Tirilazad Mesylate Protects Vitamins C and E in Brain Ischemia‐Reperfusion Injury

Sato, Paul H.; Hall, Edward D.

doi:10.1111/j.1471-4159.1992.tb10972.x

Cited by 63 publications

(26 citation statements)

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“…The precise mechanism of action of tirilazad in vivo is not known conclusively. Because the drug inhibits lipid peroxidation in vitro (Braughler et al, 1987;Braughler and Pregenzer, 1989;Hall et aI., 1991b) and attenuates depletion of endogenous antioxi dants such as vitamin E and vitamin C after isch emia in vivo (Hall et aI., 1991a;Sato and Hall, 1992), tirilazad may act by inhibiting lipid peroxida tion in vivo. If so, our results with tirilazad would be consistent with the hypothesis that acidosis aug ments ischemic injury by an oxygen radical mech anism.…”

Section: Discussionmentioning

confidence: 99%

“…This 21-aminosteroid is a potent inhibitor of lipid peroxidation in vitro including brain homogenate (Braughler et aI., 1987;Braughler and Pregenzer, 1989;Hall et aI., 1991b) and attenuates the decrease in endogenous antiox idants associated with prolonged ischemia (Hall et aI., 1991a;Sato and Hall, 1992). This agent has been found to be protective in several models of severe global ischemia (Hall and Yonkers, 1988;Hall et aI., 1988;Natale et aI., 1988;Perkins et aI., 1991), al though protection of selectively vulnerable neurons in models thought to evoke primarily excitotoxic mechanisms has been less consistent (Beck and Bielenberg, 1990;Lesiuk et aI., 1991;Buchan et aI., 1992).…”

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confidence: 99%

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Tirilazad Pretreatment Improves Early Cerebral Metabolic and Blood Flow Recovery from Hyperglycemic Ischemia

Maruki

Koehler

Kirsch

et al. 1995

J Cereb Blood Flow Metab

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Summary: Acidosis may augment cerebral ischemic in jury by promoting lipid peroxidation. We tested the hy pothesis that when acidosis is augmented by hyperglyce mia, pretreatment with the 21-aminosteroid tirilazad mes ylate (U74006F), a potent inhibitor of lipid peroxidation in vitro, improves early cerebral metabolic recovery. In a randomized, blinded study, anesthetized dogs received either tirilazad mesylate (1 mg/kg plus 0.2 mg/kg/h; n = 8) or vehicle (n = 8). Hyperglycemia (400-500 mg/dl) was produced prior to 30 min of global incomplete cerebral ischemia. Intracellular pH and high energy phosphates were measured by phosphorus magnetic resonance spec troscopy. During ischemia, microsphere-determined CBF decreased to 8 ± 4 ml min -I 100 g-I and intracellular pH decreased to 5.6 ± 0.2 in both groups. During the first 20 min of reperfusion, ATP partially recovered in the vehicle group to 57 ± 21% of baseline, but then declined progresAcidosis is one of several mechanisms thought to contribute to ischemic injury (Siesj6 et aI., 1993). The precise molecular mechanism whereby acidosis augments injury has not been elucidated. By alter ing protein charge, pH is expected to alter protein function. However, severe acidosis induced by ex treme hypercapnia does not produce irreversible in jury (Xu et aI., 1991), suggesting that pH-induced changes in protein charge per se are insufficient to cause injury. Even in the presence of ischemia and ATP depletion, augmenting acidosis by hypercap nia does not produce the same impairment of met- 88sively in association with elevated intracranial pressure. By 30 min, ATP recovery was greater in the tirilazad group (77 ± 35 vs. 36 ± 19%), although postischemic hyperemia was similar. By 45 min, the tirilazad group had a higher intracellular pH (6.5 ± 0.5 vs. 5.9 ± 0.6) and a lower intracranial pressure (18 ± 6 vs. 52 ± 24 mm Hg). By 180 min, blood flow and ATP were undetectable in seven of eight vehicle-treated dogs, whereas ATP was >67% and pH was >6.7 in six of eight tirilazad-treated dogs. Thus, tirilazad acts during early reperfusion to pre vent secondary metabolic decay associated with severe acidotic ischemia. If tirilazad acts by inhibiting lipid per oxidation, then these data are consistent with extreme acidosis limiting recovery by a mechanism involving lipid peroxidation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Tirilazad Pretreatment Improves Early Cerebral Metabolic and Blood Flow Recovery from Hyperglycemic Ischemia

