Inhibition of GABA transporters fails to afford significant protection following focal cerebral ischemia

Journal of Cerebral Blood Flow and Metabolism

Volumn 38, Issue 1, 2018, Pages 166-173

  Lie, Maria E K ^a,b   Gowing, Emma K ^b   Clausen, Rasmus P ^a   Wellendorph, Petrine ^a   Clarkson, Andrew N ^b,c  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b UNIVERSITY OF OTAGO   (New Zealand)

^c UNIVERSITY OF SYDNEY   (Australia)

Author keywords

GABA transporters; GAT inhibition; neuroprotection; stroke; tonic inhibition

Indexed keywords

4 AMINOBUTYRIC ACID CARRIER; GABA TRANSPORTER 1; GABA TRANSPORTER 3; TIAGABINE; 4 AMINOBUTYRIC ACID RECEPTOR BLOCKING AGENT; NEUROPROTECTIVE AGENT;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BEHAVIOR ASSESSMENT; BRAIN INFARCTION SIZE; BRAIN ISCHEMIA; CEREBROVASCULAR ACCIDENT; EC50; EXCITOTOXICITY; ISCHEMIA; MALE; MORTALITY; MOTOR CORTEX; MOTOR PERFORMANCE; MOUSE; NEUROPROTECTION; NONHUMAN; PRIORITY JOURNAL; SEIZURE; WALK TEST; ANIMAL; C57BL MOUSE; CONVALESCENCE; DRUG EFFECT; METABOLISM; PATHOLOGY;

ANIMALS; BRAIN ISCHEMIA; GABA ANTAGONISTS; GABA PLASMA MEMBRANE TRANSPORT PROTEINS; MALE; MICE; MICE, INBRED C57BL; NEUROPROTECTIVE AGENTS; RECOVERY OF FUNCTION;

EID: 85039848133     PISSN: 0271678X     EISSN: 15597016     Source Type: Journal    
DOI: 10.1177/0271678X17743669     Document Type: Article

References (44)

