Abstract
Over the last 20 years, it has been shown that complex signaling cascades are involved in zinc excitotoxicity. Free zinc rapidly induces PKC activation, which causes reactive oxygen species (ROS) production at least in part through NADPH oxidase. It also promotes neuronal nitric oxide synthase, thereby increasing nitric oxide (NO) production. Extracellular signal-regulated kinase activation and Egr-1 transcription factor activity were quickly induced by zinc, too. These concurrent actions of kinases consequently produce oxygen free radical, ROS, and NO, which may cause severe DNA damage. Following the excessive activity of poly(ADP-ribose) polymerase-1 depletes NAD+/ATP in the cells. Zinc excitotoxicity exhibits distinct characteristics of apoptosis, too. Activation of caspase-3 is induced by liver kinase B1 (LKB1)-AMP-activated kinase (AMPK)-Bim cascade signaling and induction of p75NTR receptors and p75NTR-associated Death Executor. Thus, zinc excitotoxicity is a mechanism of neuronal cell death showing various cell death patterns. In addition to the above signaling cascades, individual intracellular organelles also play a crucial role in zinc excitotoxicity. Mitochondria and lysosomes function as zinc reservoirs, and as such, are capable of regulating zinc concentration in the cytoplasm. However, when loaded with too much zinc, they may undergo mitochondrial permeability transition pore (mPTP) opening, and lysosomal membrane permeabilization (LMP), both of which are well-established mechanisms of cell death. Since zinc excitotoxicity has been reported to be associated with acute brain injuries, including stroke, trauma, and epilepsy, we performed to find the novel AMPK inhibitors as therapeutic agents for these diseases. Since we thought acute brain injury has complicated neuronal death pathways, we tried to see the neuroprotection against zinc excitotoxicity, calcium-overload excitotoxicity, oxidative damage, and apoptosis. We found that two chemicals showed significant neuroprotection against all cellular neurotoxic models we tested. Finally, we observed the reduction of infarct volume in a rat model of brain injury after middle cerebral artery occlusion (MCAO). In this review, we introduced the AMPK-mediated cell death mechanism and novel strategy for the development of stroke therapeutics. The hope is that this understanding would provide a rationale for acute brain injury and eventually find new therapeutics.
Highlights
More than 50 years ago, John Olney reported a seminal finding that natural amino acid, monosodium glutamate (MSG) could cause neuronal death in immature murine brains (Olney, 1969a)
We have reported that liver kinase B1 (LKB1)-activated AMPactivated kinase (AMPK) can induce caspase-3 activation through increased expression of Bim protein, one of the pro-apoptotic Bcl-2 family members (Eom et al, 2016)
To find candidates with broad-spectrum efficacy against diverse cell death mechanisms in brain ischemia, we examined the protective effects of chemicals against zinc excitotoxicity and calcium-overload excitotoxicity, oxidative free radical damage, and apoptosis
Summary
More than 50 years ago, John Olney reported a seminal finding that natural amino acid, monosodium glutamate (MSG) could cause neuronal death in immature murine brains (Olney, 1969a). Under pathological conditions such as ischemic brain injury or seizure, excessive levels of free zinc may be taken up into the mitochondria or lysosomes, which triggers ROS generation in mitochondria and membrane permeabilization of mitochondria and lysosome, which leads to the cell death (Trushina and McMurray, 2007; Hwang et al, 2008). Studies have demonstrated that mitochondria dysfunction causes AMPK signaling defects in the hypoxic pulmonary vasoconstriction (HPV) model (Evans, 2006; Evans et al, 2006), a representative example of directly linking mitochondria dysfunction and AMPK pathway Another possible role of mitochondria in zinc excitotoxicity is to activate the well-established cascade of apoptosis (Calderone et al, 2004).
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