Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Neurodegener Dis ; 8(5): 331-44, 2011.
Article in English | MEDLINE | ID: mdl-21311166

ABSTRACT

BACKGROUND/AIMS: Impaired mitochondrial function has been described in Alzheimer's disease. We previously reported that, in neuronal cells, ß-amyloid 1-42 (Aß(1-42)) is targeted to mitochondria. We have also reported that, when incubated with isolated rat brain mitochondria, Aß(1-42) inhibits complex IV, uncouples the mitochondrial respiratory chain, and promotes opening of the membrane permeability transition pore. Here, we further analyzed the targeting and mitotoxicity of Aß(1-42). METHODS AND RESULTS: Immunoelectron microscopy revealed that the mitochondrial targeting of Aß(1-42) was concentration- and time-dependent. Incubation of human neuroblastoma cells with Aß(1-42) increased the release of adenylate kinase, a mitochondrial enzyme released after membrane permeability transition pore opening. However, it failed to trigger DNA fragmentation and apoptosis, suggesting that the ability of this peptide to uncouple the respiratory chain underlies its mitotoxicity and cytotoxicity. Aß(1-42) targeting to mitochondria was blocked by caprospinol, a steroid derivative shown to protect neuronal cells against Aß(1-42)-induced neurotoxicity. Further experiments revealed that the mitotoxic effect of Aß(1-42) is specific to its primary amino acid sequence and suggested that it may be also related to its tertiary structure. Importantly, the mitotoxic effect of Aß(1-42) was not restricted to brain cells, indicating that it is not cell- or tissue-specific. CONCLUSION: Taken together, these results suggest that extracellular Aß(1-42) targets neuronal mitochondria to exert its toxic effects.


Subject(s)
Amyloid beta-Peptides/poisoning , Cytotoxins/poisoning , Drug Delivery Systems/methods , Mitochondria/pathology , Neurons/pathology , Peptide Fragments/poisoning , Amyloid beta-Peptides/administration & dosage , Amyloid beta-Peptides/physiology , Cell Line, Tumor , Cytotoxins/administration & dosage , Cytotoxins/physiology , Extracellular Space/drug effects , Extracellular Space/metabolism , Extracellular Space/physiology , HEK293 Cells , Hep G2 Cells , Humans , Mitochondria/drug effects , Neurons/drug effects , Peptide Fragments/administration & dosage , Peptide Fragments/physiology
2.
Mitochondrion ; 11(1): 13-21, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20817045

ABSTRACT

The impairment of the respiratory chain or defects in the detoxification system can decrease electron transfer efficiency, reduce ATP production, and increase reactive oxygen species (ROS) production by mitochondria. Accumulation of ROS results in oxidative stress, a hallmark of neurodegenerative diseases such as Alzheimer's disease (AD). ß-amyloid has been implicated in the pathogenesis of AD, and its accumulation may lead to degeneration of neuronal or non-neuronal cells. There is evidence that ß-amyloid interacts with mitochondria but little is known concerning the significance of this interaction in the physiopathology of AD. This review explores possible mechanisms of ß-amyloid-induced mitochondrial toxicity.


Subject(s)
Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Mitochondria/drug effects , Amyloid beta-Peptides/pharmacology , Animals , Cell Line , Humans , Mitochondria/metabolism , Mitochondria/pathology , Rats
3.
Med Chem ; 6(3): 123-40, 2010 May.
Article in English | MEDLINE | ID: mdl-20438444

ABSTRACT

We report herein the synthesis and biological evaluation of dimethyl-carbamic acid 2,3-bis-dimethylcarbamoyloxy-6-(4-ethyl-piperazine-1-carbonyl)-phenyl ester (SP-04), a new drug candidate that is designed to offer a multi-target therapeutic neuroprotective approach as a treatment for Alzheimer's disease (AD). SP-04 inhibits acetylcholinesterase (AchE) activity both in vitro and in vivo, and induces a dose-dependent increase in Ach levels. SP-04 releases the metabolite 4-(4-ethyl-piperazin-1-yl)-1-(2,3,4-trihydroxy-phenyl)-butan-1-one (SP-04m). Both SP-04 and SP-04m are s1-receptor antagonists supporting their interest in relieving symptoms related to psychosis, a non-cognitive condition often associated with AD. SP-04m displays important antioxidant properties and both SP-04 and SP-04m offers neuroprotection against Ab42 toxicity in various neuronal cell lines. In addition, both SP-04 and SP-04m protect neuronal cells and rat brain mitochondria exposed to various mitochondrial respiratory chain complex toxins. Taken together these data suggest that the SP-04 multi-targeting approach might offer a novel therapeutic strategy for the treatment of AD.


