The PPARγ agonist pioglitazone produces a female-predominant inhibition of hyperalgesia associated with surgical incision, peripheral nerve injury, and painful diabetic neuropathy

Santos, Diogo F. S.; Donahue, Renée R.; Laird, D.; Oliveira, Maria Cláudia G.; Taylor, Bradley K.

doi:10.1016/j.neuropharm.2021.108907

Cited by 17 publications

(9 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies have shown that PPAR ligands can reduce animal models of inflammatory pain and neuropathic pain (Maeda and Kishioka, 2009 ). More specifically, PPARγ agonists can alleviate a variety of pain conditions, including trigeminal neuropathic pain, post-operative pain, and chemotherapy-induced peripheral neuropathic pain (Lyons et al, 2017 ; Santos et al, 2022 ; Zhang M. et al, 2022 ). In some studies, it has been found that PPARγ expression is decreased and contributes to pain mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Characterization of pain-related behaviors and gene expression profiling of peripheral sensory ganglia in a mouse model of acute ankle sprain

Pan

Yang

et al. 2023

Front. Behav. Neurosci.

View full text Add to dashboard Cite

IntroductionLateral ankle sprain (LAS) is a very common type of joint injury. It occurred with high incidence among general population and especially among individuals participating sports and outdoor activities. A certain proportion of individuals who once developed LAS may suffer persistent ankle pain that affects daily activities. However, the mechanisms underlying LAS-induced pain still remained largely unknown.MethodsWe established a LAS mouse model and systematically evaluated the pain-related behaviors in this mouse model. RNA sequencing (RNA-Seq), combined with bioinformatics analysis, was undertaken to explore gene expression profiles. Immunostaining was used to study glial cell and neuron activation in ipsilateral spinal cord dorsal horn (SCDH) of LAS model mice. Ibuprofen was used to treat LAS model mice.ResultsThe LAS model mice developed obvious signs of mechanical and heat hypersensitivities as well as gait impairments in ipsilateral hind paws. Besides, LAS model mice developed signs of pain-related emotional disorder, including pain-induced aversion. By RNA-Seq, we were able to identify certain differentially expressed genes and signaling pathways that might contribute to pain mechanisms of LAS mouse model. In addition, LAS model mice showed increased c-Fos and p-ERK immunoreactivity as well as astrocyte and microglia overactivation in ipsilateral spinal cord dorsal horn, indicating central sensitization might occur. Finally, LAS model mice respond to ibuprofen, a drug clinically used to treat ankle sprain pain.ConclusionOur study found LAS model mice may be used as a preclinical animal model for screening novel targets or therapies for ankle sprain. Thus, the study may further help to understand molecular mechanisms contributing to ankle sprain-induced pain.

show abstract

Section: Discussionmentioning

confidence: 99%

Characterization of pain-related behaviors and gene expression profiling of peripheral sensory ganglia in a mouse model of acute ankle sprain

Pan

Yang

et al. 2023

Front. Behav. Neurosci.

View full text Add to dashboard Cite

show abstract

“…injection and in tap water for oral administration. The doses of TZD‐A1 and pioglitazone used here are based on published papers and pilot experiments (Khasabova et al, 2019; Morgenweck et al, 2013; Santos et al, 2022) and the dose of GW9662 used was based on data from Morgenweck et al (2013).…”

Section: Methodsmentioning

confidence: 99%

A partial agonist of PPARγ prevents paclitaxel‐induced peripheral neuropathy in mice, by inhibiting neuroinflammation

Benvenutti,

Wolff,

Corrêa

et al. 2023

British J Pharmacology

View full text Add to dashboard Cite

Background and PurposeChemotherapy‐induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel (PTX), affecting 30 to 50% of patients. The increase in survival rate and the concern with patients' quality of life have encouraged the search for new tools to prevent PTX‐induced neuropathy. This study presents the glitazone 4‐[(Z)‐(2,4‐dioxo‐1,3‐thiazolidin‐5‐ylidene)methyl]‐N‐phenylbenzene‐sulfonamide (TZD‐A1) as PPARγ partial‐agonist, its toxicological profile, and effect on PTX‐induced CIPN in mice.Experimental ApproachThe interaction of TZD‐A1 with PPARγ was tested using in silico docking analysis and in vitro reporter gene assay. The pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo analysis. The effects of TZD‐A1 on CIPN were investigated in PTX‐injected mice. Axonal and DRG damage, mitochondrial complex activity, and cytokine levels, BDNF, Nrf2 and PPARγ were also evaluated.Key ResultsDocking analysis predicted TZD‐A1 interaction with PPARγ compatible for partial agonists, data corroborated by the in vitro reporter gene assay. TZD‐A1 presented oral bioavailability and safety profile evidenced by in silico, in vitro and in vivo experiments. PTX‐injected mice, concomitantly treated with TZD‐A1 by systemic or oral route, presented reduction of mechanical and thermal hypersensitivity. The mechanisms involved in TZD‐A1 effect seem to be the inhibition of neuroinflammation and mitochondrial damage by increasing Nrf2 and PPARγ levels together with BDNF upregulation.Conclusion and ImplicationsTZD‐A1, partially activating PPARγ, caused neuroprotection and reduced the hypersensitivity induced by PTX. Allied to its safety profile and good bioavailability, TZD‐A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.

