Neuregulin-1 protects mouse cerebellum against oxidative stress and neuroinflammation

Cerebellum undergoes degenerative changes in neurodegenerative diseases. Two main factors including oxidative stress and neuroinflammation mediate neurodegeneration. Neuregulin-1 (Nrg1) has been implicated in many neurodegenerative diseases, while the underlying mechanisms are unknown. We hypothesized that Nrg1 prevents oxidative stress and neuroinflammation in neurodegeneration. We found a positive correlation between Nrg1 protein levels and ErbB4 and ErbB2 receptor phosphorylation in microarrays of normal human cerebellar tissue. In addition, Nrg1 was also co-localized with pErbB4 and pErbB2. Primary mouse cerebellar granule neurons (CGNs) were treated with H₂O₂ or LPS combined with recombinant Nrg1β (rNrg1β). Western blot analysis and immunofluorescence revealed that H₂O₂ and LPS-induced neuronal toxicity down-regulated the activation of ErbB receptors and Akt1, and the ratio of Bcl2/Bax, which was reversed by rNrg1β. In vivo studies showed that LPS-induced neuroinflammation in mouse cerebellum down-regulated pErbB4, pErbB2, pAkt1/Akt1 and Bcl2/Bax levels, whereas rNrg1β treatment reversed the changes. Immunohistochemistry and Western blot analysis showed that rNrg1β alleviates neuroinflammation by reducing the number of microglial cells and astrocytes and the expression of IL1β. Our results indicate that Nrg1 protects against oxidative stress and neuroinflammation in mouse cerebellum, suggesting potential therapeutic application in neuroinflammation associated with neurodegenerative diseases.