Preconditioning with 4-aminopyridine protects cerebellar granule neurons against excitotoxicity

Smith, A., Tauskela, J.S., Stone, T.W. and Smith, R.A. (2009) Preconditioning with 4-aminopyridine protects cerebellar granule neurons against excitotoxicity. Brain Research, 1294, pp. 165-175. (doi: 10.1016/j.brainres.2009.07.061)

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Preconditioning by excitatory stimuli such as <i>N</i>-methyl-D-aspartate (NMDA) offers good neuroprotection against excitotoxic insults, but is potentially limited by the risk of damage associated with the treatment. We report here on the potential of an alternative strategy, tested on rat neonatal cerebellar granule neurons, which involves a 48-hour preconditioning step using the potassium channel blocker 4-aminopyridine (4-AP), at a low (50 µM) and at a higher (2500 µM) concentration (in the presence or absence of the GABA<sub>A</sub> receptor antagonist, bicuculline). 4-Aminopyridine gave extensive protection against a number of stressors (glutamate, NMDA and 3-nitropropionic acid) applied 24 hours following the end of the preconditioning period. Blockade of neuronal depolarisation by tetrodotoxin during preconditioning attenuated but did not eliminate protection, whilst co-application with the NMDA receptor blocker MK-801 increased protection. Western blot analysis showed that CREB phosphorylation was significantly increased by the 4-AP preconditioning, although bcl-2 expression was not stimulated. Glutamate induced cell death without significant activation of caspase-3, suggesting that 4-AP preconditioning is effective primarily against necrotic excitotoxicity. Since 4-AP preconditioning affords extensive protection against a range of neurotoxic insults we propose that it could provide the basis for a novel neuroprotective therapy worthy of further investigation

Item Type:Articles
Keywords:4-Aminopyridine, Cerebellar granule neuron, Excitotoxicity, Glutamate, Neuroprotection, CREB, 3-Nitropropionic acid, NMDA receptor
Glasgow Author(s) Enlighten ID:Stone, Professor Trevor and Smith, Professor Robert
Authors: Smith, A., Tauskela, J.S., Stone, T.W., and Smith, R.A.
Subjects:R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Q Science > QH Natural history > QH301 Biology
Q Science > QM Human anatomy
College/School:College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Brain Research
ISSN (Online):1872-6240

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