Protection against focal ischemic injury to the brain by trans-sodium crocetinate: Laboratory investigation

Department of Neuroscience, University of Virginia, Charlottesville, Virginia 22908, USA.
Journal of Neurosurgery (Impact Factor: 3.74). 12/2009; 113(4):802-9. DOI: 10.3171/2009.10.JNS09562
Source: PubMed


Ischemic injury is a potential complication in a variety of surgical procedures and is a particular impediment to the success of surgeries involving highly vulnerable neural tissue. One approach to limiting this form of injury is to enhance metabolic supply to the affected tissue. Trans-sodium crocetinate (TSC) is a carotenoid compound that has been shown to increase tissue oxygenation by facilitating the diffusivity of small molecules, such as oxygen and glucose. The present study examined the ability of TSC to modify oxygenation in ischemic neural tissue and tested the potential neuroprotective effects of TSC in permanent and temporary models of focal cerebral ischemia.
Adult male rats (330–370 g) were subjected to either permanent or temporary focal ischemia by simultaneous occlusion of both common carotid arteries and the left middle cerebral artery (3-vessel occlusion [3-VO]). Using the permanent ischemia paradigm, TSC was administered intravenously beginning 10 minutes after the onset of ischemia at 1 of 8 dosages, ranging from 0.023 to 4.580 mg/kg. Cerebral infarct volume was measured 24 hours after the onset of ischemia. The effect of TSC on infarct volume was also tested after temporary (2-hour) ischemia using a dosage of 0.092 mg/kg. In other animals undergoing temporary ischemia, tissue oxygenation was monitored in the ischemic penumbra using a Licox probe.
Administration of TSC reduced infarct volume in a dose-dependent manner in the permanent ischemia model, achieving statistical significance at dosages ranging from 0.046 to 0.229 mg/kg. The most effective dosage of TSC in the permanent ischemia experiment (0.092 mg/kg) was further tested using a temporary (2-hour) ischemia paradigm. Infarct volume was reduced significantly by TSC in this ischemia-reperfusion model as well. Recordings of oxygen levels in the ischemic penumbra of the temporary ischemia model showed that TSC increased tissue oxygenation during vascular occlusion, but reduced the oxygen overshoot (hyperoxygenation) that occurs upon reperfusion.
The novel carotenoid compound TSC exerts a neuroprotective influence against permanent and temporary ischemic injury when administered soon after the onset of ischemia. The protective mechanism of TSC remains to be confirmed; however, the permissive effect of TSC on the diffusivity of small molecules is a plausible mechanism based on the observed increase in tissue oxygenation in the ischemic penumbra. This represents a form of protection based on “metabolic reflow” that can occur under conditions of partial vascular perfusion. It is particularly noteworthy that TSC could conceivably limit the progression of a wide variety of cellular injury mechanisms by blunting the ischemic challenge to the brain.

Download full-text


Available from: Ryon Clarke, Mar 06, 2014
  • Source
    • "Even though the postulated mechanism of action (i.e. increased tissue oxygenation ) has been directly demonstrated (Manabe et al., 2010), carotenoid molecules possess anti-oxidant activity, which could conceivably contribute to the protective actions of TSC. However, although TSC can serve as an anti-oxidant, this effect occurs at dosages much higher than those needed to produce an effect on diffusivity (Stennett et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Trans-sodium crocetinate (TSC) is a novel carotenoid compound capable of enhancing the diffusion of small molecules in aqueous solutions. TSC improves the diffusion of oxygen and glucose, and increases oxygenation in ischemic brain tissue. TSC also dampens the intensity of an ischemic challenge during an ongoing ischemic event. The current study examined the impact of TSC in rat models of ischemic and hemorrhagic stroke. Rat three vessel occlusion (3VO), and combined 3VO and one vessel occlusion (3VO/1VO) models of ischemic stroke were evaluated for structural and behavioral outcomes. The effects of TSC were also tested in a rat model of intracerebral hemorrhage (ICH). Delayed treatment with TSC reduced infarct volume in a rodent model of transient focal ischemia involving either 2 or 6 hours of ischemia. Neurological outcomes, based on a multi-scale assessment and automated gait analysis, also were improved by TSC treatment. Additionally, TSC reduced edema and hemorrhagic volume in a rat model of ICH. An optimal therapeutic candidate for early intervention in ischemic stroke should be effective when administered on a delayed basis and should not aggravate outcomes associated with hemorrhagic stroke. The current findings demonstrate that delayed TSC treatment improves outcomes in experimental models of both ischemic and hemorrhagic stroke. Together, these findings suggest that TSC may be a safe and beneficial therapeutic modality for early stroke intervention, irrespective of the type of stroke involved.
    Full-text · Article · Oct 2014 · Brain Research
  • Source
    • "The numbers of animal studies, which are designed to support and further investigate clinical pbtO2 applications in trauma, resuscitation models and the effects of various drugs have once again increased since the previous edition of this report [12] [23] [102-141]. It is used to measure oxygen delivery to brain parenchyma in animal models [111] [113] [115] [133] [135] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151]. The utility in traumatic brain injury and severe uncontrolled haemorrhage with short delay prehospital resuscitation was examined in a swine model [152]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This review has been compiled to assess publications related to the clinical application of direct cerebral tissue oxygenation (pbtO2) monitoring published in international, peer-reviewed scientific journals, or major meeting reports published as journal supplements. Its goal was to extract relevant, i.e. positive and negative, information on indications, clinical application, safety issues and impact on clinical situations, as well as treatment strategies in neurosurgery, neurosurgical anaesthesiology, neurosurgical intensive care, neurology, and related specialties. For completeness’ sake it also presents related basic science research and case reports. This review is an update of its previous edition published elsewhere in 2007. This review reflects publications from 2004 to 2012. Only relevant publications prior to 2004, which explicitly addressed or systematically examined the above issues, are included in this review and are listed in the reference section. Based on 349 citations it is the most comprehensive review available on direct cerebral oxygen monitoring to this date.
    Full-text · Article · May 2013 · The Open Critical Care Medicine Journal
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ischemic neuronal damage is a common feature of occlusive strokes, hemorrhagic strokes, and traumatic brain injury. In addition, ischemia can be an anticipated or unanticipated complication of a variety of surgical procedures. Most therapeutic strategies for managing ischemic injury seek to re-establish blood flow, suppress neural metabolism, and/or limit specific cellular injury cascades. An alternative therapeutic approach is to enhance the delivery of metabolic substrates to ischemic tissue. This strategy is typified by efforts to increase tissue oxygenation by elevating the levels of circulating oxygen. Our studies are examining a complementary approach in which the delivery of metabolic substrates is enhanced by facilitating the diffusion of oxygen and glucose from the vasculature into neural tissue during ischemia. This is achieved by increasing the diffusivity of small molecules in aqueous solutions, such as plasma and interstitial fluid. The carotenoid compound, trans-sodium crocetinate (TSC) is capable of increasing oxygen and glucose diffusivity, and our studies demonstrate that TSC increases cerebral tissue oxygenation in the penumbra of a focal ischemic event. In addition, TSC treatment reduces the volume of cerebral infarction in rodent models of both permanent and temporary focal ischemia. This strategy of "metabolic reflow" thus blunts the metabolic challenge in partially-perfused tissue and reduces ischemic neural injury.
    Full-text · Article · Jan 2011 · Acta neurochirurgica. Supplement
Show more