Rosiglitazone

Rationale: Stimulation of the NLRP3 inflammasome by metabolic byproducts is known to result in inflammatory responses and metabolic diseases. However, how the host controls aberrant NLRP3 inflammasome activation remains unclear. PPARγ, a known regulator of energy metabolism, plays an anti-inflammatory role through the inhibition of NF-κB activation and additionally attenuates NLRP3-dependent IL-1β and IL-18 production. Therefore, we hypothesized that PPARγ serves as an endogenous modulator that attenuates NLRP3 inflammasome activation in macrophages. Methods: Mouse peritoneal macrophages with exposure to a PPARγ agonist at different stages and the NLRP3 inflammasome-reconstituted system in HEK293T cells were used to investigate the additional anti-inflammatory effect of PPARγ on NLRP3 inflammasome regulation. Circulating mononuclear cells of obese patients with weight-loss surgery were used to identify the in vivo correlation between PPARγ and the NLRP3 inflammasome. Results: Exposure to the PPARγ agonist, rosiglitazone, during the second signal of NLRP3 inflammasome activation attenuated caspase-1 and IL-1β maturation. Moreover, PPARγ interfered with NLRP3 inflammasome formation by decreasing NLRP3-ASC and NLRP3-NLRP3 interactions as well as NLRP3-dependent ASC oligomerization, which is mediated through interaction between the PPARγ DNA-binding domain and the nucleotide-binding and leucine-rich repeat domains of NLRP3. Furthermore, PPARγ was required to limit metabolic damage-associated molecular pattern-induced NLRP3 inflammasome activation in mouse macrophages. Finally, the mature caspase-1/PPARγ ratio was reduced in circulating mononuclear cells of obese patients after weight-loss surgery, which we define as an "NLRP3 accelerating index". Conclusions: These results revealed an additional anti-inflammatory role for PPARγ in suppressing NLRP3 inflammasome activation through interaction with NLRP3. Thus, our study highlights that PPARγ agonism may be a therapeutic option for targeting NLRP3-related metabolic diseases.

AimsActivated microglia have been found in the forebrains and hippocampi of temporal lobe epilepsy (TLE) patients and status epileptic (SE) animal models. The peroxisome proliferator-activated receptor γ (PPAR γ) agonist rosiglitazone has been shown to prevent microglial activation. However, its role in pilocarpine-induced status epilepticus remains unknown. We aimed to examine the effect of the PPAR γ agonist rosiglitazone in protecting against pilocarpine-induced status epileptic resulting from over-activation and to explore phenotypic changes in microglia as the underlying mechanism.MethodsMale C57BL/6 mice were assigned to three groups: the control group, pilocarpine-induced (SE) group, and rosiglitazone-treated (SE+Rosi) group. Status epileptic mice were administered 300 mg/kg pilocarpine via intraperitoneal injection. SE+Rosi mice were administered rosiglitazone (0.1 mg/kg, i.p.) after SE. Flow cytometry, immunofluorescence staining, and quantitative real-time PCR were used to examine the activation of and phenotypic changes in microglia in the brain and to evaluate neuroinflammation.ResultsWe found that the expression of proinflammatory CD86 and iNOS was increased and that the expression of antiinflammatory CD206 and Arg-1 was decreased in the brains of pilocarpine-induced SE mice compared to control mice. The mRNA levels of proinflammatory and antiinflammatory cytokines were not significantly changed in the brain. Rosiglitazone treatment significantly inhibited the proinflammatory polarization of microglia and rescued neuron loss in the temporal lobe and hippocampi of the brain after SE.ConclusionRosiglitazone reverses microglial polarization in the brains of SE mice and also affords neuroprotection against pilocarpine-induced status epilepticus without inducing significant changes in brain inflammation.

Drug-induced liver injury (DILI) causes one in three market withdrawals due to adverse drug reactions, causing preventable human suffering and massive financial loss. We applied evidence-based methods to investigate the role of preclinical studies in predicting human DILI using two anti-diabetic drugs from the same class, but with different toxicological profiles: troglitazone (withdrawn from US market due to DILI) and rosiglitazone (remains on US market). Evidence Stream 1: A systematic literature review of in vivo studies on rosiglitazone or troglitazone was conducted (PROSPERO registration CRD42018112353). Evidence Stream 2: in vitro data on troglitazone and rosiglitazone were retrieved from the US EPA ToxCast database. Evidence Stream 3: troglitazone- and rosiglitazone-related DILI cases were retrieved from WHO Vigibase. All three evidence stream analyses were conducted according to evidence-based methodologies and performed according to pre-registered protocols. Evidence Stream 1: 9288 references were identified, with 42 studies included in analysis. No reported biomarker for either drug indicated a strong hazard signal in either preclinical animal or human studies. All included studies had substantial limitations, resulting in "low" or "very low" certainty in findings. Evidence Stream 2: Troglitazone was active in twice as many in vitro assays (129) as rosiglitazone (60), indicating a strong signal for more off-target effects. Evidence Stream 3: We observed a fivefold difference in both all adverse events and liver-related adverse events reported, and an eightfold difference in fatalities for troglitazone, compared to rosiglitazone. In summary, published animal and human trials failed to predict troglitazone's potential to cause severe liver injury in a wider patient population, while in vitro data showed marked differences in the two drugs' off-target activities, offering a new paradigm for reducing drug attrition in late development and in the market. This investigation concludes that death and disability due to adverse drug reactions may be prevented if mechanistic information is deployed at early stages of drug development by pharmaceutical companies and is considered by regulators as a part of regulatory submissions.

Cellular stress is implicated in the progression of lipopolysaccharide (LPS)-evoked acute lung injury (ALI). The goal of this study was to evaluate the effect of oral supplementation with rosiglitazone (RSG), which is an agonist of peroxisome proliferator-activated receptor (PPAR)-γ, on pulmonary inflammatory response, oxidative stress, and endoplasmic reticulum (ER) stress during LPS-evoked ALI in mice. The mice were randomly divided into four groups and orally supplemented with or without RSG (10 mg/kg) once daily for 5 consecutive days before LPS (1 mg/kg) intraperitoneal injection. The mice were sacrificed at 12 h after LPS injection. As expected, LPS-evoked ALI and death were attenuated in mice that were pretreated with RSG. LPS-evoked increase in chemokines (KC, MIP-2, and MCP-1) and proinflammatory cytokines (TNF-α and IL-1β) was inhibited in the mouse lungs by RSG. RSG pretreatment significantly mitigated LPS-evoked nuclear translocation of NF-κB p65 and p50, which regulate inflammatory gene transcription in the lungs. Additionally, LPS-evoked glutathione depletion and lipid peroxidation were alleviated by RSG. The abnormal expression of NADPH oxidases and antioxidant enzymes was restored in the lung tissues by RSG. Further experiments revealed that LPS-evoked upregulation of GRP78, p-IRE1α, and p-EIF2α was blocked by RSG pretreatment. Mechanistically, RSG pretreatment enhanced PPARγ activity in the mouse lungs and bronchial epithelial cells. RSG promoted the interaction between NF-κB p65 and PPARγ in the mouse lungs. Overall, RSG pretreatment protects against LPS-evoked ALI partially through enhancing PPARγ activity and inhibiting the cellular stress response in the mouse lungs.