Incorporation of sodium channel blocking and free radical scavenging activities into a single drug, AM‐36, results in profound inhibition of neuronal apoptosis

Callaway, Jennifer K.; Beart, Philip M; Jarrott, Bevyn; Giardina, Sarah F.

doi:10.1038/sj.bjp.0704018

Cited by 42 publications

(31 citation statements)

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“…This lazaroid compound is a potent antioxidant that inhibits lipid peroxidation in many models of oxidative stress. [33][34][35][36][37] Our data showed that U83836E significantly reduced hemoglobin neurotoxicity in a dose-dependent manner. Combination therapy using both U83836E and the broad-spectrum caspase inhibitor zVADfmk did not yield any additional protection.…”

Section: Discussionmentioning

confidence: 64%

Hemoglobin-Induced Cytotoxicity in Rat Cerebral Cortical Neurons

Wang

Mori

Sumii

et al. 2002

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184

141

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Background and Purpose-Apoptotic-like pathways may contribute to brain cell death after intracerebral hemorrhage. In this study, we used a simplified in vitro model of hemoglobin neurotoxicity to map the caspase cascades involved and to document the role of oxidative stress. Methods-Primary neuronal cultures were obtained from rat cerebral cortex and exposed to hemoglobin to induce cell death. Cytotoxicity was assessed via measurements of mitochondrial viability (MTT assay) and lactate dehydrogenase (LDH assay). Activation of caspase-3, -8, and -9 was measured by Western blot and enzyme activity assays. Various caspase inhibitors (zVADfmk, zDEVDfmk, zIETDfmk, and zLEHDfmk) were tested for neuroprotective efficacy. The role of oxidative stress was assessed with the use of U83836E as a potent scavenger of free radicals. Results-Exposure of primary cortical neurons to hemoglobin induced a dose-and time-dependent cytotoxicity. Western blots showed upregulation of cleaved caspase-3. Enzyme assays showed an increase in caspase-9 -like and caspase-3-like activity. However, caspase inhibition did not result in neuroprotection. In contrast, the free radical scavenger U83836E significantly reduced hemoglobin-induced neuronal death. Combination treatment with both U83836E and the broad spectrum caspase inhibitor zVADfmk did not yield additional protection. Conclusions-Upstream and downstream caspases were upregulated after hemoglobin-induced neurotoxicity in vitro, but only an antioxidant approach with a potent free radical scavenger significantly improved neuronal survival. These data suggest that in addition to the activation of caspase cascades, parallel pathways of oxidative stress may predominate in this model of hemoglobin neurotoxicity.

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Section: Discussionmentioning

confidence: 64%

Hemoglobin-Induced Cytotoxicity in Rat Cerebral Cortical Neurons

Wang

Mori

Sumii

et al. 2002

Stroke

184

141

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“…Staurosporine is typically used as an apoptotic inducer. It has been shown to increase [Ca 2+ ] i and ROS, release of cytochrome c from mitochondria, and to activate caspases (7,21,34,48). In cortical neurons 3-AP, at 10 ìM for 24 h prior to and during the insult, reduced neurotoxicity of 1 ìM staurosporine by 47% (9).…”

Section: Pharmacology Neuroprotective Efficacy and Ec 50 Of 3-ap In Vmentioning

confidence: 99%

Neuroprotective Activity of 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (PAN-811), a Cancer Therapeutic Agent

2006

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ABSTRACT3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a highly-hydrophobic small molecule that was originally developed for cancer therapy (Triapine ® , Vion Pharmaceuticals) due to its ability to inhibit ribonucleotide reductase, a key enzyme required for DNA synthesis. 3-AP has a high affinity for divalent cations, chelating the Fe 2+ at the R2 subunit of the enzyme and inhibiting formation of a tyrosyl radical essential for ribonucleotide reduction. We have demonstrated that 3-AP is also a potent neuroprotectant (as such, it is referred to as "PAN-811"). In vitro it completely blocks ischemic neurotoxicity at a concentration of 0.5 ìM (EC 50 » 0.35 ìM) and hypoxic toxicity at 1.2 ìM (EC 50 » » 0.75 ìM). Full protection of primary cortical and striatal neurons can be achieved with 3-AP when it is added to the medium at up to six hours after an ischemic insult. 3-AP also suppresses cell death induced by neurotoxic agents, including staurosporine, veratridine and glutamate, indicating activity against a central target(s) in the neurodegenerative process. 3-AP acts via neutralization of two important intracellular effectors of excitatory neurotoxicity; calcium and free radicals. Its reported ability to elevate anti-apoptotic proteins is likely to be a consequence of the suppression of excessive intracellular free calcium. In a rat model of transient ischemia, a single bolus delivery of 3-AP 1 h after the initiation of ischemic attack reduced infarct volume by 59% when administered i.c.v. (50 ìg per rat) and by 35% when administered i.v. (1 mg/kg). In Phase I clinical trials in cancer therapy 3-AP had no cardiovascular, CNS or other major adverse effects. Thus, 3-AP has a 77

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“…Therefore, in recent years synthetic and natural antioxidants have gained tremendous interest because of their potential use as neuroprotective compounds in the clinic (Callaway et al, 2001;Herin et al, 2001;Mackensen et al, 2001). Antioxidants were found to decrease reactive oxygen species-induced brain damage produced in different experimental models, as well as after ischemic insults (Uyama et al, 1990;Clements et al, 1993;Watanabe et al, 1994).…”

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confidence: 97%

Neuroprotective effects of carnosine and homocarnosine on pheochromocytoma PC12 cells exposed to ischemia

Tabakman

Lazarovici

Kohen

2002

J of Neuroscience Research

117

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The development of neuroprotective drugs against ischemic insults is hampered by the lack of pharmacological in vitro models. We developed an ischemic model using PC12 cell cultures exposed to oxygen-glucose-deprivation (OGD) followed by reoxygenation (18 hr) under regular atmospheric oxygen level. The toxicity induced in this model, that is partially caused by generation of reactive oxygen species (ROS), was measured morphologically as well as by the release of lactate dehydrogenase (LDH) and the prostaglandin PGE(2) from the cells. Carnosine and homocarnosine, histidine dipeptides antioxidants, found in high concentration in the brain, have been suggested to provide neuroprotection. Using the OGD model we found that 5 mM carnosine and 1 mM homocarnosine provided maximal neuroprotection of about 50% against OGD insult. This neuroprotective effect was similar to that of a known antioxidant, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol), and was not observed in a serum-deprivation toxicity model of PC12 cells, indicating that carnosine and homocarnosine may act as antioxidant-neuroprotective agents in the brain. Our ischemic model may provide a useful tool for investigating the mechanisms involved in the neuroprotection afforded by histidine dipeptides.

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Incorporation of sodium channel blocking and free radical scavenging activities into a single drug, AM‐36, results in profound inhibition of neuronal apoptosis

Cited by 42 publications

References 50 publications

Hemoglobin-Induced Cytotoxicity in Rat Cerebral Cortical Neurons

Hemoglobin-Induced Cytotoxicity in Rat Cerebral Cortical Neurons

Neuroprotective Activity of 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (PAN-811), a Cancer Therapeutic Agent

Neuroprotective effects of carnosine and homocarnosine on pheochromocytoma PC12 cells exposed to ischemia

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