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Special Issue "Mitochondrial Drugs for Neurodegenerative Diseases"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (31 August 2012)

Special Issue Information

Dear Colleagues,

Mitochondria, cytoplasmic organelles found in virtually every eukaryotic cell, are essential for life and death. In the last two decades tremendous progress has been made in mitochondrial research and has provided significant findings to link mitochondrial dysfunction in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis and Huntington’s disease. Further, recently, several groups developed mitochondrial-targeted antioxidants and tested in cell and mouse models of neurodegenerative diseases. The purpose of this special issue is to assess the current status of mitochondrial therapeutics, particularly mitochondrially targeted molecules in aging and age-related neurodegenerative diseases, and also to discuss the issues related to the development of molecules that cross blood brain barrier, reach mitochondria and protect mitochondria from the toxicity of mutant proteins and other toxic insults.

Prof. Dr. P. Hemachandra Reddy
Guest Editor

Keywords

  • Mitochondria
  • Aging
  • Neurodegenerative Disease
  • Mitochondrial-targeted antioxidants
  • Cyclophilin D
  • Mitochondrial permeability pore
  • Alzheimer\'s Disease
  • Parkinson\'s Disease
  • Calcium Dyshomeostasis

Published Papers (10 papers)

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Review

Open AccessReview Neurotransmitter CART as a New Therapeutic Candidate for Parkinson’s Disease
Pharmaceuticals 2013, 6(1), 108-123; doi:10.3390/ph6010108
Received: 5 November 2012 / Revised: 13 December 2012 / Accepted: 14 January 2013 / Published: 18 January 2013
Cited by 3 | PDF Full-text (241 KB) | HTML Full-text | XML Full-text
Abstract
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. To date, there is no effective treatment that halts its progression. Increasing evidence indicates that mitochondria play an important role in the development of PD. Hence mitochondria-targeted approaches or agents may [...] Read more.
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. To date, there is no effective treatment that halts its progression. Increasing evidence indicates that mitochondria play an important role in the development of PD. Hence mitochondria-targeted approaches or agents may have therapeutic promise for treatment of the disease. Neuropeptide CART (cocaine-amphetamine-regulated transcript), a hypothalamus and midbrain enriched neurotransmitter with an antioxidant property, can be found in mitochondria, which is the main source of reactive oxygen species. Systemic administration of CART has been found to ameliorate dopaminergic neuronal loss and improve motor functions in a mouse model of PD. In this article, we summarize recent progress in studies investigating the relationship between CART, dopamine, and the pathophysiology of PD, with a focus on mitochondria-related topics. Full article
(This article belongs to the Special Issue Mitochondrial Drugs for Neurodegenerative Diseases)
Open AccessReview Mitochondria-Targeted Antioxidant SS31 Prevents Amyloid Beta-Induced Mitochondrial Abnormalities and Synaptic Degeneration in Alzheimer’s Disease
Pharmaceuticals 2012, 5(10), 1103-1119; doi:10.3390/ph5101103
Received: 5 September 2012 / Revised: 4 October 2012 / Accepted: 8 October 2012 / Published: 16 October 2012
Cited by 9 | PDF Full-text (460 KB) | HTML Full-text | XML Full-text
Abstract
In neuronal systems, the health and activity of mitochondria and synapses are tightly coupled. For this reason, it has been postulated that mitochondrial abnormalities may, at least in part, drive neurodegeneration in conditions such as Alzheimer’s disease (AD). Mounting evidence from multiple Alzheimer’s disease cell and mouse models and postmortem brains suggest that loss of mitochondrial integrity may be a key factor that mediates synaptic loss. Therefore, the prevention or rescue of mitochondrial dysfunction may help delay or altogether prevent AD-associated neurodegeneration. Since mitochondrial health is heavily dependent on antioxidant defenses, researchers have begun to explore the use of mitochondria-targeted antioxidants as therapeutic tools to prevent neurodegenerative diseases. This review will highlight advances made using a model mitochondria-targeted antioxidant peptide, SS31, as a potential treatment for AD. Full article
