ArticleJournal of molecular medicine (Berlin, Germany)2021
Neuroprotective and antioxidative effects of pioglitazone in brain tissue adjacent to the ischemic core are mediated by PI3K/Akt and Nrf2/ARE pathways.
Article in Journal of molecular medicine (Berlin, Germany), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 29 citations in OpenAlex.
- Pioglitazone mitigates early brain injury by suppressing neuroinflammation and oxidative stress after subarachnoid hemorrhage: a rodent model study.Annals of medicine · 2026Article
- PPARγ Signaling in the Central Nervous System: A Review of the Implications in Synaptic Plasticity, Neuroinflammatory and Neoplastic Processes.Neurochemical research · 2026Review
- Pioglitazone protects against trimethyltin hippocampal injury by reducing pyroptosis, mitochondrial dysregulation and ER stress.Scientific reports · 2026Article
- Effect of Locally-Administered Pioglitazone on the Survival of Dermal Skin Flaps in an Experimental Study on Rats.Cureus · 2026Article
- The possible mechanisms linking chronic obstructive pulmonary disease and coronary atherosclerosis based on coronary computed tomography angiography and animal experiments.Frontiers in physiology · 2026Article
- Development of a Human Preclinical Platform for the Identification of Neuroprotective Compounds.The European journal of neuroscience · 2025Article
- Ineffectiveness of pioglitazone in cognitive impairment induced by cyclophosphamide, methotrexate, and fluorouracil via oxidative stress and neuroinflammation.Frontiers in neuroscience · 2025Article
- Exploring the molecular mechanisms of PPARγ agonists in modulating memory impairment in neurodegenerative disorders.Molecular biology reports · 2024Review
- Pioglitazone, a peroxisome proliferator‑activated receptor γ agonist, induces cell death and inhibits the proliferation of hypoxic HepG2 cells by promoting excessive production of reactive oxygen species.Oncology letters · 2024Article
- Interactions Between the Ubiquitin-Proteasome System, Nrf2, and the Cannabinoidome as Protective Strategies to Combat Neurodegeneration: Review on Experimental Evidence.Neurotoxicity research · 2024Review
- Article
- Discovery of 2-deoxy glucose surfaced mixed layer dendrimer: a smart neuron targeted systemic drug delivery system for brain diseases.Theranostics · 2024Article
- The Protection of EGCG Against 6-OHDA-Induced Oxidative Damage by Regulating PPARγ and Nrf2/HO-1 Signaling.Nutrition and metabolic insights · 2024Article
- Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets.Molecules (Basel, Switzerland) · 2023Article
- Cognitive Impairment in Multiple Sclerosis.Bioengineering (Basel, Switzerland) · 2023Review
- Review
- Gintonin, aJournal of ginseng research · 2023Article
- Pioglitazone enhances brain mitochondrial biogenesis and phase II detoxification capacity in neonatal rats with 6-OHDA-induced unilateral striatal lesions.Frontiers in neuroscience · 2023Article
- The impact of aging and oxidative stress in metabolic and nervous system disorders: programmed cell death and molecular signal transduction crosstalk.Frontiers in immunology · 2023Review
- Angiotensin-converting enzyme - human amniotic mesenchymal stem cells improve pulmonary vascular remodeling in rats with pulmonary hypertension by promoting angiogenesis and counteracting inflammation.International journal of clinical and experimental pathology · 2023Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The present study elucidates the neuroprotective mechanisms of the PPARγ (peroxisome proliferator-activated receptor γ) agonist pioglitazone in survival of ischemic neurons following middle cerebral artery occlusion with reperfusion (MCAO). Intracerebroventricular infusion of pioglitazone over 5 days before and 24 or 48 h after MCAO alleviated neurological impairments, inhibited apoptosis 24 h, and activated the PI3K/Akt pathway along with increased phosphorylation of Akt (ser473) and GSK-3β (ser9) in the peri-infarct cortical areas 48 h after MCAO. In primary cortical neurons, pioglitazone suppressed the glutamate-induced release of lactate dehydrogenase by a PPARγ-dependent mechanism. This protective effect was reversed after co-treatment with PI3K and Akt inhibitors, LY294002 and SH-6, respectively. Pioglitazone enhanced the expression of the antioxidative transcription factor Nrf2 and its target gene protein, heme oxidase-1, in the peri-infarct area. Pioglitazone also increased activation of the antioxidant response element (ARE) in neuronal PC12 cells transfected with the pNQO1-rARE plasmid. We demonstrate in primary cortical neurons from Nrf2 knockout mice that the lack of Nrf2 completely abolished the neuroprotective effects of pioglitazone against oxidative and excitotoxic damage. Our results strongly suggest that the neuroprotective effects of PPARγ in peri-infarct brain tissues comprise the concomitant activation of the PI3K/Akt and Nrf2/ARE pathways. KEY MESSAGES: Pioglitazone inhibits apoptosis in ischemic brain tissue. Pioglitazone acting on PPARγ activates PI3K/Akt pathway in ischemic brain tissue. Pioglitazone activates via Nrf2 the antioxidant defense pathway in injured neurons. Pioglitazone activates the antioxidant response element in neuronal PC12 cells. Pioglitazone fails to protect primary neurons lacking Nrf2 against oxidative damage. Activation of PPARγ supports the survival of viable neurons in peri-infarct regions.
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