Trans-sodium crocetinate improves outcomes in rodent models of occlusive and hemorrhagic stroke

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.

Perihematomal Cellular Injury Is Reduced by Trans-sodium Crocetinate in a Model of Intracerebral Hemorrhage

“…Previous evidence has shown that hematoma size is not significantly affected by TSC treatment [11]. The locations of the sampling areas in the vicinity of the hematoma are illustrated in Fig.…”

“…The rationale for that study was TSC might reasonably be used for treating ischemic stroke prior to differential diagnosis of the type of stroke underway, if it does not to aggravate outcomes under conditions of hemorrhagic stroke. Although TSC did not significantly affect hematoma volume, it actually improved certain outcomes after experimental ICH, including edema and a hemorrhagic volume [11]. Finally, TSC has successfully completed two phase I safety trials and a phase I/IIa trial for peripheral artery disease, indicating that this compound can be administered safely in humans [18,19].…”

“…It has also been shown to increase oxygenation in a variety of tissues [16,17], including ischemic brain tissue in the penumbra of a model of focal stroke [3]. Moreover, TSC can improve structural and functional outcomes in animal models of ischemic stroke [3,11,12]. An overview of the effects of TSC in animal models of stroke is presented in Table 1.…”

“…An overview of the effects of TSC in animal models of stroke is presented in Table 1. Recently, the effects of TSC have also begun to be evaluated in a model of hemorrhagic stroke [11]. The rationale for that study was TSC might reasonably be used for treating ischemic stroke prior to differential diagnosis of the type of stroke underway, if it does not to aggravate outcomes under conditions of hemorrhagic stroke.…”

“…This strategy does not target a specific injury cascade but rather seeks to improve the overall health of the tissue by blunting the intensity of an ongoing ischemic event. Recent studies have shown that TSC is a promising candidate in this regard [3,11,12]. TSC modifies the structure of water in a manner that facilitates the diffusion of small molecules, such as oxygen and glucose, in aqueous solutions [14,15].…”