrupted nervous conduction in the somatosensory-evoked potential (SSEP) test. Consistently, the intranasally administered EPO promoted the remyelination and synapse formation in chronic alcohol-affected neocortex and hippocampus as evidenced by immunofluorescence staining and transmission electron microscopy. Additionally, we discovered that the exogenous rhEPO, which entered the cerebrum through intranasal route, activated the erythropoietin receptor (EPOR) and the downstream ERKs and PI3K/AKT signaling, and suppressed autophagy-related degradation of nuclear factor, erythroid 2-like 2 (Nrf2). Furthermore, the intranasal EPO-exerted neuroprotection was almost abolished when the specific Nrf2 antagonist ATRA was administered intraperitoneally prior to intranasal EPO treatment. Collectively, our data demonstrated the repairing potential of EPO for the neurological disorders and neural pathology caused by chronic alcoholism, and identified the Nrf2 activity as the key mechanism mediating the protective effects of EPO.