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Pertussis toxin reduces calcium influx to protect ischemic stroke in a middle cerebral artery occlusion model

Tang, Z;Li, S;Han, P;Yin, J;Gan, Y;Liu, Q;Wang, J;Wang, C;Li, Y;Shi, J;

Increased calcium influx secondary to glutamate induced excitotoxicity initiates and potentiates devastating pathological changes following ischemic stroke. Pertussis toxin (PTx), a G-protein blocker, is known to suppress intracellular calcium accumulation. We hypothesize that PTx can protect against stroke by blocking calcium influx. In a permanent middle cerebral artery occlusion model, PTx (1000 ng) was given intraperitoneally 30 min after inducing stroke. Magnetic Resonance Imaging of perfusion and T2-weighted brain scans were obtained to evaluate cerebral blood flow (CBF) and infarct volume. Primary neuronal culture was used to test glutamate induced excitotoxicity and calcium influx. We established a non-linear exponential curve model to minimize variations in animal cerebrovasculature. A reduction of 40-60% in relative CBF was a critical window where infarct volume started to increase as rCBF reduced. PTx showed maximal effects in reducing infarct volume at this window. In vitro studies further demonstrated PTx increased neuronal cell survival by decreasing glutamate-induced calcium influx into neurons and preventing neurons from apoptosis. PTx salvages the ischemic penumbra by blocking calcium influx. This provides us a new mechanism upon which experimental therapies can be explored to treat ischemic stroke. In ischemic stroke, excessive glutamate binds to AMPA receptor that depolarizes calcium channel and/ or NMDA receptor. Both of them allow calcium to enter the cell. The overload of calcium triggers cellular cascade that includes Caspase activation and release, leading to pre-mature cell death. We have demonstrated that PTx, a G-protein inhibitor, blocks calcium entry which in turn prevents further cellular damage.