Catalytic antioxidants to treat amyotropic lateral sclerosis

Catalytic antioxidants are comprised of specialised classes of organometallic complexes that can catalyse the decomposition of injurious biological oxidants. These complexes have been shown to prevent the formation of several oxidative markers in spinal cord of G93A amyotropic lateral sclerosis mice and markedly extend survival, even when administered at symptom onset; however, it is now clear that some complexes lacking in antioxidant activity are also protective. New proteomics data suggest that these complexes also induce a broad spectrum of endogenous cellular defense mechanisms. The combination of antioxidant and adaptive resistance effects may explain the remarkable potency of these compounds and may also suggest wide applicability for them in a number of neurodegenerative diseases.     

Long-term administration of a small molecular weight catalytic metalloporphyrin antioxidant, AEOL 10150, protects lungs from radiation-induced injury

PURPOSE: To determine whether administration of a catalytic antioxidant, Mn(III) tetrakis(N,N'-diethylimidazolium-2-yl) porphyrin, AEOL 10150, with superoxide dismutase (SOD) mimetic properties, reduces the severity of radiation-induced injury to the lung from single-dose irradiation (RT) of 28 Gy. METHODS AND MATERIALS: Rats were randomly divided into four different dose groups (0, 1, 10, and 30 mg/kg/day of AEOL 10150), receiving either short-term (1 week) or long-term (10 weeks) drug administration via osmotic pumps. Rats received single-dose irradiation (RT) of 28 Gy to the right hemithorax. Breathing rates, body weights, blood samples, histopathology, and immunohistochemistry were used to assess lung damage. RESULTS: There was no significant difference in any of the study endpoints between the irradiated controls and the three groups receiving RT and short-term administration of AEOL 10150. For the long-term administration, functional determinants of lung damage 20 weeks postradiation were significantly worse for RT + phosphate-buffered saline (PBS) and RT + 1 mg/kg/day of AEOL 10150 as compared with the irradiated groups treated with higher doses of AEOL 10150 (10 or 30 mg/kg/day). Lung histology at 20 weeks revealed a significant decrease in structural damage and collagen deposition in rats receiving 10 or 30 mg/kg/day after radiation in comparison to the RT + PBS and 1 mg/kg/day groups. Immunohistochemistry demonstrated a significant reduction in macrophage accumulation, oxidative stress, and hypoxia in rats receiving AEOL 10150 (10 or 30 mg/kg/day) after lung irradiation compared with the RT + PBS and 1 mg/kg/day groups. CONCLUSIONS: The chronic administration of a novel catalytic antioxidant, AEOL 10150, demonstrates a significant protective effect from radiation-induced lung injury. AEOL 10150 has its primary impact on the cascade of events after irradiation, and adding the drug before irradiation and its short-term administration have no significant additional benefits.     

Flavin-dependent antioxidant properties of a new series of meso-N,N'-dialkyl-imidazolium substituted manganese(III) porphyrins

A number of synthetic manganese complexes exhibit both in vitro and in vivo catalytic antioxidant activities. This study reports that the antioxidant potencies of a new series of meso-N,N'-dialkyl-imidazolium substituted manganese(III) porphyrins are dependent, in part, on their ability to redox cycle with endogenous flavin-dependent oxidoreductases. Inhibition of lipid peroxidation activities of these novel cationic porphyrins was compared using rat brain homogenate as a source of lipids and endogenous oxidoreductases. Iron and ascorbate was used as initiators of lipid peroxidation, and two indices of lipid peroxidation (thiobarbituric acid reactive species (TBARS) and F(2)-isoprostanes) were determined. All meso-N,N'-dialkyl-imidazolium substituted porphyrins tested were potent inhibitors of lipid peroxidation with IC(50) ranging from 0.1 to 34 microM with a metal-dependent potency of Mn(III)>Co(III)>Zn(II). A flavin-dependent oxidoreductase antioxidant process was supported by the ability of the diphenyleneiodonium chloride (DPI, a flavoenzyme inhibitor) to decrease the potency of Mn-porphyrins in the lipid peroxidation model and that Mn-porphyrins stimulate NADPH oxidation in rat brain homogenates. These data suggest that metalloporphyrins may have differential antioxidant effects in tissues due to the presence or absence of flavin-dependent oxidoreductases.     

Mitochondrial dysfunction in ALS

In the present article, we review the many facets of mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease due to loss of upper motor neurons in cerebral cortex and lower motor neurons in brainstem and spinal cord. Accumulating evidence from recent studies suggests that the many, interconnected facets of mitochondrial dysfunction may play a more significant role in the etiopathogenesis of this disorder than previously thought. This notion stems from our expanding knowledge of the complex physiology of mitochondria and of alteration of their properties that might confer an intrinsic susceptibility to long-lived, post-mitotic motor neurons to energy deficit, calcium mishandling and oxidative stress. The wealth of evidence implicating mitochondrial dysfunction as a major event in the pathology of ALS has prompted new studies aimed to the development of new mitochondria-targeted therapies. However, it is now clear that drugs targeting more than one aspect of mitochondrial dysfunction are needed to fight this devastating disease.     

催化性抗氧化剂AEOL-10150对氮芥诱导小鼠急性肝损伤的保护作用

目的： 探讨催化性抗氧化剂AEOL-10150对氮芥诱导小鼠肝损伤的保护作用及其机制。方法： 实验对象为C57BL/6小鼠,采用腹腔单次注射盐酸氮芥（2 mg/kg）构建急性肝损伤模型,染毒后0.5和6 h分别给予AEOL-10150（5 mg/kg）进行治疗干预,染毒3 d后处死小鼠,收集眼球血液和肝组织,观察肝组织大体改变和HE染色后进行组织病理学检测;检测血清谷丙转氨酶（ALT）和谷草转氨酶（AST）活性,肝组织活性氧（ROS）水平、丙二醛（MDA）含量和还原型谷胱甘肽（GSH）含量,肝组织氧化还原调控分子Nrf-2的mRNA表达水平,肝组织髓过氧化物酶（MPO）活性,血清炎症因子TNF-α、IL-1β含量。结果： 2 mg/kg的氮芥单次腹腔注射3 d后可以成功诱导小鼠肝组织氧化损伤和炎症反应。与氮芥染毒组小鼠相比,AEOL-10150治疗组动物肝组织病理损伤程度减轻,血清ALT和AST活性降低,同时肝组织ROS水平和MDA含量显著减少,伴有GSH含量增加和Nrf-2的mRNA和蛋白表达水平降低（均为P<0.05）。此外,AEOL-10150治疗组小鼠的肝组织MPO活性及血清TNF-α、IL-1β浓度较氮芥染毒组显著降低（均为P<0.05）。结论： AEOL-10150能够有效减轻氮芥诱导的小鼠急性肝损伤,其机制可能与直接抗氧化作用及抗炎效应有关。