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In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: relevance to Alzheimer's disease and other oxidative stress-related neurodegenerative disorders.
Free Radic Biol Med 2006; 41(11):1694-703FR

Abstract

Tricyclodecan-9-yl-xanthogenate (D609) has in vivo and in vitro antioxidant properties. D609 mimics glutathione (GSH) and has a free thiol group, which upon oxidation forms a disulfide. The resulting dixanthate is a substrate for glutathione reductase, regenerating D609. Recent studies have also shown that D609 protects brain in vivo and neuronal cultures in vitro against the potential Alzheimer's disease (AD) causative factor, Abeta(1-42)-induced oxidative stress and cytotoxicity. Mitochondria are important organelles with both pro- and antiapoptotic factor proteins. The present study was undertaken to test the hypothesis that intraperitoneal injection of D609 would provide neuroprotection against free radical-induced, mitochondria-mediated apoptosis in vitro. Brain mitochondria were isolated from gerbils 1 h post injection intraperitoneally (ip) with D609 and subsequently treated in vitro with the oxidants Fe(2+)/H(2)O(2) (hydroxyl free radicals), 2,2-azobis-(2-amidinopropane) dihydrochloride (AAPH, alkoxyl and peroxyl free radicals), and AD-relevant amyloid beta-peptide 1-42 [Abeta(1-42)]. Brain mitochondria isolated from the gerbils previously injected ip with D609 and subjected to these oxidative stress inducers, in vitro, showed significant reduction in levels of protein carbonyls, protein-bound hydroxynonenal [a lipid peroxidation product], 3-nitrotyrosine, and cytochrome c release compared to oxidant-treated brain mitochondria isolated from saline-injected gerbils. D609 treatment significantly maintains the GSH/GSSG ratio in oxidant-treated mitochondria. Increased activity of glutathione S-transferase, glutathione peroxidase, and glutathione reductase in brain isolated from D609-injected gerbils is consistent with the notion that D609 acts like GSH. These antiapoptotic findings are discussed with reference to the potential use of this brain-accessible glutathione mimetic in the treatment of oxidative stress-related neurodegenerative disorders, including AD.

Authors+Show Affiliations

Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17145558

Citation

Ansari, Mubeen Ahmad, et al. "In Vivo Administration of D609 Leads to Protection of Subsequently Isolated Gerbil Brain Mitochondria Subjected to in Vitro Oxidative Stress Induced By Amyloid Beta-peptide and Other Oxidative Stressors: Relevance to Alzheimer's Disease and Other Oxidative Stress-related Neurodegenerative Disorders." Free Radical Biology & Medicine, vol. 41, no. 11, 2006, pp. 1694-703.
Ansari MA, Joshi G, Huang Q, et al. In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: relevance to Alzheimer's disease and other oxidative stress-related neurodegenerative disorders. Free Radic Biol Med. 2006;41(11):1694-703.
Ansari, M. A., Joshi, G., Huang, Q., Opii, W. O., Abdul, H. M., Sultana, R., & Butterfield, D. A. (2006). In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: relevance to Alzheimer's disease and other oxidative stress-related neurodegenerative disorders. Free Radical Biology & Medicine, 41(11), pp. 1694-703.
Ansari MA, et al. In Vivo Administration of D609 Leads to Protection of Subsequently Isolated Gerbil Brain Mitochondria Subjected to in Vitro Oxidative Stress Induced By Amyloid Beta-peptide and Other Oxidative Stressors: Relevance to Alzheimer's Disease and Other Oxidative Stress-related Neurodegenerative Disorders. Free Radic Biol Med. 2006 Dec 1;41(11):1694-703. PubMed PMID: 17145558.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: relevance to Alzheimer's disease and other oxidative stress-related neurodegenerative disorders. AU - Ansari,Mubeen Ahmad, AU - Joshi,Gururaj, AU - Huang,Quanzhen, AU - Opii,Wycliffe O, AU - Abdul,Hafiz Mohmmad, AU - Sultana,Rukhsana, AU - Butterfield,D Allan, Y1 - 2006/09/08/ PY - 2006/05/16/received PY - 2006/08/28/revised PY - 2006/09/04/accepted PY - 2006/12/6/pubmed PY - 2007/1/11/medline PY - 2006/12/6/entrez SP - 1694 EP - 703 JF - Free radical biology & medicine JO - Free Radic. Biol. Med. VL - 41 IS - 11 N2 - Tricyclodecan-9-yl-xanthogenate (D609) has in vivo and in vitro antioxidant properties. D609 mimics glutathione (GSH) and has a free thiol group, which upon oxidation forms a disulfide. The resulting dixanthate is a substrate for glutathione reductase, regenerating D609. Recent studies have also shown that D609 protects brain in vivo and neuronal cultures in vitro against the potential Alzheimer's disease (AD) causative factor, Abeta(1-42)-induced oxidative stress and cytotoxicity. Mitochondria are important organelles with both pro- and antiapoptotic factor proteins. The present study was undertaken to test the hypothesis that intraperitoneal injection of D609 would provide neuroprotection against free radical-induced, mitochondria-mediated apoptosis in vitro. Brain mitochondria were isolated from gerbils 1 h post injection intraperitoneally (ip) with D609 and subsequently treated in vitro with the oxidants Fe(2+)/H(2)O(2) (hydroxyl free radicals), 2,2-azobis-(2-amidinopropane) dihydrochloride (AAPH, alkoxyl and peroxyl free radicals), and AD-relevant amyloid beta-peptide 1-42 [Abeta(1-42)]. Brain mitochondria isolated from the gerbils previously injected ip with D609 and subjected to these oxidative stress inducers, in vitro, showed significant reduction in levels of protein carbonyls, protein-bound hydroxynonenal [a lipid peroxidation product], 3-nitrotyrosine, and cytochrome c release compared to oxidant-treated brain mitochondria isolated from saline-injected gerbils. D609 treatment significantly maintains the GSH/GSSG ratio in oxidant-treated mitochondria. Increased activity of glutathione S-transferase, glutathione peroxidase, and glutathione reductase in brain isolated from D609-injected gerbils is consistent with the notion that D609 acts like GSH. These antiapoptotic findings are discussed with reference to the potential use of this brain-accessible glutathione mimetic in the treatment of oxidative stress-related neurodegenerative disorders, including AD. SN - 0891-5849 UR - https://www.unboundmedicine.com/medline/citation/17145558/In_vivo_administration_of_D609_leads_to_protection_of_subsequently_isolated_gerbil_brain_mitochondria_subjected_to_in_vitro_oxidative_stress_induced_by_amyloid_beta_peptide_and_other_oxidative_stressors:_relevance_to_Alzheimer's_disease_and_other_oxidative_stress_related_neurodegenerative_disorders_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(06)00563-6 DB - PRIME DP - Unbound Medicine ER -