1,721,047 research outputs found
Mitochondria, oxidative stress and PARP-1 network: a new target for neuroprotective effects of tetracyclines?
No full textThe role of vascular factors in late-onset sporadic Alzheimer's disease. Genetic and molecular aspects
No full textAlzheimer's disease (AD) is a late-onset progressive neurodegenerative disorder which results in the irreversible loss of cortical neurons, particularly in the associative neocortex and hippocampus. AD is the most common form of dementia in the elderly. Apart from the neuronal loss, the pathological hallmarks are extracellular senile plaques, containing the peptide beta-amyloid (Abeta), and neurofibrillary tangles. The Abeta cascade hypothesis remains the main pathogenetic model, as suggested by familiar AD, mainly associated to mutation in amyloid precursor protein and presenilin genes. The remaining 95% of AD patients are mostly sporadic late-onset cases, with a complex aetiology due to interactions between environmental conditions and genetic features of the individual. A relationship between genetic and acquired vascular factors and AD has been hypothesized. Many vascular risk factors for AD, such as atherosclerosis, stroke and cardiac disease in the aging individual, could result in cerebrovascular dysfunction and trigger AD pathology. A major vascular susceptibility factor gene is the apolipoprotein E gene, found to be associated with sporadic late-onset AD cases. Another interesting vascular susceptibility gene is angiotensin converting enzyme. Other possible genes include VLDL-R, LRP, NOS3, CST3, OLR1, MTHFR, PON1 and VEGF, but many of the related studies have shown conflicting results. In this paper, we review the role of molecular vascular abnormalities and of the "vascular risk" genes supposed to be involved in the pathogenesis of AD, in an attempt to provide a comprehensive picture of what is known about the mechanisms underlying the role of vascular factors in late-onset sporadic AD
Coenzyme Q10 in neuromuscular and neurodegenerative disorders
No full textCoenzyme Q10 (CoQ10, or ubiquinone) is an electron carrier of the mitochondrial respiratory chain (electron transport chain) with antioxidant properties. In view of the involvement of CoQ10 in oxidative phosphorylation and cellular antioxidant protection a deficiency in this quinone would be expected to contribute to disease pathophysiology by causing a failure in energy metabolism and antioxidant status. Indeed, a deficit in CoQ10 status has been determined in a number of neuromuscular and neurodegenerative disorders. Primary disorders of CoQ10 biosynthesis are potentially treatable conditions and therefore a high degree of clinical awareness about this condition is essential. A secondary loss of CoQ10 status following HMG-Coa reductase inhibitor (statins) treatment has be implicated in the pathophysiology of the myotoxicity associated with this pharmacotherapy. CoQ10 and its analogue, idebenone, have been widely used in the treatment of neurodegenerative and neuromuscular disorders. These compounds could potentially play a role in the treatment of mitochondrial disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological and muscular diseases, from primary CoQ10 deficiency to neurodegenerative disorders. We also briefly report a case of the myopathic form of CoQ10 deficiency
Drugs and mitochondrial diseases: 40 queries and answers.
No full textMitochondrial disorders are a group of metabolic conditions caused by impairment of the oxidative phosphorylation system. The treatment of mitochondrial diseases is still inadequate. Therapies that have been attempted include: respiratory chain cofactors, other metabolites secondarily decreased in mitochondrial disorders, antioxidants, and agents acting on lactic acidosis. However, their role in the treatment of the majority of mitochondrial diseases is still unclear. Furthermore, some drugs may potentially have detrimental effects on mitochondrial dysfunction.
AREAS COVERED:
To critically review this still unclear field, this paper attempts to answer, on the basis of the basic and clinical literature available to date, the 'frequently asked questions', such as: Is valproic acid safe in mitochondrial patients? What about other antiepileptic drugs? May metformin trigger lactic acidosis in mitochondrial patients? Are statins safe in these subjects?
EXPERT OPINION:
Randomized clinical trials are necessary to establish efficacy and safety of drugs. Multicenter collaboration is essential for the advancement of therapy for mitochondrial disorders
.Mitochondria, mitochondrial DNA and Alzheimer's disease. What comes first?
