Ellagic acid protects from rotenone-induced dopaminergic neuronal damage via activation of Nrf2 signaling in astroglia

Abstract BackgroundParkinson’s disease (PD) is the second most prevalent central nervous system (CNS) degenerative disease. Oxidative stress is one of key contributors to the degeneration of dopamine (DA) neurons in the pathogenesis of PD. Nuclear factor erythroid-2-related factor 2 (Nrf2) is considered to be a ‘master regulator’ of many genes involved in anti-oxidant stress to attenuate cell death. Therefore, activation of Nrf2 signaling provides an effective avenue to treat PD. Ellagic acid (EA), a natural polyphenolic contained in fruits and nuts, possesses amounts of pharmacological activities, such as anti-oxidant stress and anti-inflammation. Recent studies have confirmed EA could be used as a neuroprotective agent in neurodegenerative diseases. However, the underlying mechanisms have not yet been entirely elucidated. MethodsIn this study, mice subcutaneous injection of rotenone (ROT)-induced DA neuronal damage was performed to investigate EA-mediated neuroprotection. In addition, adult Nrf2 knockout mice and different cell cultures including MN9D-enciched, MN9D-BV-2 and MN9D-C6 cell co-cultures were applied to explore the underlying mechanisms. ResultsThe present study demonstrated EA protected DA neurons against ROT-induced neurotoxicity. Furtherly, activation of astroglial Nrf2 signaling pathway participated in EA-mediated neuroprotection as evidenced by the following observations. First, EA activated Nrf2 signaling pathway in ROT-induced DA neuronal injury. Second, EA generated neuroprotection with the presence of astroglia and silence of Nrf2 in astroglia abolished EA-conferred DA neuroprotection. Third, EA failed to produce DA neuroprotection in Nrf2 knockout mice. ConclusionThis study identified EA protected against DA neuronal loss via an Nrf2-dependent manner in astroglia.