The PPARγ agonist rosiglitazone prevents cognitive impairment by inhibiting astrocyte activation and oxidative stress following pilocarpine-induced status epilepticus

Sun, Hong; Yu, Xiao-Chun; Wu, Haiqin; Zhang, Guilian; Zhang, Ru; Zhan, Shuqin; Wang, Huqing; Yao, Li; Du, Youwei

doi:10.1007/s10072-011-0774-2

Cited by 41 publications

(21 citation statements)

References 38 publications

(50 reference statements)

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“…An ERK-MAPK-dependent genetic program initiated by stimulation of PPARγ has been proposed as a plausible candidate pathway and signaling axis that globally restores neuronal activity by normalizing the expression of critical target molecules, ultimately affecting intracellular signaling (Harrington et al, 2007; Denner et al, 2012; Jahrling et al, 2014; Escribano et al, 2009; Mandrekar-Colucci et al, 2012). In addition, we and others have demonstrated additional beneficial effects of RSG, indicating links between insulin signaling, cognition and AD (Xu et al, 2014; Bosco et al, 2011; Hong et al, 2012; Mattos et al, 2012; Li et al, 2011). However, we currently lack mechanistic insights into how this network operates and affects key molecular targets.…”

Section: Discussionmentioning

confidence: 53%

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

Hsu

Wildburger

Haidacher

et al. 2017

Experimental Neurology

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Background Cognitive impairment in humans with Alzheimer's disease (AD) and in animal models of Aβ-pathology can be ameliorated by treatments with the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ) agonists, such as rosiglitazone (RSG). Previously, we demonstrated that in the Tg2576 animal model of AD, RSG treatment rescued cognitive deficits and reduced aberrant activity of granule neurons in the dentate gyrus (DG), an area critical for memory formation. Methods We used a combination of mass spectrometry, confocal imaging, electrophysiology and split-luciferase assay and in vitro phosphorylation and Ingenuity Pathway Analysis. Results Using an unbiased, quantitative nano-LC-MS/MS screening, we searched for potential molecular targets of the RSG-dependent rescue of DG granule neurons. We found that S226 phosphorylation of fibroblast growth factor 14 (FGF14), an accessory protein of the voltage-gated Na+ (Nav) channels required for neuronal firing, was reduced in Tg2576 mice upon treatment with RSG. Using confocal microscopy, we confirmed that the Tg2576 condition decreased PanNav channels at the AIS of the DG, and that RSG treatment of Tg2576 mice reversed the reduction in PanNav channels. Analysis from previously published data sets identified correlative changes in action potential kinetics in RSG-treated T2576 compared to untreated and wildtype controls. In vitro phosphorylation and mass spectrometry confirmed that the multifunctional kinase GSK–3β, a downstream target of insulin signaling highly implicated in AD, phosphorylated FGF14 at S226. Assembly of the FGF14:Nav1.6 channel complex and functional regulation of Nav1.6-mediated currents by FGF14 was impaired by a phosphosilent S226A mutation. Bioinformatics pathway analysis of mass spectrometry and biochemistry data revealed a highly interconnected network encompassing PPARγ, FGF14, SCN8A (Nav 1.6), and the kinases GSK–3 β, casein kinase 2β, and ERK1/2. Conclusions These results identify FGF14 as a potential PPARγ-sensitive target controlling Aβ-induced dysfunctions of neuronal activity in the DG underlying memory loss in early AD.

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Section: Discussionmentioning

confidence: 53%

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

Hsu

Wildburger

Haidacher

et al. 2017

Experimental Neurology

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“…In rats, 0.1 mg kg −1 rosiglitazone (i.p.) was able to decrease the cognitive impairment after status epilepticus and to inhibit astrocyte activation in the striatum [71]. On the contrary, in a rat Parkinson’s model, the neuroprotective effect induced by 3 mg kg −1 rosiglitazone (i.p.)…”

Section: Discussionmentioning

confidence: 96%

Oxaliplatin Neurotoxicity Involves Peroxisome Alterations. PPARγ Agonism as Preventive Pharmacological Approach