No full textTo date, the beta amyloid (Abeta) cascade hypothesis remains the main pathogenetic model of Alzheimer's disease (AD), but its role in the majority of sporadic AD cases is unclear. The mitochondria play central role in the bioenergetics of the cell and apoptotic cell death. In the past 20 years research has been directed at clarifying the involvement of mitochondria and defects in mitochondrial oxidative phosphorylation in late-onset neurodegenerative disorders, including AD. Morphological, biochemical and genetic abnormalities of the mitochondria in several AD tissues have been reported. Impaired mitochondrial respiration, particularly COX deficiency, has been observed in brain, platelets and fibroblasts of AD patients. The "mitochondrial cascade hypothesis" could explain many of the biochemical, genetic and pathological features of sporadic AD. Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure, increased oxidative stress and accumulation of Abeta, which in a vicious cycle reinforces the mtDNA damage and the oxidative stress. Despite the evidence of mitochondrial dysfunction in AD, no causative mutations in the mtDNA have been detected so far. Indeed, results of studies on the role of mtDNA haplogroups in AD are controversial. In this review we discuss the role of the mitochondria in the cascade of events leading to AD, and we will try to provide an answer to the question "what comes first"
Mitochondrial disorders and drugs: what every physician should know
Full text linkMitochondrial disorders are a group of metabolic conditions caused by impairment of the oxidative phosphorylation system. There is currently no clear evidence supporting any pharmacological interventions for most mitochondrial disorders, except for coenzyme Q10 deficiencies, Leber hereditary optic neuropathy, and mitochondrial neurogastrointestinal encephalomyopathy. Furthermore, some drugs may potentially have detrimental effects on mitochondrial dysfunction. Drugs known to be toxic for mitochondrial functions should be avoided whenever possible. Mitochondrial patients needing one of these treatments should be carefully monitored, clinically and by laboratory exams, including creatine kinase and lactate. In the era of molecular and ‘personalized’ medicine, many different physicians (not only neurologists) should be aware of the basic principles of mitochondrial medicine and its therapeutic implications. Multicenter collaboration is essential for the advancement of therapy for mitochondrial disorders. Whenever possible, randomized clinical trials are necessary to establish efficacy and safety of drugs. In this review we discuss in an accessible way the therapeutic approaches and perspectives in mitochondrial disorders. We will also provide an overview of the drugs that should be used with caution in these patients
.Is there a primary role of the mitochondrial genome in Alzheimer's disease?
No full textThe "mitochondrial cascade hypothesis" could explain many of the biochemical, genetic and pathological features of sporadic Alzheimer's disease (AD). Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure, increased oxidative stress and accumulation of amyloid beta, which in a vicious cycle reinforces mtDNA damage and oxidative stress. Despite the evidence of mitochondrial dysfunction in AD, and despite the cognitive impairment frequently reported in patients with mtDNA mutation, no causative mutation in the mtDNA have been linked to AD. Indeed, results of studies on the role of mtDNA polymorphisms or haplogroups in AD are controversial. In this minireview, we summarize the actual knowledge about the involvement of mtDNA in AD pathology
Neuroprotective effects of tetracyclines: molecular targets, animal models and human disease
No full textTetracyclines are a class of antibiotics which could play a therapeutic role in several neurological disorders. Minocycline, extensively studied in animal models, decreased the size of ischaemic and haemorrhagic infarct. In Parkinson's disease models minocycline protected the nigrostriatal pathway, and in Huntington's disease and motoneuron disease models delayed the progression of disease extending the lifespan. Finally, in human diseases such as stroke and multiple sclerosis tetracyclines seem to play some neuroprotective role. The main biological effects of tetracyclines are the inhibition of microglial activation, the attenuation of apoptosis, and the suppression of reactive oxygen species production. These mechanisms are involved in the pathogenesis of several neurodegenerative disorders. Several reports showed that minocycline reduced mitochondrial Ca(2+) uptake, stabilized mitochondrial membranes, and reduced the release into the cytoplasm of apoptotic factors. Other effects include up-regulation of mitochondrial bcl-2 (an antiapoptotic protein), direct scavenging of reactive oxygen species, and inhibition of mitogen activated protein kinases. It is still unclear which of these mechanisms plays the pivotal role in neuroprotective properties of tetracyclines. The anti-apoptotic effect of tetracyclines probably involves the mitochondrion. The major target for tetracyclines in neurodegeneration could lie within the complex network that links mitochondria, oxidative stress, poly (ADP-ribose) polymerase-1 and apoptosis. Here, we review the neuroprotective effects of tetracyclines in animal models and in human disease, and we focus on their possible mechanism(s) of action, with special regard to mitochondrial dysfunction in neurodegeneration
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