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.