et al. 2014

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The development of neuropathic syndromes is an important, dose limiting side effect of anticancer agents like platinum derivates, taxanes and vinca alkaloids. The causes of neurotoxicity are still unclear but the impairment of the oxidative equilibrium is strictly related to pain. Two intracellular organelles, mitochondria and peroxisomes cooperate to the maintaining of the redox cellular state. Whereas a relationship between chemotherapy-dependent mitochondrial alteration and neuropathy has been established, the role of peroxisome is poor explored. In order to study the mechanisms of oxaliplatin-induced neurotoxicity, peroxisomal involvement was evaluated in vitro and in vivo. In primary rat astrocyte cell culture, oxaliplatin (10 µM for 48 h or 1 µM for 5 days) increased the number of peroxisomes, nevertheless expression and functionality of catalase, the most important antioxidant defense enzyme in mammalian peroxisomes, were significantly reduced. Five day incubation with the selective Peroxisome Proliferator Activated Receptor-γ (PPAR-γ) antagonist G3335 (30 µM) induced a similar peroxisomal impairment suggesting a relationship between PPARγ signaling and oxaliplatin neurotoxicity. The PPARγ agonist rosiglitazone (10 µM) reduced the harmful effects induced both by G3335 and oxaliplatin. In vivo, in a rat model of oxaliplatin induced neuropathy, a repeated treatment with rosiglitazone (3 and 10 mg kg−1 per os) significantly reduced neuropathic pain evoked by noxious (Paw pressure test) and non-noxious (Cold plate test) stimuli. The behavioral effect paralleled with the prevention of catalase impairment induced by oxaliplatin in dorsal root ganglia. In the spinal cord, catalase protection was showed by the lower rosiglitazone dosage without effect on the astrocyte density increase induced by oxaliplatin. Rosiglitazone did not alter the oxaliplatin-induced mortality of the human colon cancer cell line HT-29. These results highlight the role of peroxisomes in oxaliplatin-dependent nervous damage and suggest PPARγ stimulation as a candidate to counteract oxaliplatin neurotoxicity.

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“…PPARγ agonists and the KD regulate similar anti-inflammatory, anti-oxidant and pro-mitochondrial pathways. These include, but are not limited to, upregulation of IκB, inhibition of NFκB, reduction of cytokines such as IL-1β, IL-6 and TNF-α, upregulation of genes encoding mitochondrial enzymes involved in oxidative phosphorylation (e.g., multiple subunits of complexes I, II, IV and V), induction of mitochondrial biogenesis and upregulation of UCP2, catalase and glutathione (Masino and Rho, 2012; Mandrekar-Colucci et al, 2013; Fong et al, 2010; Bernardo et al, 2006; Heneka and Landreth, 2007; Chuang et al, 2012; Hong et al, 2008, 2012, 2013; Abdallah, 2010; Adabi Mohazab et al, 2012; Bough et al, 2006; Miglio et al, 2009; Sullivan et al, 2004; Yang and Cheng, 2010; Yu et al, 2008). All of these have been suggested as possible disease modifying targets for epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy

Simeone

Matthews

Samson

et al. 2017

Experimental Neurology

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The ketogenic diet (KD) is an effective therapy primarily used in pediatric patients whom are refractory to current anti-seizure medications. The mechanism of the KD is not completely understood, but is thought to involve anti-inflammatory and anti-oxidant processes. The nutritionally-regulated transcription factor peroxisome proliferator activated receptor gamma, PPARγ, regulates genes involved in anti-inflammatory and anti-oxidant pathways. Moreover, endogenous ligands of PPARγ include fatty acids suggesting a potential role in the effects of the KD. Here, we tested the hypothesis that PPARγ contributes to the anti-seizure efficacy of the KD. We found that the KD increased nuclear protein content of the PPARγ2 splice variant by 2–4 fold (p < 0.05) in brain homogenates from wild-type (WT) and epileptic Kv1.1 knockout (KO) mice, while not affecting PPARγ1. The KD reduced the frequency of seizures in Kv1.1KO mice by ~70% (p < 0.01). GW9662, a PPARγ antagonist, prevented KD-mediated changes in PPARγ2 expression and prevented the anti-seizure efficacy of the KD in Kv1.1KO mice. Further supporting the association of PPARγ2 in mediating KD actions, the KD significantly prolonged the latency to flurothyl-induced seizure in WT mice by ~20–35% (p < 0.01), but was ineffective in PPARγ2KO mice and neuron-specific PPARγKO mice. Finally, administering the PPARγ agonist pioglitazone increased PPARγ2 expression by 2-fold (p < 0.01) and reduced seizures in Kv1.1KO mice by ~80% (p < 0.01). Our findings implicate brain PPARγ2 among the mechanisms by which the KD reduces seizures and strongly support the development of PPARγ2 as a therapeutic target for severe, refractory epilepsy.

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The PPARγ agonist rosiglitazone prevents cognitive impairment by inhibiting astrocyte activation and oxidative stress following pilocarpine-induced status epilepticus

Cited by 41 publications

References 38 publications

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

Oxaliplatin Neurotoxicity Involves Peroxisome Alterations. PPARγ Agonism as Preventive Pharmacological Approach

Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy

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