Zinc is an essential trace element obtained from the diet that regulates the expression of many biological molecules and activation of signalling pathways. Zinc deficiency affects up to 2 billion people worldwide and has profound effects on immune and neurological system functions[1]. In the central nerves system zinc is one of the most abundant oligoelements, involves in the balance of excitatory and inhibitory signals of synapse[2]. During neuronal activity, zinc is released in the form of free ionic (Zn2+) from synaptic vesicles. Maintaining the homeostasis of zinc is thus essential for the physiological function of the brain[3]. Excessive zinc in the extracellular fluid has been shown to increase neurotoxicity, induce mitochondrial dysfunction, and oxidative stress. Abnormal increase in the levels of metal ions including Zn2+, have been found in Aβ, form Aβ–Zn complexes[4], which results in a loss of zinc modulatory activity and cognitive deficits in animal models of Alzheimer’s disease (AD)[5].
In addition, zinc accumulation has been shown to cause mitochondrial dysfunction and oxidative stress in AD[6, 7] as well as in ischemic stroke models[8, 9]. Mitochondrial Zn2+ accumulation is a possible trigger of hippocampal ischemic injury[8]. The synergistic interaction between Zn2+ and reactive oxygen species (ROS) has been shown to amplify the ischemic brain injury in rodent model[9] through direct ROS generation or through, mitochondrial Ca2+ uniporter[10]. Recent study indicates that zinc status introduce through Inflammation through NLRP3-mediated pathway[11].
Emodin, an anthraquinone derivative, is a major active ingredient of many herbs including Rheum palmatum, Polygonum cuspidatum, Aloe Vera, and Cassia obtusifolia etc[12]. Emodin shows neuroprotective, anti-inflammatory effects in animal models of cerebral ischemia stroke, traumatic brain injury, AD, and Parkinson’s disease[13–15]. Different signaling pathways have been reported that mediate the effect of emodin such as the Nrf2, Phosphatidylinositol 3-Kinase/Beclin-1/B-Cell Lymphoma 2, and AMP-activated protein kinase signaling pathway[16–18]. Previous studies from our and other groups have reported that emodin demonstrates neuroprotective effect, and can inhibit the neurotoxic effect of NaF on SH-SY5Y cells via reducing reactive oxygen substrates (ROS) overproduction and oxidative stress [19].the underlying mechanism of emodin remains to be elucidated.
The Extracellular signal-regulated kinase 1/2 (ERK1/2) is activated by neurotrophins and other chemicals an plays an important role in differentiation, survival, structural plasticity, and long-term potentiation of neurons, as well as memory formation in animal models[20]; Emerging evident suggest that ERK1/2 signal pathway is implicated in a number of neurodegenerative diseases with oxidative stress[21]. Aberrant accumulation of activated ERK1/2 in neurons has been reported in AD brains[22, 23]. Here, we hypothesized that emodin can protect against neurotoxicity induced by pathological concentrations of zinc via ERK1/2 signaling pathway, and alleviate the oxidative stress and mitochondria dysfunction. We exposed human neuroblastoma SH-SY5Y cells to high dose of zinc sulfate, and assessed the effect of emodin on attenuating synaptic impairment, mitochondria function and oxidative stress damage.