Inhibition of rat liver microsomal lipid peroxidation elicited by simple 2,2-dimethylchromenes and chromans structurally related to precocenes

Casas, Josefina; Gorchs, Gloria.; Sánchez‐Baeza, Francisco; Teixidor, Pilar; Messeguer, Ángel

doi:10.1021/jf00016a011

Cited by 25 publications

(21 citation statements)

References 19 publications

(25 reference statements)

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“…This increase in H 2 O 2 levels was completely abrogated by the radical scavenger CR-6 (3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran) 14,17 ( Figure 1b). Furthermore, H 2 O 2 production was significantly reduced by the Nox inhibitor diphenyleneiodonium (DPI), suggesting a role for the Nox system in H 2 O 2 generation.…”

Section: Resultsmentioning

confidence: 98%

Redox survival signalling in retina-derived 661W cells

et al. 2008

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Reactive oxygen species have been implicated in processes involving cellular damage and subsequent cell death, especially in organs such as the eye that are constantly exposed to excitatory signals. However, recent studies have shown that oxidant species can also act as intracellular signalling molecules promoting cell survival, but little is known about this mechanism in the retina. The present study demonstrates for the first time that hydrogen peroxide (H 2 O 2 ) is generated rapidly and acts as a prosurvival signal in response to a variety of apoptotic stimuli in retina-derived 661W cells and in the retinal ganglion cell line RGC-5. Focussing on 661Ws and serum deprivation, we systematically investigated pro-survival and pro-death pathways and discovered that the rapid and transient burst of H 2 O 2 activates the AKT survival pathway. Activation of the apoptotic machinery takes place following the decline of H 2 O 2 to basal levels. To substantiate this proposed pro-survival role of H 2 O 2 , we inhibited the oxidant burst, which exacerbated cell death. Conversely, maintenance of the oxidant signal using exogenous H 2 O 2 enhanced cell survival. Overall, the results presented in this study provide evidence for a novel role of H 2 O 2 in mediating survival of retinal cells in response to apoptotic stimuli.

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Section: Resultsmentioning

confidence: 98%

Redox survival signalling in retina-derived 661W cells

et al. 2008

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“…Ischemic rats were treated either with CR-6 (100 mg/kg in 1 ml of olive oil) or vehicle (1 ml of olive oil) administered orally at 2 and 8 h after the onset of ischemia. CR-6 was chemically synthesized as reported previously (Casas et al, 1992). The dose used was previously shown to protect against oxidative stress damage (Miranda et al, 2007).…”

Section: Methodsmentioning

confidence: 99%

“…We also tested the beneficial effects of CR-6, a structurally simple derivative of vitamin E (Casas et al, 1992), with capacity to scavenge oxygen and nitrogen reactive species. CR-6 has previously shown some beneficial effects against oxidative stress in vivo (Miranda et al, 2007) and in vitro (Montoliu et al, 1999;Sanvicens et al, 2006).…”

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confidence: 99%

Participation of Oxidative Stress on Rat Middle Cerebral Artery Changes Induced by Focal Cerebral Ischemia: Beneficial Effects of 3,4-Dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran (CR-6)

Jiménez‐Altayó¹,

Caracuel²,

Pérez-Asensio³

et al. 2009

J Pharmacol Exp Ther

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Cerebral ischemia followed by reperfusion alters vessel properties of brain arteries in rats, inducing an inflammatory response and excessive generation of reactive oxygen species. This study investigated the participation of oxidative stress on vessel properties after ischemia/reperfusion and the beneficial effects of 3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran (CR-6). The right middle cerebral artery was occluded (90 min) and reperfused (24 h). Sham-operated animals were used as controls. Ischemic rats were treated either with CR-6 (100 mg/kg in 1 ml olive oil) or vehicle (1 ml olive oil) administered orally at 2 and 8 h after the onset of ischemia. The structural, mechanical, and myogenic properties of the middle cerebral artery (MCA) were assessed by pressure myography. Superoxide anion (O 2 . ) production was evaluated by ethidium fluorescence, and protein tyrosine nitrosylation was determined by immunofluorescence. Infarct volume was smaller in rats treated with CR-6. In MCA, ischemia/reperfusion increased wall thickness, cross-sectional area, wall/lumen, and decreased wall stress. CR-6 treatment prevented all of these changes induced by ischemia/reperfusion. However, impaired myogenic response and larger lumen diameter in active conditions observed after ischemia/reperfusion were not modified by CR-6. Treatment with CR-6 prevented the increase in O 2 . production and partially prevented the enhanced protein tyrosine nitrosylation that occurred in response to ischemia/reperfusion. Our findings suggest that oxidative stress is involved in the alterations of MCA properties observed after ischemia/reperfusion and that CR-6 induces protection.Stroke is a complex neurodegenerative disorder characterized by interruption of blood flow supply to the brain. There are several mechanisms involved in ischemic brain injury. Increasing evidence indicates that cerebral ischemia and particularly reperfusion are responsible for oxidative stress caused by free radical production. After reperfusion, there is a surge in production of superoxide anion (O 2 . ), nitric oxide (NO), and peroxynitrite (ONOO Ϫ ). Formation of these species in the vicinity of blood vessels plays an important role in reperfusion-induced injury (Doyle et al., 2008). In healthy individuals, antioxidant activity counterbalances free radical production, but in the case of ischemia, the balance between reactive oxygen species (ROS) and antioxidant activity is shifted toward free radicals, causing oxidative stress.All vascular cells can produce ROS through different sources, including NADPH oxidase, mitochondria, cyclooxygenases, and ABBREVIATIONS: ROS, reactive oxygen species; MCA, middle cerebral artery; I/R, ischemia/reperfusion; CR-6, 3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran; KHS, Krebs-Henseleit solution; DHE, dihydroethidium; SOD, superoxide dismutase; ANOVA, analysis of variance; CSA, cross-sectional area; PEG, polyethylene glycol; WT, wall thickness; D iCa 2ϩ, internal diameter measured in active c...

