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. In the central nerves system zinc is one of the most abundant oligoelements, involves in the balance of excitatory and inhibitory signals of synapse. 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. 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, which results in a loss of zinc modulatory activity and cognitive deficits in animal models of Alzheimer’s disease (AD).
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. The synergistic interaction between Zn2+ and reactive oxygen species (ROS) has been shown to amplify the ischemic brain injury in rodent model through direct ROS generation or through, mitochondrial Ca2+ uniporter. Recent study indicates that zinc status introduce through Inflammation through NLRP3-mediated pathway.
Emodin, an anthraquinone derivative, is a major active ingredient of many herbs including Rheum palmatum, Polygonum cuspidatum, Aloe Vera, and Cassia obtusifolia etc. 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 .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; Emerging evident suggest that ERK1/2 signal pathway is implicated in a number of neurodegenerative diseases with oxidative stress. 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.