Extracellular ferritin contributes to neuronal injury in an in vitro model of ischemic stroke.

Previous clinical and experimental studies have shown that neurological decline and poor functional outcome after acute ischemic stroke in humans are associated with high ferritin levels in serum and cerebrospinal fluid (CSF) within 24 h of ischemic stroke onset. The aim of the present study was to find out if and how high extracellular ferritin concentrations can increase the excitotoxicity effect in a neuronal cortical culture model of stroke. Extracellular ferritin (100 ng/ml) significantly increased the excitotoxic effect caused by excessive exogenous glutamate (50 μM and 100 μM) by leading to an increase in lipid peroxidation, a reduction in mitochondrial membrane potential, and a decrease in neuron viability. Extracellular apoferritin (100 ng/ml), the iron-free form of the protein, does not increase the excitotoxicity of glutamate, which proves that iron was responsible for the neurotoxic effect of the exogenous ferritin. We present evidence that extracellular ferritin iron exacerbates the neurotoxic effect induced by glutamate excitotoxicity and that the effect of ferritin iron is dependent of glutamate excitotoxicity. Our results support the idea that body iron overload is involved in the severity of the brain damage caused by stroke and reveal the need to control systemic iron homeostasis.