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  • Valproic acid in experimental and clinical SAH: Neuroprotective?

    Final Number:

    Michael K. Tso MD; Jinglu Ai; R Loch Macdonald MD PHD FRCS FAANS

    Study Design:

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2014 Annual Meeting

    Introduction: Subarachnoid hemorrhage (SAH) is associated with substantial morbidity and mortality. New treatments are needed. Valproic acid (VPA) is an antiepileptic drug with multiple mechanisms of action, including the ability to alter the cellular transcription apparatus as a histone deacetylase inhibitor. VPA may be beneficial in SAH.

    Methods: Fifty male C57Bl/6J mice were randomly allocated to 4 groups: SAH (n=13), SAH + VPA treatment (n=13), Sham (n=12), and Sham + VPA treatment (n=12). SAH was induced using a pre-chiasmatic injection model. Mice were administered intraperitoneal injections of 400mg/kg VPA or saline vehicle after the procedure, every 12 hours for the first 48 hours, followed by daily injections up to 7 days. Global neurobehavioral assessments were made at 24 hours and 48 hours using the modified Garcia score [2]. Spatial memory and anxiety were assessed using modified versions of the Morris water maze (days 3-7) and open field test (day 7), respectively. To investigate the clinical effects of VPA in SAH, we used propensity score matching in patients enrolled in CONSCIOUS-1, a randomized controlled trial studying the effects of clazosentan on angiographic vasospasm after SAH.

    Results: SAH mice demonstrated significantly worse acute neurobehavioral scores (ANOVA, p<0.05) and impaired spatial memory (ANOVA, p<0.05), which were both improved with VPA treatment. Anxiety was not affected by SAH or VPA in our animal model. When compared to control SAH patients with similar covariate status (n=20), the CONSCIOUS-1 data suggests that SAH patients treated with VPA (n=19) may have had less risk of overall death and less risk of poor outcome (National Institute of Health Stroke Scale, NIHSS>=10) at 6 weeks, although not quite reaching statistical significance (p=0.139 and p=0.135, respectively).

    Conclusions: VPA improves neurological outcomes in an animal model of SAH and may be beneficial to SAH patients beyond merely preventing and treating seizures.

    Patient Care: Addresses the need for new therapies for SAH.

    Learning Objectives: By the conclusion of this session, participants should be able to 1) describe the use of various behavioral tests in assessing neurological outcomes in animal models; 2) discuss the use of propensity score matching in the post hoc analysis of randomized controlled trial data; and 3) identify valproic acid as a potential therapy not just for preventing and treating seizures, but also to improve neurological outcome after SAH.

    References: 1. Sabri M, Jeon H, Ai J, Tariq A, Shang X, Chen G, & Macdonald RL (2009) Anterior circulation mouse model of subarachnoid hemorrhage. Brain Res. 1295:179-185. 2. Sherchan P, Lekic T, Suzuki H, Hasegawa Y, Rolland W, Duris K, Zhan Y, Tang J, & Zhang JH (2011) Minocycline improves functional outcomes, memory deficits, and histopathology after endovascular perforation-induced subarachnoid hemorrhage in rats. J. Neurotrauma. 28:2503-2512. 3. Jeon H, Ai J, Sabri M, Tariq A, & Macdonald RL (2010) Learning deficits after experimental subarachnoid hemorrhage in rats. Neuroscience. 169:1805-1814. 4. Prut L, & Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharm. 463:3-33. 5. Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, Frey A, Roux S, Pasqualin A (2008) Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke. 39:3015-3021. 6. Rubin DB (1997) Estimating causal effects from large data sets using propensity scores. Ann Intern Med. 127:57-763.

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