Neuroprotective and anti-inflammatory properties of a novel non-thiazolidinedione PPARγ agonist in vitro and in MPTP-treated mice

Lecca, Daniele; Nevin, Dk; Mulas, Giovanna; Casu, Maria Antonietta; Diana, Andrea; Rossi, Damiano; Sacchetti, G.; Carta, Annarosa

doi:10.1016/j.neuroscience.2015.04.026

Cited by 38 publications

(40 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, the non-TZD PPARγ agonists FK614 60 , MBX-102 10, 29 , or MDG548 46 reduce insulin insensitivity, hyperglycemia, and inflammation and are neuroprotective 46 . Second, TZDs 28, 111 or the novel ligand TT01001 95 reduce diabetic mitochondrial dysfunction by targeting the mitochondrial protein mitoNEET, which is thought to alleviate other neurological diseases 23, 111 .…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

Griggs

Donahue

Adkins

et al. 2016

The Journal of Pain

View full text Add to dashboard Cite

Thiazolidinedione drugs (TZDs) such as pioglitazone are FDA-approved for the treatment of insulin resistance in type 2 diabetes. However, whether TZDs reduce painful diabetic neuropathy (PDN) remains unknown. Therefore we tested the hypothesis that chronic administration of pioglitazone would reduce PDN in Zucker Diabetic Fatty (ZDFfa/fa) rats. Compared to Zucker Lean (ZLfa/+) controls, ZDF developed: (1) elevated blood glucose, HbA1c, methylglyoxal and insulin; (2) mechanical and thermal hyperalgesia at the hindpaw; (3) increased avoidance of noxious mechanical probes in a mechanical conflict avoidance behavioral assay, the first report of a measure of affective-motivational pain-like behavior in ZDF; and (4) exaggerated lumbar dorsal horn immunohistochemical expression of pressure-evoked phosphorylated extracellular signal-regulated kinase (pERK). Seven weeks of pioglitazone (30 mg · kg−1 · d−1 in food) reduced blood glucose, HbA1c, hyperalgesia, and pERK expression in ZDF. This is the first report to reveal hyperalgesia and spinal sensitization in the same ZDF animals, both evoked by a noxious mechanical stimulus that reflects pressure pain frequently associated with clinical PDN. As pioglitazone provides the combined benefit of reducing hyperglycemia, hyperalgesia, and central sensitization, we suggest that TZDs represent an attractive pharmacotherapy in patients with type 2 diabetes-associated pain.

show abstract

Section: Discussionmentioning

confidence: 99%

Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

Griggs

Donahue

Adkins

et al. 2016

The Journal of Pain

View full text Add to dashboard Cite

show abstract

“…Similarly, a PPARγ agonist called rosiglitazone has also been shown to induce IL-4 expression in the rat brain as well as age-dependent M1 microglial activation in an IL-4 dependent manner (Loane et al, 2009). A novel compound, MDG548, was found to induce neuroprotection in MPTP-treated mice and decrease LPS-induced NF-κB activation in a dose-dependent manner (Lecca et al, 2015). Finally, an N -carbamolylated urethane compound (SNU-BP) has been identified as a novel PPARγ agonist, and inhibits LPS-induced pro-inflammatory cytokine and nitric oxide production as well as potentiates IL-4-induced M2 marker expression in microglia and astrocytes.…”

Section: Pharmacological Approaches For Modulating Microglial Phenotypesmentioning

confidence: 99%

Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases

Song

Suk

2017

Front. Aging Neurosci.

149

112

View full text Add to dashboard Cite

Microglia are the resident innate immune cells of the central nervous system that mediate brain homeostasis maintenance. Microglia-mediated neuroinflammation is a hallmark shared by various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Numerous studies have shown microglial activation phenotypes to be heterogeneous; however, these microglial phenotypes can largely be categorized as being either M1 or M2 type. Although the specific classification of M1 and M2 functionally polarized microglia remains a topic for debate, the use of functional modulators of microglial phenotypes as potential therapeutic approaches for the treatment of neurodegenerative diseases has garnered considerable attention. This review discusses M1 and M2 microglial phenotypes and their relevance in neurodegenerative disease models, as described in recent literature. The modulation of microglial polarization toward the M2 phenotype may lead to development of future therapeutic and preventive strategies for neuroinflammatory and neurodegenerative diseases. Thus, we focus on recent studies of microglial polarization modulators, with a particular emphasis on the small-molecule compounds and their intracellular target proteins.

show abstract

“…In differentiated neuroblastoma SH-SY5Y cells associated with chronic partial inhibition of complex I with rotenone and with loss of PINK1 function, as cellular models related to sporadic and familial PD respectively, rosiglitazone increased mitochondrial biogenesis, increased oxygen consumption, increased mitochondrial mass, ΔΨ m , mtDNA copy number, decreased autophagy and suppressed free radical generation [35]. A novel thiobarbituric-like compound MDG548, which acts as a functional PPARγ agonist, was tested in vitro and in vivo models of PD, MDG548 protected against H 2 O 2 and MPP + neurotoxicity in PC12 cells and in the mice treated with MPTP, the MDG548 reduced reactive microglia and iNOS induction in the substantia nigra [91].…”

Section: Mechanisms Of Protection By Pparγ In Neurodegenerative Diseasesmentioning

confidence: 99%

PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease

Corona

Duchen

2016

Free Radical Biology and Medicine

202

127

View full text Add to dashboard Cite

There is increasing evidence for the involvement of mitochondrial dysfunction and oxidative stress in the pathogenesis of many of the major neurodegenerative and neuroinflammatory diseases, suggesting that mitochondrial and antioxidant pathways may represent potential novel therapeutic targets. Recent years have seen a rapidly growing interest in the use of therapeutic strategies that can limit the defects in, or even to restore, mitochondrial function while reducing free radical generation. The peroxisome proliferation-activated receptor gamma (PPARγ), a ligand-activated transcription factor, has a wide spectrum of biological functions, regulating mitochondrial function, mitochondrial turnover, energy metabolism, antioxidant defence and redox balance, immune responses and fatty acid oxidation. In this review, we explore the evidence for potential beneficial effects of PPARγ agonists in a number of neurological disorders, including Parkinson’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis and Huntington’s disease, ischaemia, autoimmune encephalomyelitis and neuropathic pain. We discuss the mechanisms underlying those beneficial effects in particular in relation to mitochondrial function, antioxidant defence, cell death and inflammation, and suggest that the PPARγ agonists show significant promise as therapeutic agents in otherwise intractable neurological disease.

show abstract

Neuroprotective and anti-inflammatory properties of a novel non-thiazolidinedione PPARγ agonist in vitro and in MPTP-treated mice

Cited by 38 publications

References 62 publications

Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases

PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease

Contact Info

Product

Resources

About