show abstract

“…Several studies have described the effects of pioglitazone activation of PPARγ in reducing hyperalgesic behaviors in rodents with surgical nerve injury or chemotherapeutic neuropathies. 20 Some may hypothesize that by activating PPARγ and increasing glucose uptake in the skeletal muscle, less glucose is accumulated in the periphery where glucose crystals can lead to nerve damage and activation of NLRP3 (glucose crystals can act as damage-associated molecular patterns (DAMPs) and be sensed by the inflammasome). Recent studies have shown that this may be the case in some but not all models of chronic pain and may be sex-specific, depending on the pain model utilized.…”

Section: ■ Role Of the Nlrp3 Inflammasome In Chronic Painmentioning

confidence: 99%

“…Growing preclinical evidence has also shown that the activation of PPARγ decreases behavioral signs in rodent models of inflammatory and neuropathic pain. Several studies have described the effects of pioglitazone activation of PPARγ in reducing hyperalgesic behaviors in rodents with surgical nerve injury or chemotherapeutic neuropathies …”

Section: Nuclear Receptors As Regulators Of Inflammasome-mediated Painmentioning

confidence: 99%

“…Some may hypothesize that by activating PPARγ and increasing glucose uptake in the skeletal muscle, less glucose is accumulated in the periphery where glucose crystals can lead to nerve damage and activation of NLRP3 (glucose crystals can act as damage-associated molecular patterns (DAMPs) and be sensed by the inflammasome). Recent studies have shown that this may be the case in some but not all models of chronic pain and may be sex-specific, depending on the pain model utilized. , Other studies have shown that, while peripheral glucose reduction is important in the behavioral response, the activation of PPARγ modulates pathways involved in the activation of NLRP3 by directly down-regulating chemokine expression and release and induces the expression of anti-inflammatory cytokine interleukin-10 (IL-10), suggesting that PPARγ activation may have anti-inflammatory consequences in pain models . With PPARγ compounds actively used in the clinic, there is likely a route to utilize these drugs in a manner to identify whether they have utility in treating T2D patients with chronic inflammatory pain including diabetic peripheral neuropathies.…”

Section: Nuclear Receptors As Regulators Of Inflammasome-mediated Painmentioning

confidence: 99%

See 1 more Smart Citation

Targeting Nuclear Receptors for Chronic Inflammatory Pain: A Potential Alternative

Griffett

2022

ACS Pharmacol. Transl. Sci.

View full text Add to dashboard Cite

Pain is the unpleasant consequence of detrimental neuronal activity that can be triggered by chronic inflammation, noxious stimuli, and nerve damage. In the case of chronic inflammatory pain, the establishment and maintenance of pain states often depend on the chronic activation and immune response occurring at the site of the peripheral nerve injury. Many current analgesic drugs lack efficacy in long-term pain management. Targeting the nuclear receptor family of transcription factors may provide a novel avenue for the treatment of chronic inflammatory pain. Peroxisome proliferator-activated receptor (PPAR) ligands have demonstrated efficacy in several diabetic-related neuropathic pain models, while the REV-ERB receptors play a key role in the regulation of both P2X7 receptor expression and NLRP3 inflammasome expression and activation. As such, activating the REV-ERB receptor may provide an anti-inflammatory and analgesic option for chronic inflammatory pain sufferers.

show abstract

The PPARγ agonist pioglitazone produces a female-predominant inhibition of hyperalgesia associated with surgical incision, peripheral nerve injury, and painful diabetic neuropathy

Cited by 17 publications

References 77 publications

Characterization of pain-related behaviors and gene expression profiling of peripheral sensory ganglia in a mouse model of acute ankle sprain

Characterization of pain-related behaviors and gene expression profiling of peripheral sensory ganglia in a mouse model of acute ankle sprain

A partial agonist of PPARγ prevents paclitaxel‐induced peripheral neuropathy in mice, by inhibiting neuroinflammation

Targeting Nuclear Receptors for Chronic Inflammatory Pain: A Potential Alternative

Contact Info

Product

Resources

About