Maruki

Koehler

Kirsch

et al. 1995

J Cereb Blood Flow Metab

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“…Tetramethylsilane was used as the internal reference (d 0.00) for 1 H-NMR spectra measured in chloroform-d 1 . This solvent was also used for 13 C-NMR spectra. Infrared (IR) spectra were determined with an FT/IR-470 Pulse Fourier Transform Infrared Spectrometer using a KBr disk.…”

Section: Methodsmentioning

confidence: 99%

“…For example, vitamin C increases enzyme activity [9][10][11] ; acts as an inducer of the collagen pathway 12) ; and scavenges free radicals as an antioxidant during oxidant stress. 13,14) An essential function of vitamin C is to act as a cofactor for the hydroxylation of proline and lysine residues in collagen, a major protein component of the body. Vitamin C also increases the transcription rate of procollagen genes and stabilizes procollagen mRNA.…”

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confidence: 99%

Effect of a Novel Ascorbic Derivative, Disodium Isostearyl 2-O-L-Ascorbyl Phosphate on Human Dermal Fibroblasts: Increased Collagen Synthesis and Inhibition of MMP-1

Shibayama

Hisama²,

Matsuda³

et al. 2008

Biological & Pharmaceutical Bulletin

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Normal cells, including fibroblasts, show density-dependent growth and form monolayers in culture. 1) This is quite different from cell behavior in vivo, where the cells are multilayered and surrounded by extracellular matrix (ECM) components, such as collagen and proteoglycan produced by the cells themselves. The active role of ECM in cell attachment, proliferation 2) and differentiation 3) has recently been recognized. Artificial collagen gels 4) and insoluble ECM 5) obtained from various tissues have been used in studies on cell growth and differentiation. Type I collagen is a major structural protein and is found in large quantities in various parts of the body, especially in the skin, bones, teeth and tendons. A decrease in the production of type I collagen, or that of defective molecules, induces organ deformity or dysfunction and retards embryo and fetus development in extreme cases. [6][7][8] On the other hand, aberrant accumulation of type I collagen in tissues and organs results in organ fibrosis, such as in progressive systemic sclerosis (scleroderma) of the skin, liver fibrosis and pulmonary fibrosis, and also occasionally endangers the life of affected individuals. 7,8) L-Ascorbic acid (vitamin C) is known to be a neutral bioactive agent, and its multifarious activities in many biological systems have been reported. For example, vitamin C increases enzyme activity [9][10][11] ; acts as an inducer of the collagen pathway 12) ; and scavenges free radicals as an antioxidant during oxidant stress. 13,14) An essential function of vitamin C is to act as a cofactor for the hydroxylation of proline and lysine residues in collagen, a major protein component of the body. Vitamin C also increases the transcription rate of procollagen genes and stabilizes procollagen mRNA. 15,16) Its ability to cure scurvy is possibly due to stimulation of collagen synthesis in connective tissues.17) However, vitamin C is unstable in aqueous solutions, even under normal culture conditions at neutral pH and 37°C. To solve this problem, a number of stable derivatives, including L-ascorbic acid 2-sulfate and L-ascorbic acid 2-phosphate (VCP-Na), have been developed. 18,19) VCP-Na shows antiscorbutic activity in guinea pigs, 20,21) and has a stimulatory effect on collagen synthesis in cultured human skin fibroblasts, 22,23) while L-ascorbic acid 2-sulfate does not show these effects. 24)We have recently synthesized a novel lipophilic alkyl vitamin C derivative, sodium isostearyl 2-O-L-ascorbyl phosphate (VCP-IS-Na), which is characterized by its high stability in various aqueous solutions, throughout a wide range of pH values, and its non-reducibility. 25) We have also demonstrated that VCP-IS-Na is superior to VCP-Na with regard to enzymatic hydrolysis by tissue esterase and/or phosphatase to give vitamin C. These findings indicate that vitamin C, released from VCP-IS-Na by enzymatic hydrolysis, exhibits these biological activities.Structurally, the difference between the existing vitamin C derivative VCP-Na and the novel vitamin ...