(This article belongs to the Special Issue Mitochondrial Drugs for Neurodegenerative Diseases)
Open AccessReview Unlocking the Door to Neuronal Woes in Alzheimer’s Disease: Aβ and Mitochondrial Permeability Transition Pore
Pharmaceuticals 2010, 3(6), 1936-1948; doi:10.3390/ph3061936
Received: 10 May 2010 / Revised: 10 June 2010 / Accepted: 14 June 2010 / Published: 14 June 2010
Cited by 3 | PDF Full-text (250 KB) | HTML Full-text | XML Full-text
Abstract
Mitochondrial dysfunction occurs early in the progression of Alzheimer’s disease. Amyloid-β peptide has deleterious effects on mitochondrial function and contributes to energy failure, respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species in Alzheimer’s disease. The mechanisms underlying [...] Read more.
Mitochondrial dysfunction occurs early in the progression of Alzheimer’s disease. Amyloid-β peptide has deleterious effects on mitochondrial function and contributes to energy failure, respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species in Alzheimer’s disease. The mechanisms underlying amyloid-β induced mitochondrial stress remain unclear. Emerging evidence indicates that mitochondrial permeability transition pore is important for maintenance of mitochondrial and neuronal function in aging and neurodegenerative disease. Cyclophilin D (Cyp D) plays a central role in opening mitochondrial permeability transition pores, ultimately leading to cell death. Interaction of amyloid-β with cyclophilin D triggers or enhances the formation of mitochondrial permeability transition pores, consequently exacerbating mitochondrial and neuronal dysfunction, as shown by decreased mitochondrial membrane potential, impaired mitochondrial respiration function, and increased oxidative stress and cytochrome c release. Blockade of cyclophilin D by genetic abrogation or pharmacologic inhibition protects mitochondria and neurons from amyloid-β induced toxicity, suggesting that cyclophilin D dependent mitochondrial transition pores are a therapeutic target for Alzheimer’s disease. Full article
(This article belongs to the Special Issue Mitochondrial Drugs for Neurodegenerative Diseases)
Open AccessReview Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases
Pharmaceuticals 2010, 3(4), 839-915; doi:10.3390/ph3040839
Received: 31 December 2009 / Revised: 22 March 2010 / Accepted: 23 March 2010 / Published: 25 March 2010
Cited by 54 | PDF Full-text (810 KB) | HTML Full-text | XML Full-text
Abstract
Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes [...] Read more.
Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal cell death are unresolved. Morphological, biochemical, genetic, as well as cell and animal model studies reveal that mitochondria could have roles in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations, triggering neurodegeneration according to a cell death matrix theory. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review summarizes how mitochondrial pathobiology might contribute to neuronal death in AD, PD, and ALS and could serve as a target for drug therapy. Full article
(This article belongs to the Special Issue Mitochondrial Drugs for Neurodegenerative Diseases)
Open AccessReview Olesoxime (TRO19622): A Novel Mitochondrial-Targeted Neuroprotective Compound
Pharmaceuticals 2010, 3(2), 345-368; doi:10.3390/ph3020345
Received: 23 December 2009 / Revised: 20 January 2010 / Accepted: 25 January 2010 / Published: 28 January 2010
Cited by 20 | PDF Full-text (413 KB) | HTML Full-text | XML Full-text
Abstract
Olesoxime (TRO19622) is a novel mitochondrial-targeted neuroprotective compound undergoing a pivotal clinical efficacy study in Amyotrophic Lateral Sclerosis (ALS) and also in development for Spinal Muscular Atrophy (SMA). It belongs to a new family of cholesterol-oximes identified for its survival-promoting activity on [...] Read more.
