Research ReportVagus nerve stimulation reduces infarct size in rat focal cerebral ischemia: An unlikely role for cerebral blood flow
Research highlights
► Stimulation of the vagus nerve decreases infarct size after focal cerebral ischemia. ► Stimulation of the vagus nerve improves motor function loss after ischemia. ► The protective effect is not mediated by an increase in blood flow.
Introduction
Electrical stimulation of the left cervical vagus nerve is an approved treatment by the FDA as an adjunctive therapy for partial epilepsy and drug-resistant depression and has been used clinically since 1997. We have recently shown that the right-sided vagus nerve stimulation (VNS) initiated 30 min after an ipsilateral transient middle cerebral artery (MCA) occlusion reduces infarct volume by approximately 50% in rat (Ay et al., 2009). The mechanism by which VNS reduces infarct size is not known. It has been suggested that VNS causes cerebral vasodilation and increased cerebral blood flow (CBF) under non-ischemic conditions (Nakai et al., 1982, Nakai et al., 1993). Positron emission tomography (PET) and functional MRI (fMRI) studies in patients with epilepsy and depression have demonstrated that VNS augments CBF in certain brain regions including bilateral frontal and prefrontal cortices, thalamus, and right anterior insula (Conway et al., 2006, Henry et al., 1998, Henry et al., 1999, Henry et al., 2004, Lomarev et al., 2002). Because compromise of blood flow is the key event in the pathophysiology of ischemic brain injury, augmentation of CBF is certainly desirable.
In the present study, we sought to reproduce our earlier findings on the effect of VNS on tissue outcome by the left-sided VNS and explore whether infarct reducing effect of VNS is mediated by an increase in CBF.
Section snippets
Results
There was no difference in body temperature, arterial blood gases, and pH between control and treatment groups. Three animals (all in the left VNS protocol; one in the stimulation group and two in the control group) died during electrode implantation, most likely due to cardiac arrest. However, mortality rate during the survival period in both protocols was less than 10%.
Transient occlusion of the right MCA resulted in infarct in the ipsilateral cerebral cortex and underlying striatum. In the
Discussion
The present study confirms our prior findings that the right VNS, initiated within 30 min after the onset of an ipsilateral transient MCA occlusion, reduces infarct volume by approximately 50% in rats (Ay et al., 2009) and provides new information in multiple domains. First, it demonstrates that the stimulation of the left vagus nerve is also as effective as the right side in reducing the infarct volume. Second, stimulation of vagus nerve exerts infarct reducing effect in the contralateral
Experimental procedures
All experiments were performed in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Massachusetts General Hospital Subcommittee on Research Animal Care. Adult male Wistar rats (350–400 g, Charles River Laboratories, Wilmington, MA) were anesthetized by isoflurane (4-5% for induction, 1-2% for maintenance; in 30% oxygen 70% nitrous oxide) and were kept under anesthesia throughout the experimental period. Rectal temperature was intermittently
Acknowledgments
This study was supported by American Heart Association (10SDG2600218 to I.A.). H.A. was supported by NINDS (RO1-NS059710). A.G.S. was supported by PHS NS38477. Partial support was also provided by P41-RR14075 and the MIND Institute. A full listing of A.G.S.'s competing interests is available at www.biomarkers.org.
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