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Original research
Intra-arterial nitroglycerin as directed acute treatment in experimental ischemic stroke
  1. Michael E Maniskas1,2,3,4,
  2. Jill M Roberts1,2,3,
  3. Rebecca Trueman5,
  4. Annastazia E Learoyd5,
  5. Amanda Gorman2,3,
  6. Justin F Fraser1,3,4,6,7,
  7. Gregory J Bix1,2,3,4,6
  1. 1Department of Anatomy & Neurobiology, University of Kentucky, Lexington, Kentucky, USA
  2. 2Sanders Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA
  3. 3Center for Advanced Translational Stroke Science, University of Kentucky, Lexington, Kentucky, USA
  4. 4Department of Neurosurgery, University of Kentucky, Lexington, Kentucky, USA
  5. 5School of Life Sciences, University of Nottingham, Nottingham, UK
  6. 6Department of Neurology, University of Kentucky, Lexington, Kentucky, USA
  7. 7Department of Radiology, University of Kentucky, Lexington, Kentucky, USA
  1. Correspondence to Dr Gregory Bix, Department of Anatomy & Neurobiology, University of Kentucky, Sanders Brown Center on Aging, 800 S. Limestone Street, Rm 430, Lexington, KY 40536, USA; gregorybix{at}uky.edu

Abstract

Background Nitroglycerin (also known as glyceryl trinitrate (GTN)), a vasodilator best known for treatment of ischemic heart disease, has also been investigated for its potential therapeutic benefit in ischemic stroke. The completed Efficacy of Nitric Oxide in Stroke trial suggested that GTN has therapeutic benefit with acute (within 6 hours) transdermal systemic sustained release therapy.

Objective To examine an alternative use of GTN as an acute therapy for ischemic stroke following successful recanalization.

Methods We administered GTN IA following transient middle cerebral artery occlusion in mice. Because no standard dose of GTN is available following emergent large vessel occlusion, we performed a dose–response (3.12, 6.25, 12.5, and 25 µg/µL) analysis. Next, we looked at blood perfusion (flow) through the middle cerebral artery using laser Doppler flowmetry. Functional outcomes, including forced motor movement rotor rod, were assessed in the 3.12, 6.25, and 12.5 µg/µL groups. Histological analysis was performed using cresyl violet for infarct volume, and glial fibrillary activating protein (GFAP) and NeuN immunohistochemistry for astrocyte activation and mature neuron survival, respectively.

Results Overall, we found that acute post-stroke IA GTN had little effect on vessel dilatation after 15 min. Functional analysis showed a significant difference between GTN (3.12 and 6.25 µg/µL) and control at post-stroke day 1. Histological measures showed a significant reduction in infarct volume and GFAP immunoreactivity and a significant increase in NeuN.

Conclusions These results demonstrate that acute IA GTN is neuroprotective in experimental ischemic stroke and warrants further study as a potentially new stroke therapy.

  • Blood Flow
  • Drug
  • Pharmacology
  • Stroke
  • Intracranial Pressure

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Footnotes

  • MEM and JMR are coauthors.

  • Contributors Study design was based on collaborative efforts of MEM, JMR, JFF, RT, and GJB. MEM and JMR performed stroke surgeries, behavior, tissue processing and analysis. AEL processed and analyzed blood samples. AG contributed to animal care and ordering of supplies. MEM, JMR, JFF, RT, and GJB compiled the manuscript, images and figure presentation. JFF, RT and GJB provided oversight for the project. A completed copy of the manuscript was provided to all authors for their input and approval.

  • Funding This work was supported by the National Institute on Health grant number 3R01NS065842-08S1.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement We agree to share data upon request. Unpublished data concerns the physiological response of IA nitroglycerin only. It was used to determine if a chosen dose was lethal.

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