Olesoxime (TRO19622) is a novel mitochondrial-targeted neuroprotective compound undergoing a pivotal clinical efficacy study in Amyotrophic Lateral Sclerosis (ALS) and also in development for Spinal Muscular Atrophy (SMA). It belongs to a new family of cholesterol-oximes identified for its survival-promoting activity on purified motor neurons deprived of neurotrophic factors. Olesoxime targets proteins of the outer mitochondrial membrane, concentrates at the mitochondria and prevents permeability transition pore opening mediated by, among other things, oxidative stress. Olesoxime has been shown to exert a potent neuroprotective effect in various in vitro and in vivo models. In particular olesoxime provided significant protection in experimental animal models of motor neuron disorders and more particularly ALS. Olesoxime is orally active, crosses the blood brain barrier, and is well tolerated. Collectively, its pharmacological properties designate olesoxime as a promising drug candidate for motor neuron diseases. Full article
(This article belongs to the Special Issue Mitochondrial Drugs for Neurodegenerative Diseases)
Open AccessReview Oxidative Stress Induced Mitochondrial Failure and Vascular Hypoperfusion as a Key Initiator for the Development of Alzheimer Disease
Pharmaceuticals 2010, 3(1), 158-187; doi:10.3390/ph3010158
Received: 28 November 2009 / Revised: 11 January 2010 / Accepted: 14 January 2010 / Published: 19 January 2010
Cited by 12 | PDF Full-text (815 KB) | HTML Full-text | XML Full-text
Abstract
Mitochondrial dysfunction may be a principal underlying event in aging, including age-associated brain degeneration. Mitochondria provide energy for basic metabolic processes. Their decay with age impairs cellular metabolism and leads to a decline of cellular function. Alzheimer disease (AD) and cerebrovascular accidents [...] Read more.
Mitochondrial dysfunction may be a principal underlying event in aging, including age-associated brain degeneration. Mitochondria provide energy for basic metabolic processes. Their decay with age impairs cellular metabolism and leads to a decline of cellular function. Alzheimer disease (AD) and cerebrovascular accidents (CVAs) are two leading causes of age-related dementia. Increasing evidence strongly supports the theory that oxidative stress, largely due to reactive oxygen species (ROS), induces mitochondrial damage, which arises from chronic hypoperfusion and is primarily responsible for the pathogenesis that underlies both disease processes. Mitochondrial membrane potential, respiratory control ratios and cellular oxygen consumption decline with age and correlate with increased oxidant production. The sustained hypoperfusion and oxidative stress in brain tissues can stimulate the expression of nitric oxide synthases (NOSs) and brain endothelium probably increase the accumulation of oxidative stress products, which therefore contributes to blood brain barrier (BBB) breakdown and brain parenchymal cell damage. Determining the mechanisms behind these imbalances may provide crucial information in the development of new, more effective therapies for stroke and AD patients in the near future. Full article
(This article belongs to the Special Issue Mitochondrial Drugs for Neurodegenerative Diseases)
Open AccessReview Insulin and Insulin-Sensitizing Drugs in Neurodegeneration: Mitochondria as Therapeutic Targets
Pharmaceuticals 2009, 2(3), 250-286; doi:10.3390/ph2030250
Received: 5 November 2009 / Revised: 21 December 2009 / Accepted: 22 December 2009 / Published: 23 December 2009
PDF Full-text (437 KB) | HTML Full-text | XML Full-text
Abstract
Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria [...] Read more.
Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ). Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed. Full article
(This article belongs to the Special Issue Mitochondrial Drugs for Neurodegenerative Diseases)
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Open AccessReview Mitochondrial Drugs for Alzheimer Disease
Pharmaceuticals 2009, 2(3), 287-298; doi:10.3390/ph2030287
Received: 23 October 2009 / Revised: 14 December 2009 / Accepted: 16 December 2009 / Published: 23 December 2009
Cited by 6 | PDF Full-text (919 KB) | HTML Full-text | XML Full-text
Abstract
Therapeutic strategies for Alzheimer disease (AD) have yet to offer a diseasemodifying effect to stop the debilitating progression of neurodegeneration and cognitive decline. Rather, treatments thus far are limited to agents that slow disease progression without halting it, and although much work [...] Read more.
