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Mitochondrial Drugs for Alzheimer Disease.

Bonda DJ, Wang X, Gustaw-Rothenberg KA, Perry G, Smith MA, Zhu X - Pharmaceuticals (Basel) (2009)

Bottom Line: 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.We suspect that, with a revived focus on mitochondrial repair and protection, an effective and realistic therapeutic agent can be successfully developed.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.

ABSTRACT
Therapeutic strategies for Alzheimer disease (AD) have yet to offer a disease-modifying 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.

No MeSH data available.


Related in: MedlinePlus

(A) A mitochondrion with intact components typical of healthy brain: functional oxidative phosphorylation (OXPHOS) system, non-mutated mtDNA, closed, impermeable mPTP. (B) In an aging, AD-prone brain, mitochondrial dysfunction mediates much of the characteristic neurodegeneration. Free radical accumulation produces damages to mtDNA and the OXPHOS system, eliciting further oxidative stress; As Aβ aggregates, it promotes cycliphilin D (cypD)-induced mitochondrial permeability transition pore (mPTP) opening (shown by the dotted line connecting them), collapsing mitochondrial membrane potential (Δψm) and releasing apoptogenic factors. (C) Mitochondrial intervention thus provides an adequate therapeutic access point to AD prevention and control: the antioxidants MitoQ and CoQ10 are under investigation as is the mPTP protector Dimebon.
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pharmaceuticals-02-00287-f001: (A) A mitochondrion with intact components typical of healthy brain: functional oxidative phosphorylation (OXPHOS) system, non-mutated mtDNA, closed, impermeable mPTP. (B) In an aging, AD-prone brain, mitochondrial dysfunction mediates much of the characteristic neurodegeneration. Free radical accumulation produces damages to mtDNA and the OXPHOS system, eliciting further oxidative stress; As Aβ aggregates, it promotes cycliphilin D (cypD)-induced mitochondrial permeability transition pore (mPTP) opening (shown by the dotted line connecting them), collapsing mitochondrial membrane potential (Δψm) and releasing apoptogenic factors. (C) Mitochondrial intervention thus provides an adequate therapeutic access point to AD prevention and control: the antioxidants MitoQ and CoQ10 are under investigation as is the mPTP protector Dimebon.

Mentions: MitoQ is known to concentrate within mitochondria (several hundred-fold) due to the large mitochondrial membrane potential [43]. Its selective accumulation in the metabolic organelle, and its continual recycling by mitochondrial enzymes (including those of the ETC), make MitoQ a much more potent antioxidant than those that are non-targeted [44]. Indeed, studies have confirmed the beneficial role of MitoQ in neurodegenerative models [40,45]. Specifically, in parental leukemic CEM cell cultures, the effects of MitoQ were demonstrated to be remarkably protective after depletion of glutathione (GSH), a regulator of mitochondrial permeability transition [40]. That is, MitoQ: (1) effectively blocked ROS generation; (2) protected mitochondrial protein redox status; (3) preserved the integrity of mitochondrial structures; and (4) blocked cell death after depletion of GSH [40]. Moreover, MitoQ was determined to be a more effective antioxidant for mitochondria, when compared to CoQ10, and was demonstrated to be effective in the absence of a functioning ETC [40]. While these data correspond to cell cultures and non-neuronal tissues, they nonetheless indicate the potential benefits of MitoQ in the treatment of oxidative stress-related disease. In fact, MitoQ is currently under development in phase II clinical trials for Parkinson’s disease and liver damage associated with HCV infection [45], and the results will hopefully shed light on the applicability of the drug to other diseases, such as AD (Figure 1).


Mitochondrial Drugs for Alzheimer Disease.

Bonda DJ, Wang X, Gustaw-Rothenberg KA, Perry G, Smith MA, Zhu X - Pharmaceuticals (Basel) (2009)

(A) A mitochondrion with intact components typical of healthy brain: functional oxidative phosphorylation (OXPHOS) system, non-mutated mtDNA, closed, impermeable mPTP. (B) In an aging, AD-prone brain, mitochondrial dysfunction mediates much of the characteristic neurodegeneration. Free radical accumulation produces damages to mtDNA and the OXPHOS system, eliciting further oxidative stress; As Aβ aggregates, it promotes cycliphilin D (cypD)-induced mitochondrial permeability transition pore (mPTP) opening (shown by the dotted line connecting them), collapsing mitochondrial membrane potential (Δψm) and releasing apoptogenic factors. (C) Mitochondrial intervention thus provides an adequate therapeutic access point to AD prevention and control: the antioxidants MitoQ and CoQ10 are under investigation as is the mPTP protector Dimebon.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2909133&req=5

pharmaceuticals-02-00287-f001: (A) A mitochondrion with intact components typical of healthy brain: functional oxidative phosphorylation (OXPHOS) system, non-mutated mtDNA, closed, impermeable mPTP. (B) In an aging, AD-prone brain, mitochondrial dysfunction mediates much of the characteristic neurodegeneration. Free radical accumulation produces damages to mtDNA and the OXPHOS system, eliciting further oxidative stress; As Aβ aggregates, it promotes cycliphilin D (cypD)-induced mitochondrial permeability transition pore (mPTP) opening (shown by the dotted line connecting them), collapsing mitochondrial membrane potential (Δψm) and releasing apoptogenic factors. (C) Mitochondrial intervention thus provides an adequate therapeutic access point to AD prevention and control: the antioxidants MitoQ and CoQ10 are under investigation as is the mPTP protector Dimebon.
Mentions: MitoQ is known to concentrate within mitochondria (several hundred-fold) due to the large mitochondrial membrane potential [43]. Its selective accumulation in the metabolic organelle, and its continual recycling by mitochondrial enzymes (including those of the ETC), make MitoQ a much more potent antioxidant than those that are non-targeted [44]. Indeed, studies have confirmed the beneficial role of MitoQ in neurodegenerative models [40,45]. Specifically, in parental leukemic CEM cell cultures, the effects of MitoQ were demonstrated to be remarkably protective after depletion of glutathione (GSH), a regulator of mitochondrial permeability transition [40]. That is, MitoQ: (1) effectively blocked ROS generation; (2) protected mitochondrial protein redox status; (3) preserved the integrity of mitochondrial structures; and (4) blocked cell death after depletion of GSH [40]. Moreover, MitoQ was determined to be a more effective antioxidant for mitochondria, when compared to CoQ10, and was demonstrated to be effective in the absence of a functioning ETC [40]. While these data correspond to cell cultures and non-neuronal tissues, they nonetheless indicate the potential benefits of MitoQ in the treatment of oxidative stress-related disease. In fact, MitoQ is currently under development in phase II clinical trials for Parkinson’s disease and liver damage associated with HCV infection [45], and the results will hopefully shed light on the applicability of the drug to other diseases, such as AD (Figure 1).

Bottom Line: 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.We suspect that, with a revived focus on mitochondrial repair and protection, an effective and realistic therapeutic agent can be successfully developed.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.

ABSTRACT
Therapeutic strategies for Alzheimer disease (AD) have yet to offer a disease-modifying 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.

No MeSH data available.


Related in: MedlinePlus