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. 2014 Oct 2;1583:245-54.
doi: 10.1016/j.brainres.2014.08.013. Epub 2014 Aug 14.

Trans-sodium Crocetinate Improves Outcomes in Rodent Models of Occlusive and Hemorrhagic Stroke

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Free PMC article

Trans-sodium Crocetinate Improves Outcomes in Rodent Models of Occlusive and Hemorrhagic Stroke

Yi Wang et al. Brain Res. .
Free PMC article

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 6h 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.

Keywords: Hemorrhage; Ischemia; Rat; Stroke; Therapy; Trans sodium crocetinate.

Figures

Fig 1
Fig 1
Treatment with TSC is protective in a rat protocol of temporary (2 hours) focal cerebral ischemia when administered 1½ hours after the onset of ischemia. A. The timeline depicts the period of ischemia (3VO), and the treatment protocol for administering Vehicle or TSC. B. Serial sections stained with 2,3,5 triphenyltetrazolium chloride are shown from the brains of representative animals from the Vehicle and TSC groups. The pinkish-red staining represents healthy tissue, while the white areas are regions of infarction. C. The bar graph presents infarction volumes for the two groups measured at 24 hours post-ischemic onset. Values are means and SEMs. The difference in infarct volume between the Vehicle Group (n=6) and the TSC Group (n=7) was statistically significant (** p<0.01, Student's t-test)
Fig 2
Fig 2
Treatment with TSC is protective in a rat protocol of temporary cerebral ischemia, involving partial reperfusion followed by delayed-complete reperfusion (3VO/1VO). A. The timeline depicts the periods of ischemia for 3VO and 1VO, and shows the treatment protocol for administering Vehicle or TSC. B. Serial sections stained with 2,3,5 triphenyltetrazolium chloride are shown from the brains of representative animals from the Vehicle and TSC groups. The pinkish-red staining represents healthy tissue, while the white areas are regions of infarction. C. The bar graph presents infarction volumes for the two groups measured at 24 hours post-ischemic onset. Values are means and SEMs. The difference in infarct volume between the Vehicle Group (n=6) and the TSC Group (n=6) was statistically significant (** p<0.01, Student's t-test)
Fig 3
Fig 3
TSC improves post-ischemic performance on an 18-point neurological assessment scale. No significant differences were observed between groups prior to surgery. Significant impairments were observed on both post-operative days in the Vehicle and TSC Groups, as compared with: (a) the pre-operative baseline within a group, and (b) the Sham Group at the matched post-surgical time point. TSC treatment improved performance significantly at both post-operative time points, as compared with the Vehicle Group. P-values of less than 0.01 were obtained for all of these comparisons. Values shown are means and SEMs; n=6 animals per group
Fig 4
Fig 4
TSC improves gait function after 3VO/1VO ischemia, as assessed by the CatWalk system. Multiple gait function parameters were impaired by the 3VO/1VO challenge, including Step Sequence Regularity Index, Speed, Cadence, Swing Speed, Stand and Stride Length in all four paws, Base of Support, Support, Phase Dispersions, and Max Intensity. Notably, post-ischemic performance by the 3VO/1VO+TSC Group was significantly better than that of the 3VO/1VO+Saline Group on several measures. Outcomes of statistical comparisons are shown below. Abbreviations: L=Left, R=Right, F=Front, H=Hind 1. Spatial parameters related to individual paws: Max Contact (%) RH p=0.042, LF p=0.017 ; Max Contact Area RF P<0.001; Max Contact Mean Intensity RF p<0.001, LF p<0.001; Print Length RH p<0.018; Print Area RF p<0.001, LF p<0.001; Max Intensity At (%) RF p=0.002 LF p<0.001; Min Intensity RF p=0.01, LH p=0.007 . 2. Relative spatial relationship between different paws: Base of Support FP p=0.003; HP p<0.001; Stride Length RF, RH, LF, LH: all p<0.001 ; Swing speed RF p<0.001 ; Duty Cycle(%) RF p<0.001, RH p=0.007, LF p<0.001, LH p=0.001. 3. Interlimb coordination: Phase Dispersions LH-RH Cstat p=0.007, LF-RF Cstat p=0.005, RF-RH C stat p<0.001 ; Support Lateral p<0.001. 4. Temporal parameters: Speed p<0.001; Cadence p<0.001; Stand(s) RF p<0.001 ; Stand Index RF, RH, LF, LH: all p<0.001
Fig 5
Fig 5
TSC improved outcomes after ICH. Photographs show examples of serial sections from a vehicle-treated and a TSC-treated animal. Hematomas appear dark-red in these unstained, thick sections. Hematoma volume was reduced slightly in the TSC Group; however, this difference did not achieve statistical significance (n=6 for each group). Treatment with TSC reduced significantly hemispheric swelling by a 46% and hemorrhage volume by 20% (* p<0.05, Student's t-test; n=6 for each group). Values are means and SEMs

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