Therapeutic strategies for Alzheimer disease (AD) have yet to offer a diseasemodifying effect to stop the debilitating progression of neurodegeneration and cognitive decline. Rather, treatments thus far are limited to agents that slow disease progression without halting it, and although much work towards a cure is underway, a greater understanding of disease etiology is certainly necessary for any such achievement. Mitochondria, as the centers of cellular metabolic activity and the primary generators of reactive oxidative species in the cell, received particular attention especially given that mitochondrial defects are known to contribute to cellular damage. Furthermore, as oxidative stress has come to the forefront of AD as a causal theory, and as mitochondrial damage is known to precede much of the hallmark pathologies of AD, it seems increasingly apparent that this metabolic organelle is ultimately responsible for much, if not all of disease pathogenesis. In this review, we review the role of neuronal mitochondria in the pathogenesis of AD and critically assess treatment strategies that utilize this upstream access point as a method for disease prevention. We suspect that, with a revived focus on mitochondrial repair and protection, an effective and realistic therapeutic agent can be successfully developed. Full article
(This article belongs to the Special Issue Mitochondrial Drugs for Neurodegenerative Diseases)
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Open AccessReview Mitochondrial Medicine and the Neurodegenerative Mitochondriopathies
Pharmaceuticals 2009, 2(3), 150-167; doi:10.3390/ph2030150
Received: 19 November 2009 / Revised: 27 November 2009 / Accepted: 2 December 2009 / Published: 3 December 2009
Cited by 19 | PDF Full-text (328 KB) | HTML Full-text | XML Full-text
Abstract
Neurodegenerative diseases are a common late-life scourge for which diseasemodifying treatments are sorely needed. Mitochondrial perturbation is commonly observed in these diseases, so pursuing treatment development strategies that target mitochondria or processes affected by mitochondria seems reasonable. This review discusses the rationale [...] Read more.
Neurodegenerative diseases are a common late-life scourge for which diseasemodifying treatments are sorely needed. Mitochondrial perturbation is commonly observed in these diseases, so pursuing treatment development strategies that target mitochondria or processes affected by mitochondria seems reasonable. This review discusses the rationale underlying past and current efforts to treat neurodegenerative diseases using mitochondrial medicine, and tries to predict how future efforts might proceed. Full article
(This article belongs to the Special Issue Mitochondrial Drugs for Neurodegenerative Diseases)
Open AccessReview Coenzyme Q10 and Neurological Diseases
Pharmaceuticals 2009, 2(3), 134-149; doi:10.3390/ph203134
Received: 29 September 2009 / Revised: 26 November 2009 / Accepted: 30 November 2009 / Published: 1 December 2009
Cited by 8 | PDF Full-text (213 KB) | HTML Full-text | XML Full-text
Abstract
Coenzyme Q10 (CoQ10, or ubiquinone) is a small electron carrier of the mitochondrial respiratory chain with antioxidant properties. CoQ10 supplementation has been widely used for mitochondrial disorders. The rationale for using CoQ10 is very powerful when this compound is primary decreased because [...] Read more.
Coenzyme Q10 (CoQ10, or ubiquinone) is a small electron carrier of the mitochondrial respiratory chain with antioxidant properties. CoQ10 supplementation has been widely used for mitochondrial disorders. The rationale for using CoQ10 is very powerful when this compound is primary decreased because of defective synthesis. Primary CoQ10 deficiency is a treatable condition, so heightened “clinical awareness” about this diagnosis is essential. CoQ10 and its analogue, idebenone, have also been widely used in the treatment of other neurodegenerative disorders. These compounds could potentially play a therapeutic role in 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 diseases, from primary CoQ10 deficiency to neurodegenerative disorders. Full article
(This article belongs to the Special Issue Mitochondrial Drugs for Neurodegenerative Diseases)
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