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“…The synthesis of CR-6 has been described elsewhere (28). Cell Signaling Technology (Beverly, MA) provided antipoly(ADP-ribose) polymerase (PARP) (catalog no.…”

Section: Methodsmentioning

confidence: 99%

Oxidative Stress-induced Apoptosis in Retinal Photoreceptor Cells Is Mediated by Calpains and Caspases and Blocked by the Oxygen Radical Scavenger CR-6

Sanvicens

Gómez‐Vicente

Masip

et al. 2004

Journal of Biological Chemistry

109

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A critical role for reactive oxygen species (ROS) in photoreceptor apoptosis has been established. However, the exact molecular mechanisms triggered by oxidative stress in photoreceptor cell death remain undefined. This study delineates the molecular events that occur after treatment of the photoreceptor cell line 661W with the nitric oxide donor sodium nitroprusside (SNP). Cytosolic calcium levels increased during photoreceptor apoptosis, leading to activation of the calcium-dependent proteases calpains. Furthermore, caspase activation also occurred following SNP insult. However, although treatment with the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone inhibited caspase activity per se in SNP-treated 661W cells, it did not prevent apoptosis. On the other hand, CR-6 (3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran) acted as a scavenger of ROS and reduced 661W photoreceptor apoptosis induced by SNP by preventing the activation of a pathway in which calpains have a key role. In summary, we report for the first time that both caspases and calpains are involved in 661W photoreceptor apoptosis and that calpain activation can be prevented by the ROS scavenger CR-6.The cell death process of apoptosis is characterized by a series of morphological and biochemical changes, including membrane blebbing, loss of plasma membrane asymmetry, chromatin cleavage, and DNA fragmentation (1, 2). Apoptosis plays a central role in tissue modeling during development and, together with the cell-generating process of mitosis, is responsible for the maintenance of cell numbers in multicellular organisms. Deregulation of apoptosis has been well documented in several human pathologies, including cancer, neurodegenerative diseases, and AIDS (3,4). Apoptosis also appears to be responsible for the cell loss seen in several disorders of the retina, including retinitis pigmentosa (a heterogeneous group of inherited disorders), glaucoma, and macular degeneration (5-8). Experiments aimed at unraveling the signaling pathways of apoptosis have identified several distinct mechanisms, and it has largely been accepted that caspases play a key role in both the initiation and execution pathways of apoptosis. However, the involvement of caspases does not seem to be clear-cut in some tissue systems. For example, there is still considerable controversy as to whether caspases play a role in retinal cell death (9 -12). There is also some uncertainty about the role of caspases in neurodegenerative conditions (13-15). Recent work from our laboratory has indicated that photoreceptor death in animal models of retinitis pigmentosa proceeds in the absence of caspase activity, suggesting a caspase-independent mechanism of cell destruction (11,12,16). The exact mechanisms operating in photoreceptor death are still unclear but may involve calpains rather than caspases as the executing enzymes. These studies also suggested a key role for reactive oxygen species (ROS) 1 and reactive nitrogen intermediates (RNI) since inhibitors of...

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Inhibition of rat liver microsomal lipid peroxidation elicited by simple 2,2-dimethylchromenes and chromans structurally related to precocenes

Cited by 25 publications

References 19 publications

Redox survival signalling in retina-derived 661W cells

Redox survival signalling in retina-derived 661W cells

Participation of Oxidative Stress on Rat Middle Cerebral Artery Changes Induced by Focal Cerebral Ischemia: Beneficial Effects of 3,4-Dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran (CR-6)

Oxidative Stress-induced Apoptosis in Retinal Photoreceptor Cells Is Mediated by Calpains and Caspases and Blocked by the Oxygen Radical Scavenger CR-6

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