| Autor: |
Lie ME; 1 Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.; 2 Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin, New Zealand., Gowing EK; 2 Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin, New Zealand., Clausen RP; 1 Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark., Wellendorph P; 1 Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark., Clarkson AN; 2 Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin, New Zealand.; 3 Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia. |
| Abstrakt: |
Brain ischemia triggers excitotoxicity and cell death, yet no neuroprotective drugs have made it to the clinic. While enhancing GABAergic signaling to counterbalance excitotoxicity has shown promise in animal models, clinical studies have failed. Blockade of GABA transporters (GATs) offers an indirect approach to increase GABA inhibition to lower the excitation threshold of neurons. Among the GATs, GAT1 is known to promote neuroprotection, while the protective role of the extrasynaptic transporters GAT3 and BGT1 is elusive. A focal lesion was induced in the motor cortex in two to four-month-old C57BL/6 J male mice by photothrombosis. The GAT1 inhibitor, tiagabine (1 and 10 mg/kg), the GAT2/3 inhibitor, ( S)-SNAP-5114 (5 and 30 mg/kg) and the GAT1/BGT1 inhibitor, EF-1502 (1 and 10 mg/kg) were given i.p. 1 and 6 h post-stroke to assess their impact on infarct volume and motor performance seven days post-stroke. One mg/kg tiagabine improved motor performance, while 10 mg/kg tiagabine, ( S)-SNAP-5114 and EF-1502 had no effect. None of the compounds affected infarct volume. Interestingly, treatment with tiagabine induced seizures and ( S)-SNAP-5114 led to increased mortality. Although we show that tiagabine can promote protection, our findings indicate that caution should be had when using GAT1 and GAT3 inhibitors for conditions of brain ischemia. |
