An alpha-lipoic acid–vitamin E mixture reduces post-embolism lipid peroxidation, cerebral infarction, and neurological deficit in rats

Garcı́a-Estrada, Joaquı́n; González-Pérez, Óscar; González-Castañeda, Rocío E.; Martínez-Contreras, Alicia; Luquı́n, Sonia; Mora, P. Garzón de la; Navarro-Ruíz, A.

doi:10.1016/s0168-0102(03)00200-1

Cited by 41 publications

(20 citation statements)

References 25 publications

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“…Further, several laboratories have demonstrated that administration of LA in combination with another compound can produce significant neuroprotective effects exceeding the effect of either drug alone (1,2,18,20). Our laboratory has provided further support for this hypothesis and demonstrated that when using the same stroke modes as is being used in this study, coadministration of nonprotective doses of apocynin with nonprotective doses of LA produced significant neuroprotection compared with either drug injected alone (13).…”

supporting

confidence: 68%

UPEI-100, a conjugate of lipoic acid and apocynin, mediates neuroprotection in a rat model of ischemia/reperfusion

Connell

Saleh

Khan

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Previous work in our laboratory has provided evidence that preadministration of apocynin and lipoic acid at subthreshold levels for neuroprotection enhanced the neuroprotective capacity when injected in combination. Therefore, the present investigation was designed to determine whether a co-drug consisting of lipoic acid and apocynin functional groups bound by a covalent bond, named UPEI-100, is capable of similar efficacy using a rodent model of stroke. Male rats were anesthetized with Inactin (100 mg/kg iv), and the middle cerebral artery was occluded for 6 h or allowed to reperfuse for 5.5 h following a 30-min occlusion (ischemia/reperfusion, I/R). Preadministration of UPEI-100 dose-dependently decreased infarct volume in the I/R model (P < 0.05), but not in the middle cerebral artery occlusion model of stroke. Using the optimal dose, we then injected UPEI-100 during the stroke or at several time points during reperfusion, and significant neuroprotection was observed when UPEI-100 was administered up to 90 min following the start of reperfusion (P < 0.05). A time course for this neuroprotective effect showed that UPEI-100 resulted in a decrease in infarct volume following 2 h of reperfusion compared with vehicle. The time course of this neuroprotective effect was also used to study several mediators along the antioxidant pathway and showed that UPEI-100 increased the level of mitochondrial superoxide dismutase and oxidized glutathione and decreased a marker of lipid peroxidation due to oxidative stress (HNE-His adduct formation). Taken together, the data suggest that UPEI-100 may utilize similar pathways to those observed for the two parent compounds; however, it may also act through a different mechanism of action.

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supporting

confidence: 68%

UPEI-100, a conjugate of lipoic acid and apocynin, mediates neuroprotection in a rat model of ischemia/reperfusion

Connell

Saleh

Khan

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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“…In addition, the authors reported important functional recovery as a consequence of the prophylactic administration of these antioxidants [42]. Additional findings indicate that a prophylactic treatment with an ALA-VE mixture can reduce infarct volume and lipid peroxidation after cerebral ischemia [43]. Most recent findings indicate that an ALA-VE combination increased endothelial levels of the antiapoptotic protein Bcl-2 with no significant changes in the levels of the pro-apoptotic protein Bax [44].…”

Section: Synergism Between Lipoate and Tocopherolmentioning

confidence: 92%

Therapeutic perspectives on the combination of α-lipoic acid and vitamin E

González-Pérez

González-Castañeda

2006

Nutrition Research

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Alpha-lipoic acid and vitamin E have synergistic effects, as determined in models of oxidant radical lesions. This review summarizes recent findings showing that the combination of alpha-lipoic acid plus vitamin E has beneficial effects in reducing oxidative damage in ischemic or other oxidationrelated pathological events. Both antioxidants are common in the normal human diet and side effects are very rare. Therefore, alpha-lipoic acid and vitamin E can counteract oxidative processes and could have an important role in clinical medicine.

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“…61 In animal studies, combined drug therapy targeted to reduce oxidative stress and mitochondrial dysfunction showed enhanced neuroprotection after stroke, reduced infarct volume, and improved functional-behavioral outcomes. [62][63][64][65][66] It should be emphasized that the strategy we propose is in no way to create a cocktail of all the listed agents, but rather to design a treatment with 2 agents, where each agent shows some indication of efficacy but the effects are not significant. With 2 agents acting at different sites on the mitochondria, it is quite possible that the degree of neuroprotection may become additive or even synergistic.…”

Section: Reactive Oxygen Speciesmentioning

confidence: 99%

Reperfusion brain injury

Pundik

Sundararajan

2012

Neurology

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Energy production for the maintenance of brain function fails rapidly with the onset of ischemia and is reinstituted with timely reperfusion. The key bioenergetic organelle, the mitochondrion, is strongly affected by a cascade of events occurring with ischemia and reperfusion. Enhanced production of reactive oxygen species, disruption of calcium homeostasis, and an inflammatory response are induced by reperfusion and have a profound effect on cellular bioenergetics in reversible stroke. The impact of perturbed bioenergetics on cellular homeostasis/function during and after ischemia are discussed. Because mitochondrial function can be compromised by derangements at more than one of the susceptible sites on this organelle, we propose that a combination therapy is needed for the restoration and maintenance of cellular bioenergetics after reperfusion. Neurology Stroke is a complex and dynamic disease of the brain that rates fourth in mortality and first in disability in the United States. The brain has certain unique physiologic properties that make it extremely sensitive to the loss of blood flow. In general, the energy demands of the brain are high, requiring a continual supply of oxygen and its principal substrate, glucose, mainly from the blood. Occluding blood flow to the brain disrupts the delicate balance between the energy generated by glucose oxidation and energy needed for cell processes, which leads to a rapid loss of function and cell homeostasis.The imbalance of the brain bioenergetics induced by the loss of blood flow has been shown to lead to cellular infarction of all brain cells, including neurons, astrocytes, endothelial cells, oligodendrocytes, and subpopulations of these cells. Conversely, a pronounced deranged cellular milieu resulting from ischemia elicits a plethora of reactions upon re-establishment of reflow. It is increasingly evident that many of the events center on the neurovascular unit, a functional composite of microvessels, pericytes, astrocytes, neurons, axons, and other supporting cells such as microglia and oligodendrocytes. Although many of the reflow-induced events may be pathologic and their prevention potentially beneficial, it is our contention that the status of cellular bioenergetics is the major determinant of many of the pathophysiologic sequelae manifested in the neurovascular unit and therefore is fundamental to the outcome for the tissue, following reversible focal ischemia.In the past 50 years, basic science investigations first established that loss of blood flow to the brain resulted in rapid failure of cell bioenergetics, followed by an ever-increasing list of cellular perturbations. A schematic of ischemia-induced events is shown in figure 1. Rapid energy depletion reflects very low energy reserves within the brain, a high metabolic rate, and almost a total reliance on glucose oxidation for energy production. The ischemic cascade is initiated during ischemia. Ischemia depletes adenosine triphosphate (ATP) within minutes, leading to a failure of a

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An alpha-lipoic acid–vitamin E mixture reduces post-embolism lipid peroxidation, cerebral infarction, and neurological deficit in rats

Cited by 41 publications

References 25 publications

UPEI-100, a conjugate of lipoic acid and apocynin, mediates neuroprotection in a rat model of ischemia/reperfusion

UPEI-100, a conjugate of lipoic acid and apocynin, mediates neuroprotection in a rat model of ischemia/reperfusion

Therapeutic perspectives on the combination of α-lipoic acid and vitamin E

Reperfusion brain injury

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