Prevention of glutamate neurotoxicity in cultured neurons by 3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran (CR-6), a scavenger of nitric oxide

Montoliú, Carmina; Llansola, Marta; Sáez, Rosana; Yenes, Susana; Messeguer, Àngel; Felipo, Vicente

doi:10.1016/s0006-2952(99)00104-5

Cited by 19 publications

(38 citation statements)

References 17 publications

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“…, NO, and ONOO Ϫ (Montoliu et al, 1999;Sanvicens et al, 2006). Our results show that MCA from ischemic rats presents an enhanced formation of O 2 .…”

Section: Oxidative Stress and Remodeling After Ischemiasupporting

confidence: 51%

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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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“…, NO, and ONOO Ϫ (Montoliu et al, 1999;Sanvicens et al, 2006). Our results show that MCA from ischemic rats presents an enhanced formation of O 2 .…”

Section: Oxidative Stress and Remodeling After Ischemiasupporting

confidence: 51%

“…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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“…Treatment with the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone (Z-VAD-fmk) inhibited the activation of caspases, but does not appear to be a useful strategy to prevent oxidative stressinduced apoptosis in 661W photoreceptor cells. On the other hand, in the context of this work, we show that CR-6 (a vitamin E analog that has been shown to prevent glutamate neurotoxicity in cultured neurons due to its role as a nitric oxide scavenger (27)), interfered with oxidative stress-induced apoptosis in 661W cells by preventing the activation of the calpainmediated apoptotic pathway.…”

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confidence: 68%

“…In addition to a phenol moiety, its structure contains two non-substituted and highly activated aromatic positions that confer upon the molecule the ability to react with radical species. Thus, the capacity of CR-6 to react with nitrating species such as NO and ONOO Ϫ has already been demonstrated; moreover, CR-6 has been shown to prevent glutamate neurotoxicity in primary cultures of cerebellar neurons by scavenging NO (27). Therefore, CR-6 appealed to us as a worthwhile candidate to study the effect of pretreatment with an antioxidant molecule on 661W cell death induced by SNP since we had already observed that RNI and ROS were involved in 661W cell apoptosis.…”

Section: Cr-6 Acts As a Scavenger Of Ros And Reduces Cell Death In 66mentioning

confidence: 99%

“…However, previous work has demonstrated that CR-6 exhibits a potent inhibitory activity of lipid peroxidation induced in rat liver microsomes, which could constitute evidence of ROS scavenging by CR-6 (56). Moreover, it has been suggested that scavenging of ROS could have been a contribution to the protective effect exhibited by CR-6 in primary cultures of cerebellar neurons (27). Panel c illustrates the presence of nitrites in 661W control cells treated with increasing concentrations of SNP and in those pretreated with CR-6.…”

Section: Cr-6 Acts As a Scavenger Of Ros And Reduces Cell Death In 66mentioning

confidence: 99%

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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

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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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Role of nitric oxide and cyclic GMP in glutamate-induced neuronal death

et al. 2001

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Glutamate is the main excitatory neurotransmitter in mammals. However, excessive activation of glutamate receptors is neurotoxic, leading to neuronal degeneration and death. In many systems, including primary cultures of cerebellar neurons, glutamate neurotoxicity is mainly mediated by excessive activation of NMDA receptors, leading to increased intracellular calcium which binds to calmodulin and activates neuronal nitric oxide synthase (NOS), increasing nitric oxide (NO) which in turn activates guanylate cyclase and increases cGMP. Inhibition of NOS prevents glutamate neurotoxicity, indicating that NO mediates glutamate-induced neuronal death in this system. NO generating agents such as SNAP also induce neuronal death. Compounds that can act as "scavengers" of NO such as Croman 6 (CR-6) prevent glutamate neurotoxicity. The role of cGMP in the mediation of glutamate neurotoxicity remains controversial. Some reports indicate that cGMP mediates glutamate neurotoxicity while others indicate that cGMP is neuroprotective. We have studied the role of cGMP in the mediation of glutamate and NO neurotoxicity in cerebellar neurons. Inhibition of soluble guanylate cyclase prevents glutamate and NO neurotoxicity. There is a good correlation between inhibition of cGMP formation and neuroprotection. Moreover 8-Br-cGMP, a cell permeable analog of cGMP, induced neuronal death. These results indicate that increased intracellular cGMP is involved in the mechanism of neurotoxicity. Inhibitors of phosphodiesterase increased extracellular but not intracellular cGMP and prevented glutamate neurotoxicity. Addition of cGMP to the medium also prevented glutamate neurotoxicity. These results are compatible with a neurotoxic effect of increased intracellular cGMP and a neuroprotective effect of increased extracellular cGMP.

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Prevention of glutamate neurotoxicity in cultured neurons by 3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran (CR-6), a scavenger of nitric oxide

Cited by 19 publications

References 17 publications

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)

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

Role of nitric oxide and cyclic GMP in glutamate-induced neuronal death

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