1. Kostandy BB. The role of glutamate in neuronal ischemic injury: the role of spark in fire. Neurol Sci 2012; 33: 223–237.
2. A neurotransmission and cerebral ischemia. J Neurochem 2001; 77: 353–371.
3. Emberson J, lees K, Lyden P, Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014; 385: 1929–1935.
4. Lie M, Al-Khawaja A, Damgaard M, Glial GABA transporters as modulators of inhibitory signalling in epilepsy and stroke. Adv Neurobiol 2017; 16: 137–167.
5. A receptors. Nat Rev Neurosci 2005; 6: 215–229.
6. Conti F, Minelli A, Melone M. GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications. Brain Res Brain Res Rev 2004; 45: 196–212.
7. Clarkson AN, Huang BS, Macisaac SE, Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 2010; 468: 305–309.
8. Clarkson AN. Perisynaptic GABA receptors: the overzealous protector. Adv Pharmacol Sci 2012; 2012: 708428.
9. Li H, Zhang N, Lin HY, Histological, cellular and behavioral assessments of stroke outcomes after photothrombosis-induced ischemia in adult mice. BMC Neurosci 2014; 15: 58.
10. Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology 2008; 55: 363–389.
11. A receptors mediate tonic inhibition in hippocampal dentate granule cells. Mol Pharmacol 2006; 69: 564–575.
12. A receptors: their function in the CNS and implications for disease. Neuron 2012; 73: 23–34.
13. A-mediated inhibition improves forelimb motor function after focal cortical stroke in mice. Sci Rep 2016; 6: 37823.
14. Kristensen AS, Andersen J, Jorgensen TN, SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol Rev 2011; 63: 585–640.
15. Damgaard M, Haugaard A, Kickinger S, Development of non-GAT1 selective inhibitors; challenges and achievements. Adv Neurobiol 2017; 16: 315–332.
16. Yang Y, Li Q, Wang CX, Dose-dependent neuroprotection with tiagabine in a focal cerebral ischemia model in rat. Neuroreport 2000; 11: 2307–2311.
17. Chen Xu W, Yi Y, Qiu L, Neuroprotective activity of tiagabine in a focal embolic model of cerebral ischemia. Brain Res 2000; 874: 75–77.
18. Iqbal S, Baziany A, Gordon S, Neuroprotective effect of tiagabine in transient forebrain global ischemia: an in vivo microdialysis, behavioral, and histological study. Brain Res 2002; 946: 162–170.
19. Inglefield JR, Perry JM, Schwartz RD. Postischemic inhibition of GABA reuptake by tiagabine slows neuronal death in the gerbil hippocampus. Hippocampus 1995; 5: 460–468.
20. Zhu X, Ong W. A light and electron microscopic study of betaine/GABA transporter distribution in the monkey cerebral neocortex and hippocampus. J Neurocytol 2004; 33: 233–240.
21. Kersanté F, Rowley SCS, Pavlov I, A functional role for both γ-aminobutyric acid (GABA) transporter-1 and GABA transporter-3 in the modulation of extracellular GABA and GABAergic tonic conductances in the rat hippocampus. J Physiol 2013; 591: 2429–2441.
22. A receptor agonist gaboxadol. J Pharmacol Exp Ther 2011; 338: 214–219.
23. Zhu X, Ong W. Changes in GABA transporters in the rat hippocampus after kainate-induced neuronal injury: decrease in GAT-1 and GAT-3 but upregulation of betaine/GABA transporter BGT-1. J Neurosci Res 2004; 77: 402–409.
24. White HS, Watson WP, Hansen SL, First demonstration of a functional role for central nervous system betaine/γ-aminobutyric acid transporter (mGAT2) based on synergistic anticonvulsant action among inhibitors of mGAT1 and mGAT2. J Pharmacol Exp Ther 2005; 312: 866–874.
25. Madsen KK, Clausen RP, Larsson OM, Synaptic and extrasynaptic GABA transporters as targets for anti-epileptic drugs. J Neurochem 2009; 109: 139–144.
26. Olsen M, Sarup A, Larsson OM, Effect of hyperosmotic conditions on the expression of the betaine-GABA-transporter (BGT-1) in cultured mouse astrocytes. Neurochem Res 2005; 30: 855–865.
27. Clarkson AN, López-Valdés HE, Overman JJ, Multimodal examination of structural and functional remapping in the mouse photothrombotic stroke model. J Cereb Blood Flow Metab 2013; 33: 716–723.
28. Carmichael ST. Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx 2005; 2: 396–409.
29. Schousboe A, Wellendorph P, Frølund B, Astrocytic GABA-transporters: pharmacological properties and targets for antiepileptic drugs. Adv Neurobiol 2017; 16: 283–296.
30. Dhar TGM, Borden LA, Tyagarajan S, Design, synthesis and evaluation of substituted triarylnipecotic acid derivatives as GABA uptake inhibitors: identification of a ligand with moderate affinity and selectivity for the cloned human GABA transporter GAT- 3. J Med Chem 1994; 37: 2334–2342.
31. Clausen RP, Moltzen EK, Perregaard J, Selective inhibitors of GABA uptake: synthesis and molecular pharmacology of 4-N-methylamino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol analogues. Bioorganic Med Chem 2005; 13: 895–908.
32. Wu Z, Guo Z, Gearing M, Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzhiemer’s disease model. Nat Commun 2014; 5: 4159.
33. Madsen KK, Clausen RP, Larsson OM, Synaptic and extrasynaptic GABA transporters as targets for anti-epileptic drugs. J Neurochem 2009; 109(Suppl): 139–144.
34. White HS, Watson WP, Hansen SL, First demonstration of a functional role for central nervous system betaine/γ-aminobutyric acid transporter (mGAT2) based on synergistic anticonvulsant action among inhibitors of mGAT1 and mGAT2. J Pharmacol Exp Ther 2005; 312: 866–874.
35. Bix GJ, Gowing EK, Clarkson AN. Perlecan domain V is neuroprotective and affords functional improvement in a photothrombotic stroke model in young and aged mice. Transl Stroke Res 2013; 4: 515–23.
36. Bhattacharya P, Pandey AK, Paul S, Alleviation of glutamate mediated neuronal insult by piroxicam in rodent model of focal cerebral ischemia: a possible mechanism of GABA agonism. J Physiol Biochem 2014; 70: 901–913.
37. B receptors in the hippocampus. J Neurophysiol 2003; 90: 2690–2701.
38. Seto A, Taylor S, Trudeau D, Induction of ischemic stroke in awake freely moving mice reveals that isoflurane anesthesia can mask the benefits of a neuroprotection therapy. Front Neuroenergetics 2014; 6: 1–9.
39. Chiu C-S, Brickley S, Jensen K, GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. J Neurosci 2005; 25: 3234–3245.
40. A conductances in rat neocortex. J Neurophysiol 2005; 94: 2073–2085.
41. Clarkson AN, Boothman-Burrell L, Dosa Z, et al. The flavonoid, 2'-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischemia. J Cereb Blood Flow Metab 2017 (Accepted)
42. A inhibition in typical absence epilepsy. Nat Med 2009; 15: 1392–1398.
43. Pabel J, Faust M, Prehn C, Development of an (S)-1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114] carba analogue inhibitor for murine γ-aminobutyric acid transporter type 4. Chem Med Chem 2012; 7: 1245–1255.
44. Dalby NO. GABA-level increasing and anticonvulsant effects of three different GABA uptake inhibitors. Neuropharmacology 2000; 39: 2399–2407.