Effects of the noradrenergic system in rat white matter exposed to oxygen-glucose deprivation in vitro.
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 degrees 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. alpha2 adrenergic receptor agonists UK14,304 and medetomidine improved CAP recovery to 41% and 46% after 1 h of OGD. Curiously, alpha2 antagonists alone were also highly protective (e.g., atipamezole: 86% CAP recovery), at concentrations that did not affect baseline excitability. The protective effect of alpha2 receptor modulation was corroborated by imaging fluorescent Ca(2+) and Na(+) indicators within axons during OGD. Both agonists and antagonists significantly reduced axonal Ca(2+) 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 alpha2 receptor modulation may be useful against white matter injury.
Nikolaeva
Maria A
MA
Division of Neuroscience, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Richard
Sandra
S
Mouihate
Abdeslam
A
Stys
Peter K
PK
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D005947:Glucose / Q000172:deficiency* / Q000378:metabolism; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans
D005947:Glucose; D010100:Oxygen; D009638:Norepinephrine