Ellagic acid protects dopamine neurons from rotenone‐induced neurotoxicity via activation of Nrf2 signalling

Abstract

Parkinson's disease (PD) is the second most prevalent central nervous system (CNS) degenerative disease. Oxidative stress is one of key contributors to 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 signalling 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. Here, 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. Results demonstrated EA conferred neuroprotection against ROT‐induced DA neurotoxicity. Activation of Nrf2 signalling was involved in EA‐mediated DA neuroprotection, as evidenced by the following observations. First, EA activated Nrf2 signalling in ROT‐induced DA neuronal damage. Second, EA generated neuroprotection with the presence of astroglia and silence of Nrf2 in astroglia abolished EA‐mediated neuroprotection. Third, EA failed to produce DA neuroprotection in Nrf2 knockout mice. In conclusion, this study identified EA protected against DA neuronal loss via an Nrf2‐dependent manner.

Pomegranate Juice Ameliorates Dopamine Release and Behavioral Deficits in a Rat Model of Parkinson’s Disease

“…PJ administration restored the loss of DA level and its metabolite DOPAC, and slightly improved vertical activity. These findings corroborate previous results from Wei et al (2020), who showed that treatment with ellagic acid (EA) resulted in improvements in the motor performance of rotenone-treated rats [40]. EA…”

“…PJ administration restored the loss of DA level and its metabolite DOPAC, and slightly improved vertical activity. These findings corroborate previous results from Wei et al (2020), who showed that treatment with ellagic acid (EA) resulted in improvements in the motor performance of rotenone-treated rats [ 40 ]. EA also has been reported to protect against 6-hydroxydopamine (6-OHDA) and lipopolysaccharide-induced DA neuronal damage and related motor impairment [ 41 , 42 , 43 , 44 ].…”

Ellagic Acid Prevents Dopamine Neuron Degeneration from Oxidative Stress and Neuroinflammation in MPTP Model of Parkinson’s Disease

“…Moreover, the 6-OHDA model only can be used to test motor behavior. EA has also been shown to protect DA neurons from rotenone-induced neurotoxicity through activation of Nrf2 signaling [15]. It is important to note that, although rotenone been used to model PD, it is not specific for DA neurons.…”

“…It has been demonstrated that ellagic acid prevents rotenone-induced generation of S-nitrosylation of protein disulfide isomerase (SNO-PDI), a marker of Parkinson's disease in the cellular model [14]. EA has been shown to prevent dopamine neurons from rotenone-induced neurotoxicity through activating Nrf2 signaling cascade [15]. Rotenone inhibits the complex I of mitochondrial electron transport chain in a nonspecific manner and causes cellular demise [16].…”

Ellagic acid improved diabetes mellitus-induced testicular damage and sperm abnormalities by activation of Nrf2

“…Also, some older studies have shown that EA can stimulate Nrf2 in other extra-testicular tissues. Indeed, EA protected from rotenone-induced astroglia cell damage, oxidant-induced endothelial dysfunction and atherosclerosis, methotrexate-induced, hepatocytes apoptosis via upregulation and activation of Nrf2 ( Ding et al, 2014 , Ebrahimi et al, 2019 , Wei et al, 2020 ). Besides, we have also shown that EA prevents DM-induced nephropathy by activation of Nrf2 (in press).…”