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“…1991). The 21-aminosteroidal lazeroid, which inhibits experimental brain ischaemia injury by its antioxidant sparing action on brain vitamins C and E (Sato Hall, 1992), may be expected to be of therapeutic worth in AD. The finding that the anti-inflammatory drug indomethacin is of value, supports the view that inflammatory microglial cells are of pathogenic pertinence in AD (Rogers et al 1993).…”

Section: Pharmacology Of N E U R O D E G E N E R a T I O Nmentioning

confidence: 99%

Nutrient and toxin interactions in neurodegenerative disease

Evans

1994

Proc. Nutr. Soc.

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The brain is the most complex organ of the body. Its effective function is dependent on its unique anatomical structure and neuronal cell morphology, together with the efficient coordination of its metabolic and physiological processes. The degenerative diseases of the brain, for example Huntington's, Parkinson's and Alzheimer's disease (AD), are generally characterized by an associated loss of functional neurones, with accompanying motor, memory and cognitive deficits.In the case of familial amyotrophic lateral sclerosis (ALS; Deng et al. 1993), Huntington's disease, early-onset dementia of familial AD (Martin, 1993), and the prion diseases (the spongiform encephalopathies, i.e. Creutzfeldt-Jacob disease and the Gerstmann-Straussler-Scheinker syndrome; Prusiner, 1991), a genetic aetiology has been demonstrated. The larger number of so-called sporadic cases of AD which occur in the 8th and 9th decades of life, suggests that environmental factors are also operative. Even so, recent findings concerning apolipoprotein E €4 allele indicate genetic polymorphisms are significant risk factors in the development of late-onset AD as well . Hence, senile dementia of the Alzheimer type, the most common of the neurodegenerative diseases, appears to be of multifactorial origin, presenting a complex interplay of genetic, environmental, and age-related factors (Calne et al. 1986). B R A I N R E S E A R C HUndertaking studies into the toxicological and nutritional aspects of neurodegeneration, poses a range of ethical, organizational, technical and financial, challenges. Since there is no laboratory test for AD and the definitive diagnosis is dependent on postmortem identification and quantification of the pathognomic intracellular neurofibrillary tangles and extracellular senile plaques within the brain, epidemiological and clinical investigations into AD are extremely problematic. However, tests for cognitive function, and development of new in vivo imaging techniques, namely magnetic resonance imaging and positron emission topography scans, do permit a degree of clinical assessment.The inherent difficulty of research into the brain is compounded not only by the diverse range of neuronal and glial cell types and the complexity of the integrated neural network, but also by the properties of redundancy and plasticity exhibited by the brain. Brain damage related to degenerative change may not become apparent until the loss of neurones reaches a particular threshold level. Hence, cognitive deficits appearing in later life may not be directly caused by senility or the ageing process itself, but may be the result of developmental deficits or toxic damage which has occurred several decades earlier. Studies indicating the major significance of pre-or early postnatal nutrition to infant brain development (Lucas, 1993) and the subsequent development of disease in adult life (Barker et al. 1989), are of particular importance in relation to the nonreplicative nature of neuronal cells. While the significance of proper nutrition in early b...

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Tirilazad Mesylate Protects Vitamins C and E in Brain Ischemia‐Reperfusion Injury

Cited by 63 publications

References 26 publications

Tirilazad Pretreatment Improves Early Cerebral Metabolic and Blood Flow Recovery from Hyperglycemic Ischemia

Tirilazad Pretreatment Improves Early Cerebral Metabolic and Blood Flow Recovery from Hyperglycemic Ischemia

Effect of a Novel Ascorbic Derivative, Disodium Isostearyl 2-O-L-Ascorbyl Phosphate on Human Dermal Fibroblasts: Increased Collagen Synthesis and Inhibition of MMP-1

Nutrient and toxin interactions in neurodegenerative disease

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