Pioglitazone activates paraoxonase-2 in the brain: A novel neuroprotective mechanism

Blackburn, Jennifer K.; Curry, Daniel W.; Thomsen, Anna N.; Roth, Robert H.; Elsworth, John D.

doi:10.1016/j.expneurol.2020.113234

Cited by 19 publications

(11 citation statements)

References 10 publications

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“… 71 Recently, it was shown that a portion of this neuroprotection may be due to paraoxonase-2 activation, which in turn enhances mitochondrial function and reduces oxidative stress. 72 A more recent study highlights remarkable improvement in long-term cognition following TBI after chronic pioglitazone administration, starting 45 days post-injury. 73 Interestingly, this cognitive improvement did not coincide with an increase in PGC-1α in animals treated with pioglitazone, which shows that pioglitazone may not be producing transcriptional changes but rather targeting mitoNEET to generate cognitive improvement.…”

Section: Discussionmentioning

confidence: 99%

Clinically relevant mitochondrial-targeted therapy improves chronic outcomes after traumatic brain injury

Hubbard

Spry

Gooch

et al. 2021

Brain

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Pioglitazone, an FDA-approved compound, has been shown to target the novel mitochondrial protein mitoNEET and produce short-term neuroprotection and functional benefits following traumatic brain injury. To expand on these findings, we now investigate the dose- and time-dependent effects of pioglitazone administration on mitochondrial function after experimental traumatic brain injury. We then hypothesize that optimal pioglitazone dosing will lead to ongoing neuroprotection and cognitive benefits that are dependent on pioglitazone-mitoNEET signalling pathways. We show that delayed intervention is significantly more effective than early intervention at improving acute mitochondrial bioenergetics in the brain after traumatic brain injury. In corroboration, we demonstrate that mitoNEET is more heavily expressed, especially near the cortical contusion, in the 18 h following traumatic brain injury. To explore whether these findings relate to ongoing pathological and behavioural outcomes, mice received controlled cortical impact followed by initiation of pioglitazone treatment at either 3 or 18 h post-injury. Mice with treatment initiation at 18 h post-injury exhibited significantly improved behaviour and tissue sparing compared to mice with pioglitazone initiated at 3 h post-injury. Further using mitoNEET knockout mice, we show that this therapeutic effect is dependent on mitoNEET. Finally, we demonstrate that delayed pioglitazone treatment improves serial motor and cognitive performance in conjunction with attenuated brain atrophy after traumatic brain injury. This study illustrates that mitoNEET is the critical target for delayed pioglitazone intervention after traumatic brain injury, mitochondrial-targeting is highly time-dependent after injury and there is an extended therapeutic window to effectively treat mitochondrial dysfunction after brain injury.

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Section: Discussionmentioning

confidence: 99%

Clinically relevant mitochondrial-targeted therapy improves chronic outcomes after traumatic brain injury

Hubbard

Spry

Gooch

et al. 2021

Brain

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“…96 Further, several studies have pointed to the effect of pioglitazone on increased expression of the antioxidant protein PON2. 100,101 Malondialdehyde (MDA) is one of the products generated from the peroxidation of fatty acids, and an increase in the levels of reactive oxygen species has been positively correlated with overexpression of MDA. 102,103 Pioglitazone has also been found to reduce oxidative stress through a reduction in the levels of MDA and inhibition of ROS production and inflammatory pathways; this further verifies its potent antioxidant activity.…”

Section: Dovepressmentioning

confidence: 99%

“… 95 When this receptor is activated, calcium enters into the neurons and binds to calmodulin to form the Ca 2 C/CaM complex, which is recognized by multiple enzymes and induces a molecular signaling cascade whose main function is to reshape synaptic structure and physiology, as well as regulate the expression of genes necessary for the formation of LTM. 100 It is considered that CaMKII is one of the main targets of Ca 2 C/CaM, and accordingly, CaMKII activity is increased in response to learning and its inhibition causes LTM impairment.…”

Section: Introductionmentioning

confidence: 99%

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Protective Effects of Pioglitazone on Cognitive Impairment and the Underlying Mechanisms: A Review of Literature

