Abstract
Anesthetics such as isoflurane are commonly used to sedate experimental animals during the induction of stroke. Since these agents are known to modulate synaptic excitability, inflammation and blood flow, they could hinder the development and discovery of new neuroprotection therapies. To address this issue, we developed a protocol for inducing photothrombotic occlusion of cerebral vessels in fully conscious mice and tested two potential neuroprotectant drugs (a GluN2B or α4β2 nicotinic receptor antagonist). Our data show in vehicle treated mice that just 20 min of exposure to isoflurane during stroke induction can significantly reduce ischemic cortical damage relative to mice that were awake during stroke. When comparing potential stroke therapies, none provided any level of neuroprotection if the stroke was induced with anesthesia. However, if mice were fully conscious during stroke, the α4β2 nicotinic receptor antagonist reduced ischemic damage by 23% relative to vehicle treated controls, whereas the GluN2B antagonist had no significant effect. These results suggest that isoflurane anesthesia can occlude the benefits of certain stroke treatments and warrant caution when using anesthetics for pre-clinical testing of neuroprotective agents.
Highlights
Anesthetics are commonly used in humans undergoing neurosurgery and experimental animals subjected to various kinds of ischemic stroke
Of physiological variables measured for drug therapy experiments
Arterial blood was measured with an iSTAT CG8+ analyzer in un-anesthetized mice 30 min after administration of vehicle (n = 3) or DHβE (3 mg/kg, n = 3)
Summary
Anesthetics are commonly used in humans undergoing neurosurgery and experimental animals subjected to various kinds of ischemic stroke. Inhaled anesthetics such as isoflurane can augment GABA, glutamate and nicotinic neurotransmission, mitochondrial function, apoptosis, inflammation and cortical blood flow (Eger, 1981; McPherson et al, 1994; Flood et al, 1997; De Sousa et al, 2000; Yamakura and Harris, 2000; Wu et al, 2012; Zhang et al, 2012; Hofacer et al, 2013; Kotani and Akaike, 2013; Altay et al, 2014) This is a potential concern for pre-clinical studies of cerebral neuroprotection since many potential treatments target the same signaling pathways as those affected by anesthesia. We show that can isoflurane anesthesia reduce the extent of ischemic damage after stroke, but it can mask the protective effects of a stroke therapy
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