The Thiazolidinedione Pioglitazone Alters Mitochondrial Function in Human Neuron-Like Cells

Ghosh, Somnath; Patel, Nishant; Rahn, Douglas A.; McAllister, Jenna; Sadeghi, Sina; Horwitz, Geoffrey; Berry, Diana; Wang, Kai Xuan; Swerdlow, Russell H.

doi:10.1124/mol.106.033845

Cited by 101 publications

(82 citation statements)

References 33 publications

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“…Preclinically, pioglitazone restored cerebrovascular function, reduced oxidative stress, and increased mitochondrial respiration [75][76][77]. Pioglitazone was initially tested in the human neuron-like NT2 cell line, where it induced mitochondrial biogenesis, increased mtDNA content and subunit proteins, and reduced mitochondrial oxidative damage [78]. Rosiglitazone stimulated neuronal mitochondrial biogenesis and reduced memory deficits in mouse models of AD [75][76][77].…”

Section: Mitochondrial Bioenergetics As a Therapeutic Targetmentioning

confidence: 99%

“…Rosiglitazone tested in MCI and early AD showed improved delayed recall [94], but failed to show significant cognitive benefits in a subsequent larger trial with over 1400 patients with mild-tomoderate AD (ClinicalTrials.gov identifier: NCT00490568) [95]. One major challenge for these candidates is they have poor BBB penetration [78]. However, if co-transported through the BBB, rosiglitazone and other thiazolidinediones could be therapeutically beneficial in preventing AD.…”

Section: Mitochondrial Bioenergetics As a Therapeutic Targetmentioning

confidence: 99%

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Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

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Section: Mitochondrial Bioenergetics As a Therapeutic Targetmentioning

confidence: 99%

Section: Mitochondrial Bioenergetics As a Therapeutic Targetmentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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“…We also routinely changed the culture medium one day prior to harvesting. Adherent cells were harvested and washed as previously described [20]. All experiments were independently repeated (at least 10 times) to ensure reproducibility.…”

Section: Cell Culturementioning

confidence: 99%

“…Suspended cells were disrupted in a prechilled, 45 ml nitrogen cavitation chamber (Parr Instrument Company, Moline, Ill) as previously described [20].…”

Section: Mitochondrial Enrichmentmentioning

confidence: 99%

“…For cells maintained for at least two weeks in medium containing memantine, APV, neither, or both ("chronic" exposure experiments), cytochrome oxidase and citrate synthase Vmax activities were determined on the whole cell pellets as previously described [20]. Cytochrome oxidase, citrate synthase, and complex I Vmax activities were also determined on enriched mitochondria as previously described [20].…”

Section: Cytochrome Oxidase Citrate Synthase and Complex I Vmax Assaysmentioning

confidence: 99%

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Effects of memantine on mitochondrial function

McAllister

Ghosh

Berry

et al. 2008

Biochemical Pharmacology

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Because NMDA complex and mitochondrial function are related, we hypothesized memantine would influence mitochondrial function. We addressed this in vitro by studying the effects of chronic and acute memantine exposures on mitochondrial function. For acute exposure experiments, mitochondria were isolated from NT2 cells and assayed for electron transport chain (ETC) enzyme function and peroxide production in buffers containing up to 60 uM memantine. For chronic exposure experiments, NT2 cells were maintained for at least two weeks in medium containing up to 60 uM memantine, following which we assayed cells or their mitochondria for ETC enzyme activities, cytochrome oxidase protein levels, oxidative stress, calcium levels, and mitochondrial DNA levels. The ability of the NMDA receptor antagonist aminophosphonovaleric acid (APV) to modify memantine's mitochondrial effects was evaluated. Acute and chronic memantine similarly affected complex I (increased at high concentrations) and IV (decreased at high concentrations) Vmax activities. APV did not alter the effects of chronic memantine exposure on citrate synthase and complex IV. We detected a lower mitochondrial peroxide production rate with acute exposure, and an increased mitochondrial peroxide production rate with chronic exposure. Micromolar memantine concentrations affect mitochondria, some of these effects are directly mediated, and acute and chronic effects may differ.

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Prospects of antidiabetic drugs in the treatment of neurodegenerative disease

Hu,

Wang,

Chen

et al. 2024

Brain-X

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Neurodegenerative diseases (NDs) stand for a group of disorders characterized by the progressive loss of neurons in the brain and peripheral organs, resulting in motor and cognitive dysfunction. The global prevalence of NDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, is on the rise globally, primarily due to an aging population, positioning NDs as an increasing significant public health concern. Despite intensive research, few effective therapies that prevent or delay ND progression have been developed. Mounting evidence indicates that one of the well‐defined risk factors for NDs is type 2 diabetes mellitus, and insulin resistance has also been proven to be related to cognitive decline. Certain antidiabetic drugs, such as glucagon‐like peptide‐1 receptor agonists, peroxisome proliferator‐activated receptor gamma agonists, and metformin, have shown promise in offering neuroprotective benefits and alleviating ND symptoms beyond their glucose‐lowering effects. Although the exact mechanisms remain elusive, these drugs offer a promising novel strategy for managing cognitive disorders. In this review, we first highlight the benefits and specific neuroprotective effects of multiple antidiabetic drugs and discuss the main mechanisms of action of antidiabetic drugs in treating NDs. These mechanisms include reducing protein aggregation and improving apoptosis, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Finally, we summarize clinical trials evaluating these drugs for treating NDs.

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The Thiazolidinedione Pioglitazone Alters Mitochondrial Function in Human Neuron-Like Cells

Cited by 101 publications

References 33 publications

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Effects of memantine on mitochondrial function

Prospects of antidiabetic drugs in the treatment of neurodegenerative disease

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