Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease

Sato, Toshio; Hanyu, Haruo; Hirao, Kentaro; Kanetaka, Hidekazu; Sakurai, Hirofumi; Iwamoto, Toshihiko

doi:10.1016/j.neurobiolaging.2009.10.009

Cited by 351 publications

(287 citation statements)

References 33 publications

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“…Previously, pioglitazone was assessed in 42 Alzheimer's patients accompanied with type II diabetes mellitus for 6 months. Interestingly, patients receiving pioglitazone treatment had increased regional cerebral blood flow in the parietal lobe and cognitive improvement, as well as enhanced insulin sensitivity (69). Pioglitazone has also been used as an adjunct to antipsychotics, resulting in the reduction of negative symptoms in schizophrenia (70, 71).…”

Section: Discussionmentioning

confidence: 99%

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

et al. 2018

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Schizophrenia is a devastating illness that affects over 2 million people in the U.S. and costs society billions of dollars annually. New insights into the pathophysiology of schizophrenia are needed to provide the conceptual framework to facilitate development of new treatment strategies. We examined bioenergetic pathways in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia and control subjects using western blot analysis, quantitative real-time polymerase chain reaction, and enzyme/substrate assays. Laser-capture microdissection-qPCR was used to examine these pathways at the cellular level. We found decreases in hexokinase (HXK) and phosphofructokinase (PFK) activity in the DLPFC, as well as decreased PFK1 mRNA expression. In pyramidal neurons, we found an increase in monocarboxylate transporter 1 mRNA expression, and decreases in HXK1, PFK1, glucose transporter 1 (GLUT1), and GLUT3 mRNA expression. These results suggest abnormal bioenergetic function, as well as a neuron-specific defect in glucose utilization, in the DLPFC in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

et al. 2018

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“…Rosiglitazone stimulated neuronal mitochondrial biogenesis and reduced memory deficits in mouse models of AD [75][76][77]. A small clinical trial of 32 patients with mild AD showed significant improvements with pioglitazone treatment on both the AD Assessment Scale-Cognitive subscale scores and Wechsler Memory Scale-Revised Logical Memory Performance tests [92,93]. The patients also had improved cerebral blood flow in parietal lobes [93].…”

Section: Mitochondrial Bioenergetics As a Therapeutic Targetmentioning

confidence: 99%

“…A small clinical trial of 32 patients with mild AD showed significant improvements with pioglitazone treatment on both the AD Assessment Scale-Cognitive subscale scores and Wechsler Memory Scale-Revised Logical Memory Performance tests [92,93]. The patients also had improved cerebral blood flow in parietal lobes [93]. A Phase III clinical trial of pioglitazone for MCI due to AD is currently underway (ClinicalTrials.gov identifier: NCT01931566).…”

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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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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“…Clinical trials are focusing on the use of gamma peroxisome proliferator-activated receptor (PPARγ) agonists such as rosiglitazone and pioglitazone as an alternative therapy to enhance cognition 106 . PPARγ agonists induce the transcription of specific genes leading to the increase in the body's sensitivity to insulin, amongst other effects, and were first used in clinical trials with the aim of treating diabetes mellitus and atherosclerosis (http://www.diabetesselfmanagement.com/Articles/ Diabetes-Definitions/ppar_agonists/).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Os efeitos do estresse na função do eixo hipotalâmico-pituitário-adrenal em indivíduos com esquizofrenia

Guest

Martins-de-Souza²,

Rahmoune

et al. 2012

Arch. Clin. Psychiatry (São Paulo)

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Over the last few decades, evidence has been emerging that the pathogenesis of psychiatric disorders such as schizophrenia can involve perturbations of the hypothalamic-pituitary-adrenal (HPA) axis. Variations in the manifestation of these effects could be related to the differences in clinical symptoms between affected individuals as well as to differences in treatment response. Such effects can also arise from the complex interaction between genes and environmental factors. Here, we review the effects of maternal stress on abnormalities in HPA axis regulation and the development of psychiatric disorders including schizophrenia. Studies in this area may prove critical for increasing our understanding of the multi-dimensional nature of schizophrenia. Further research in this area could ultimately lead to the development of improved diagnostics and novel therapeutic approaches for treating this debilitating psychiatric condition.Guest FL, et al. / Rev Psiq Clín. 2013;40(1):20-7 Keywords: Psychiatric disorders, schizophrenia, HPA axis dysfunction, diagnosis, biomarkers. ResumoNas últimas décadas, têm surgido evidências sugerindo que a patogênese de desordens psiquiátricas, tais como a esquizofrenia, pode envolver perturbações no eixo hipotalâmico-pituitário-adrenal (HPA). Variações na manifestação desses efeitos poderiam estar relacionadas a diferenças em sintomas clínicos entre os indivíduos afetados, assim como a diferenças na resposta ao tratamento. Tais efeitos podem também ser originados de complexas interações entre genes e fatores ambientais. Aqui, revisamos os efeitos do estresse maternal em anormalidades na regulação do eixo HPA e desenvolvimento de desordens psiquiátricas, incluindo a esquizofrenia. Estudos nessa área podem gerar o aumento do nosso entendimento da natureza multidimensional da esquizofrenia. Posterior pesquisa nesse campo poderia, em última instância, levar ao desenvolvimento de melhores diagnósticos e novas abordagens terapêuticas para essa debilitante condição psiquiátrica.Guest FL, et al. / Rev Psiq Clín. 2013;40(1):20-7 Palavras-chave: Desordens psiquiátricas, esquizofrenia, disfunção do eixo HPA, diagnóstico, biomarcadores.

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Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease

Cited by 351 publications

References 33 publications

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

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

Os efeitos do estresse na função do eixo hipotalâmico-pituitário-adrenal em indivíduos com esquizofrenia

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