Alhowail¹,

Alsikhan²,

Alsaud³

et al. 2022

DDDT

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Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is known to have anti-inflammatory and anti-oxidant effects on the brain, and its clinical potential in the treatment of cognitive impairment in diseases such as Alzheimer's disease (AD) and Parkinson disease (PD) is currently being explored. This review focused on the reported beneficial effects of pioglitazone on cognitive dysfunction and summarized the associated mechanisms associated with pioglitazone-induced improvement in cognitive dysfunction. Our review of the relevant literature indicated that there is conclusive evidence of the effect of pioglitazone on improving cognitive impairment via its agonistic effect on PPAR-γ. Further, several mechanisms of action have been reported, and these include enhanced NF-kB and p38 activity; regulation of the pro-inflammatory cytokines IL-1, IL-6, and TNF-α; inhibition of Aβ production; alterations in the levels of mitochondrial proteins such as mitoNEET; regulation of protein kinases such as CDK5 and JNK; regulation of ROS and MDA levels and the levels of the antioxidant proteins TRX1 and PON2; and increased expression of thyroid hormone receptors. Despite these promising findings, pioglitazone treatment is also associated with cardiovascular risks, such as weight gain and edema, which subsequently increase the risk of mortality. Further, it has been documented that pioglitazone may be unable to cross the blood–brain barrier when administered in certain forms, and it can also cause cell death when administered at high concentrations. Therefore, further research is required to explore the effects of acute and chronic pioglitazone treatment on memory function and the associated risks, in order to determine its clinical applicability in the treatment of cognitive disorders. Nonetheless, the current literature does demonstrate that pioglitazone promotes the function of PPAR receptors in ameliorating inflammation, oxidative stress, amyloidogenesis, and hypothyroidism, and enhancing neurogenesis, synaptic plasticity, and mitochondrial function. Therefore, these mechanisms of PPAR receptors warrant further investigation in order to establish the clinical applicability of pioglitazone in the treatment of cognitive disorders, such as PD and AD, and neuronal impairment in conditions such as diabetes.

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“…It is a peroxisome proliferator-activated receptor gamma (PPARγ) agonist and alters the transcription of genes implicated in fatty acid oxidation, which result in metabolic changes ( 41 ). A variety of neuroprotective mechanisms have been attributed to PPARγ, including the induction of genes involved in oxidative stress defense, induction of anti-inflammatory responses, and stimulation of mitochondrial biogenesis ( 42 ). Pioglitazone was shown to provide effective neuroprotection in an animal model of ischemic stroke, although the exact mechanism of action of its neuroprotective effect was not determined ( 43 ).…”

Section: Strokementioning

confidence: 99%

Anti-inflammatory and Neuroprotective Agents in Clinical Trials for CNS Disease and Injury: Where Do We Go From Here?

et al. 2020

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Neurological disorders are major contributors to death and disability worldwide. The pathology of injuries and disease processes includes a cascade of events that often involve molecular and cellular components of the immune system and their interaction with cells and structures within the central nervous system. Because of this, there has been great interest in developing neuroprotective therapeutic approaches that target neuroinflammatory pathways. Several neuroprotective anti-inflammatory agents have been investigated in clinical trials for a variety of neurological diseases and injuries, but to date the results from the great majority of these trials has been disappointing. There nevertheless remains great interest in the development of neuroprotective strategies in this arena. With this in mind, the complement system is being increasingly discussed as an attractive therapeutic target for treating brain injury and neurodegenerative conditions, due to emerging data supporting a pivotal role for complement in promoting multiple downstream activities that promote neuroinflammation and degeneration. As we move forward in testing additional neuroprotective and immune-modulating agents, we believe it will be useful to review past trials and discuss potential factors that may have contributed to failure, which will assist with future agent selection and trial design, including for complement inhibitors. In this context, we also discuss inhibition of the complement system as a potential neuroprotective strategy for neuropathologies of the central nervous system.

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Pioglitazone activates paraoxonase-2 in the brain: A novel neuroprotective mechanism

Cited by 19 publications

References 10 publications

Clinically relevant mitochondrial-targeted therapy improves chronic outcomes after traumatic brain injury

Clinically relevant mitochondrial-targeted therapy improves chronic outcomes after traumatic brain injury

Protective Effects of Pioglitazone on Cognitive Impairment and the Underlying Mechanisms: A Review of Literature

Anti-inflammatory and Neuroprotective Agents in Clinical Trials for CNS Disease and Injury: Where Do We Go From Here?

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