Effects of the Noradrenergic System in Rat White Matter Exposed to Oxygen–Glucose DeprivationIn Vitro

Abstract

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 ϩ -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 Ca 2ϩ and Na ϩ indicators within axons during OGD. Both agonists and antagonists significantly reduced axonal Ca 2ϩ and Na ϩ 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.

Glia as transmitter sources and sensors in health and disease

“…Functional white matter  and 1 adrenoreceptors have also been described (Sanders et al, 2005;Venugopalan et al, 2006;Nikolaeva et al, 2009;Honmou & Young, 1995), and 2 receptor protein is expressed in white matter astrocytes (Nikolaeva et al, 2009). 1 receptor activation can affect axon excitability in neonatal white matter but not adult, consistent with the transient 1 mRNA expression found here.…”

“…While there is evidence that white matter glutamate and ATP receptors help to coordinate the complex morphological arrangement between glia and axons (Ishibashi et al, 2006;Alix et al, 2008), there is little information on the physiological role of other white matter glial receptors and it is not known if their molecular properties differ from receptors in neurons. Despite this, there is growing evidence that white matter glial receptors are important in pathological conditions such as multiple sclerosis, spinal cord injury, stroke, and cerebral palsy (Karadottir et al, 2005;Salter & Fern, 2005;Micu et al, 2006;Alix & Fern, 2009;Constantinou & Fern, 2009;Nikolaeva et al, 2009;Ouardouz et al, 2009a;Ouardouz et al, 2009b).…”

“…For example, metabolic disorders associated with elevated extracellular glycine levels can produce selective white matter damage (Press et al, 1989;de Koning et al, 2000); prenatal human exposure to the adrenoreceptor 2 antagonist terbutaline is associated with reactive glial changes in white matter (Zerrate et al, 2007) and adrenoreceptors may have relevance for disease states affecting white matter from autism to cerebral palsy and stroke (Laudenbach et al, 2002;Zerrate et al, 2007; Constantinou selective white matter pathology (Froen et al, 2002;Abdel-Rahman et al, 2005;Jacobsen et al, 2007), while changes in   subunit expression is noted in multiple sclerosis (De Keyser et al, 2004), indicating a largely unexplored relevance to disease. It has been recently shown that neurotransmitters other than glutamate can be directly and acutely harmful to glial cells, in particular nicotinic and adreno-receptors in white matter glia (Constantinou & Fern, 2009;Nikolaeva et al, 2009) (Fig 4). The underlying mechanism is currently unknown, but the phenomena is consistent with the expression of these receptors in glia and may have considerable clinical significance.…”

Neurotransmitter signaling in white matter

“…In addition, electrophysiological criteria have been used to distinguish glial cell types, allowing the first descriptions of functional glutamate, GABA-A and glycine receptors in identified astrocytes, oligodendrocytes, glioblasts and OPCs in situ (Berger et al, 1992;Butt and Jennings 1994;Pastor et al, 1995 ] does not duplicate the effects of GABA upon excitability leading to the conclusion that receptor expression is axonal (Sakatani et al, 1994). In general, it may be assumed that the effects of neurotransmitters on glial Ca 21 and membrane properties appear to be mediated largely by glial expression of neurotransmitter receptors (Butt and Jennings, 1994;Hamilton et al, 2008), whereas effects upon axonal excitability appear to be mediated largely by axolemma expression, rather than glial responses that subsequently modify excitability (Nikolaeva et al, 2009;Sun and Chiu, 1999;Zhang et al, 2004). …”

“…Dopamine and noradrenaline can evoke physiological responses in rat spinal cord WM via D1 or a1/a2/b adrenoreceptors respectively, and there is some evidence for low levels of D1 receptor expression in human WM (Sovago et al, 2005;Venugopalan et al, 2006). Catecholamines can influence ischemic injury in adult WM and are toxic to developing WM (Constantinou and Fern, 2009;Nikolaeva et al, 2009); the role of neurotransmitters in WM pathology is covered in a companion review in this volume. …”