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The Journal of Neuroscience, February 11, 2009, 29(6):1796-1804; doi:10.1523/JNEUROSCI.5729-08.2009

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Neurobiology of Disease
Effects of the Noradrenergic System in Rat White Matter Exposed to Oxygen–Glucose Deprivation In Vitro

Maria A. Nikolaeva,¹ Sandra Richard,¹ Abdeslam Mouihate,² and Peter K. Stys²

¹Division of Neuroscience, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1Y 4E9, and ²Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada T2N 4N1

Correspondence should be addressed to Peter K. Stys, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, HRIC 1AA22, 3330 Hospital Drive North West, Calgary, Alberta, Canada T2N 4N1. Email: pstys{at}ucalgary.ca

Norepinephrine (NE) is released in excess into the extracellular space during oxygen–glucose deprivation (OGD) in brain, increasing neuronal metabolism and aggravating glutamate excitoxicity. We used isolated rat optic nerve and spinal cord dorsal columns to determine whether the noradrenergic system influences axonal damage in white matter. Tissue was studied electrophysiologically by recording the compound action potential (CAP) before and after exposure to 60 min of OGD at 36°C. Depleting catecholamine stores with reserpine was protective and improved CAP recovery after 1 h of reperfusion from 17% (control) to 35%. Adding NE during OGD decreased CAP recovery to 8%, and adding NE to reserpine during OGD eliminated the protective effect of the latter. Selective inhibitors of Na⁺-dependent norepinephrine transport desipramine and nisoxetine improved recovery to 58% and 44%, respectively. 2 adrenergic receptor agonists UK14,304 and medetomidine improved CAP recovery to 41% and 46% after 1 h of OGD. Curiously, 2 antagonists alone were also highly protective (e.g., atipamezole: 86% CAP recovery), at concentrations that did not affect baseline excitability. The protective effect of 2 receptor modulation was corroborated by imaging fluorescent Ca²⁺ and Na⁺ indicators within axons during OGD. Both agonists and antagonists significantly reduced axonal Ca²⁺ and Na⁺ accumulation in injured axons. These data suggest that the noradrenergic system plays an active role in the pathophysiology of axonal ischemia and that 2 receptor modulation may be useful against white matter injury.

Key words: axon; ischemia; sodium; calcium; norepinephrine; confocal microscopy

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Received Dec. 1, 2008; revised Jan. 4, 2009; accepted Jan. 5, 2009.

Correspondence should be addressed to Peter K. Stys, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, HRIC 1AA22, 3330 Hospital Drive North West, Calgary, Alberta, Canada T2N 4N1. Email: pstys{at}ucalgary.ca

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