Subject(s)
Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacology , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacology , Receptors, sigma/antagonists & inhibitors , Acetylcholinesterase , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Animals , Antioxidants/chemical synthesis , Antioxidants/pharmacology , Brain/drug effects , Carbamates/chemical synthesis , GPI-Linked Proteins/antagonists & inhibitors , Gallic Acid/analogs & derivatives , Gallic Acid/chemical synthesis , HEK293 Cells , Humans , Male , Mitochondria/drug effects , PC12 Cells , Peptide Fragments/metabolism , Piperazines/chemical synthesis , Prodrugs/chemical synthesis , Rats , Rats, Long-Evans , Sigma-1 Receptor
4.
Expert Opin Investig Drugs ; 18(3): 265-76, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19243278

ABSTRACT

In search of new drugs for Alzheimer's disease, we departed from the classic concepts and investigated the ability of normal and Alzheimer's disease brain to convert cholesterol to steroids, otherwise known as neurosteroids. We identified 22R-hydroxycholesterol to be present in much lower levels in the hippocampus and frontal cortex of Alzheimer's disease than in tissue from age-matched controls. 22R-hydroxycholesterol was shown to protect against beta-amyloid (A beta(42))-induced neurotoxicity and block the formation of A beta oligomers. In search of a 22R-hydroxycholesterol stable analog, we identified the naturally occurring heterospirostenol, (22R,25R)-20 alpha-spirost-5-en-3beta-yl hexanoate (caprospinol). The mechanism of action underlying the neuroprotective properties of caprospinol involves, first, the ability of the compound to bind A beta(42) and, second, its interaction with components of the mitochondria respiratory chain. Samaritan Pharmaceuticals is developing caprospinol as a disease-modifying drug for the treatment of Alzheimer's disease. Samaritan Pharmaceuticals filed for an Investigational New Drug application with the FDA in 2006. The pharmacokinetic and pharmacodynamic parts of the application were found satisfactory, and the FDA has requested that additional information is submitted in support of caprospinol's safety prior to initiating the Phase I clinical study.


Subject(s)
Diosgenin/analogs & derivatives , Neurons/drug effects , Steroids/pharmacology , Amyloid/metabolism , Animals , Binding Sites , Caproates , Diosgenin/chemistry , Diosgenin/pharmacology , Drug Discovery , Humans , Mitochondria/metabolism , Neurons/metabolism , Spirostans , Steroids/chemistry
5.
Steroids ; 71(8): 725-35, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16787656

ABSTRACT

Abeta(1-42) has been shown to uncouple the mitochondrial respiratory chain and promote the opening of the membrane permeability transition (MPT) pore, leading to cell death. We have previously reported that the spirostenol derivative (22R, 25R)-20alpha-spirost-5-en-3beta-yl hexanoate (SP-233) protects neuronal cells against Abeta(1-42) toxicity by binding to and inactivating the peptide. Picomolar concentrations of Abeta(1-42) decreased the mitochondrial respiratory coefficient in mitochondria isolated from the rat forebrain, and this decrease was partially reversed by SP-233. SP-233 abolished the uncoupling of oxidative phosphorylation induced by carbonyl cyanide 3-chlorophenylhydrazone on isolated mitochondria. These results are consistent with a direct effect of SP-233 on the MPT. Moreover, SP-233 displayed a neuroprotective effect on SK-N-AS human neuroblastoma cells treated with the MPT promoter, phenylarsine oxide. Treatment of SK-N-AS cells with Abeta(1-42) resulted in an accumulation of the peptide in the mitochondrial matrix; SP-233 completely scavenged Abeta(1-42) from the matrix. In addition, SP-233 protected the cells against mitochondrial toxins targeting complexes IV and V of the respiratory chain. These results indicate that Abeta(1-42) and SP-233 exert direct effects on mitochondrial function and SP-233 protects neuronal cells against Abeta-induced toxicity by targeting Abeta directly.


Subject(s)
Amyloid beta-Peptides/pharmacology , Mitochondria/drug effects , Mitochondria/metabolism , Neurons/cytology , Neurons/drug effects , Peptide Fragments/pharmacology , Spiro Compounds/pharmacology , Adenosine Triphosphatases/metabolism , Animals , Brain/drug effects , Caproates/pharmacology , Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/pharmacology , Carrier Proteins/metabolism , Cyclosporine/pharmacology , Humans , Membrane Proteins/metabolism , Mitochondrial Proton-Translocating ATPases , Models, Biological , Multiprotein Complexes/metabolism , Neuroblastoma/drug therapy , Neuroprotective Agents/pharmacology , Rats , Respiration/drug effects , Spirostans/pharmacology , Time Factors , Tumor Cells, Cultured
SELECTION OF CITATIONS
SEARCH DETAIL
...