Tocotrienol Vitamin E Protects against Preclinical Canine Ischemic Stroke by Inducing Arteriogenesis

Abstract

Vitamin E consists of tocopherols and tocotrienols, in which a-tocotrienol is the most potent neuroprotective form that is also effective in protecting against stroke in rodents. As neuroprotective agents alone are insufficient to protect against stroke, we sought to test the effects of tocotrienol on the cerebrovascular circulation during ischemic stroke using a preclinical model that enables fluoroscopy-guided angiography. Mongrel canines (mean weight = 26.3 ± 3.2 kg) were supplemented with tocotrienol-enriched (TE) supplement (200 mg b.i.d, n = 11) or vehicle placebo (n = 9) for 10 weeks before inducing transient middle cerebral artery (MCA) occlusion. Magnetic resonance imaging was performed 1 hour and 24 hours post reperfusion to assess stroke-induced lesion volume. Tocotrienol-enriched supplementation significantly attenuated ischemic strokeinduced lesion volume (P < 0.005). Furthermore, TE prevented loss of white matter fiber tract connectivity after stroke as evident by probabilistic tractography. Post hoc analysis of cerebral angiograms during MCA occlusion revealed that TE-supplemented canines had improved cerebrovascular collateral circulation to the ischemic MCA territory (P < 0.05). Tocotrienol-enriched supplementation induced arteriogenic tissue inhibitor of metalloprotease 1 and subsequently attenuated the activity of matrix metalloproteinase-2. Outcomes of the current preclinical trial set the stage for a clinical trial testing the effects of TE in patients who have suffered from transient ischemic attack and are therefore at a high risk for stroke.

Loss of miR-29b following Acute Ischemic Stroke Contributes to Neural Cell Death and Infarct Size

“…Rescue of miR-29b against stroke-induced loss was also achieved by the 12-lipoxygenase inhibitor a-tocotrienol, which is a form on natural vitamin E that might be used in nutritional intervention against stroke. 7,17,30,33 During stroke, arachidonic acid is mobilized from the membrane of GSH-deficient cells and feeds the 12-lipoxygenase pathway triggering the production of reactive lipid metabolites, which function as mitochondrial toxin. 39,40 Our laboratory was the first to report a central role of 12-lipoxygenase in regulating stroke outcomes.…”

“…28 MicroRNA Expression Assay from Laser-Captured Microdissected Somatosensory Cortex of Brain Tissue Laser microdissection and pressure catapulting was performed using the microlaser system from PALM Microlaser Technologies AG (Bernreid, Germany) as described. 17,21,26,27,29,30 Briefly, mice were euthanized immediately after MRI imaging and coronal slices of brain tissue were collected using a mouse brain matrix. OCT embedded in slices were subsequently cut in 12-mm-thick sections on a Leica CM 3050S cryostat (Leica Microsystems, Wetzlar, Germany).…”

Lipoxygenase: An Emerging Target for Stroke Therapy

“…Given by oral gavage for several weeks before the ischemic insult, a-tocotrienol reduced infarct size in rats[19]. It is not known what the time window would be for using a-tocotrienol in acute stroke, but it also reduced severity of stroke injury when dosed chronically in canines, suggesting it may have utility in secondary stroke prevention[57]. In addition to inhibiting 12/15-LOX and a general antioxidant effect, a-tocotrienol may also protect by targeting Multidrug Resistance-Associated Protein 1[58].…”

Oral Tocotrienols Are Transported to Human Tissues and Delay the Progression of the Model for End-Stage Liver Disease Score in Patients4

“…A series of studies in our laboratory have demonstrated potent in vitro as well as in vivo neuroprotective properties of aTE against neurodegeneration and stroke (5,(10)(11)(12)(13)(14)(15). Recently, we concluded a randomized, blinded, preclinical trial in canines where orally supplemented TE proved to be substantially effective in protecting against strokeinduced brain lesions as evaluated by high resolution MRI (10). In particular, TE has been shown to significantly reduce hemispherical infarct volume and prevent loss of white matter fiber tract connectivity in canines subject to MCA occlusion (10).…”