Pioglitazone prevents sevoflurane‑induced neuroinflammation and cognitive decline in a rat model of chronic intermittent hypoxia by upregulating hippocampal PPAR‑γ

Zhang,Xiyan; Li,Ning; Lu,Lingling; Lin,Quan; Li,Liang; Dong,Ping; Yang,Bo; Li,Dongliang; Fei,Jianchun

doi:10.3892/mmr.2019.10052

Pioglitazone prevents sevoflurane‑induced neuroinflammation and cognitive decline in a rat model of chronic intermittent hypoxia by upregulating hippocampal PPAR‑γ

Authors:
- Xiyan Zhang
- Ning Li
- Lingling Lu
- Quan Lin
- Liang Li
- Ping Dong
- Bo Yang
- Dongliang Li
- Jianchun Fei
View Affiliations

Affiliations: Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China, School of Public Health, Jining Medical University, Jining, Shandong 272067, P.R. China, Shandong Province Jining Health School, Jining, Shandong 272067, P.R. China, Shengli Oilfield Central Hospital, Dongying, Shandong 257000, P.R. China
Published online on: March 18, 2019 https://doi.org/10.3892/mmr.2019.10052
Pages: 3815-3822

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Post‑operative cognitive dysfunction is a common complication after anesthesia and surgery. Sevoflurane (SEV), a widely used inhalational anesthetic, can exaggerate neuroinflammation and cause cognitive dysfunction under chronic intermittent hypoxia (CIH) conditions by downregulating hippocampal peroxisome proliferator‑activated receptor‑γ (PPAR‑γ). In the present study, it was examined whether treatment with PPAR‑γ agonist pioglitazone (PIO) is beneficial in counteracting SEV‑induced neuroinflammation and cognitive decline in a rat model of CIH. Rats were exposed to CIH for 4 weeks. After 2 weeks of CIH, these animals underwent either 2.6% SEV or control (CON) exposure for 4 h. PIO (60 mg/kg) or vehicle (VEH) was administered orally twice daily for 2 weeks, starting one day prior to SEV or CON exposure. Compared with CIH‑CON+VEH rats, CIH‑SEV+VEH rats exhibited significant cognitive decline as indicated by increased latency to locate the hidden platform and shorter dwell‑time in the goal quadrant in the Morris Water Maze task. Molecular studies revealed that CIH‑SEV+VEH rats had increased proinflammatory cytokine expression and microglial activation in the hippocampus, which were associated with decreased PPAR‑γ activity. Notably, SEV‑induced cognitive decline and increases in proinflammatory cytokine expression and microglial activation were prevented by PIO, which increased hippocampal PPAR‑γ activity. PIO also increased hippocampal PPAR‑γ activity in CIH‑CON rats but did not alter proinflammatory cytokine expression and microglial activation as well as cognitive function. Additionally, expression of hippocampal PPAR‑α and PPAR‑β, two other PPAR isotypes, were comparable among the groups. These data suggest that PIO prevents SEV‑induced exaggeration of neuroinflammation and cognitive decline under CIH conditions by upregulating hippocampal PPAR‑γ. PIO may have the potential to prevent anesthetic SEV‑induced cognitive decline in surgical patients with obstructive sleep apnea.

View Figures

View References

1	Skvarc DR, Berk M, Byrne LK, Dean OM, Dodd S, Lewis M, Marriott A, Moore EM, Morris G, Page RS and Gray L: Post-operative cognitive dysfunction: An exploration of the inflammatory hypothesis and novel therapies. Neurosci Biobehav Rev. 84:116–133. 2018. View Article : Google Scholar : PubMed/NCBI
2	Jevtovic-Todorovic V, Absalom AR, Blomgren K, Brambrink A, Crosby G, Culley DJ, Fiskum G, Giffard RG, Herold KF, Loepke AW, et al: Anaesthetic neurotoxicity and neuroplasticity: An expert group report and statement based on the BJA Salzburg Seminar. Br J Anaesth. 111:143–151. 2013. View Article : Google Scholar : PubMed/NCBI
3	Callaway JK, Jones NC, Royse AG and Royse CF: Memory impairment in rats after desflurane anesthesia is age and dose dependent. J Alzheimers Dis. 44:995–1005. 2015. View Article : Google Scholar : PubMed/NCBI
4	Shen X, Dong Y, Xu Z, Wang H, Miao C, Soriano SG, Sun D, Baxter MG, Zhang Y and Xie Z: Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment. Anesthesiology. 118:502–515. 2013. View Article : Google Scholar : PubMed/NCBI
5	Feng X, Degos V, Koch LG, Britton SL, Zhu Y, Vacas S, Terrando N, Nelson J, Su X and Maze M: Surgery results in exaggerated and persistent cognitive decline in a rat model of the metabolic syndrome. Anesthesiology. 118:1098–1105. 2013. View Article : Google Scholar : PubMed/NCBI
6	Yang C, Zhu B, Ding J and Wang ZG: Isoflurane anesthesia aggravates cognitive impairment in streptozotocin-induced diabetic rats. Int J Clin Exp Med. 7:903–910. 2014.PubMed/NCBI
7	Yue T, Shanbin G, Ling M, Yuan W, Ying X and Ping Z: Sevoflurane aggregates cognitive dysfunction and hippocampal oxidative stress induced by β-amyloid in rats. Life Sci. 143:194–201. 2015. View Article : Google Scholar : PubMed/NCBI
8	Wadhwa M, Prabhakar A, Ray K, Roy K, Kumari P, Jha PK, Kishore K, Kumar S and Panjwani U: Inhibiting the microglia activation improves the spatial memory and adult neurogenesis in rat hippocampus during 48 h of sleep deprivation. J Neuroinflammation. 14:2222017. View Article : Google Scholar : PubMed/NCBI
9	Li Z, Ni C, Xia C, Jaw J, Wang Y, Cao Y, Xu M and Guo X: Calcineurin/nuclear factor-κB signaling mediates isoflurane-induced hippocampal neuroinflammation and subsequent cognitive impairment in aged rats. Mol Med Rep. 15:201–209. 2017. View Article : Google Scholar : PubMed/NCBI
10	Cai JC, Liu W, Lu F, Kong WB, Zhou XX, Miao P, Lei CX and Wang Y: Resveratrol attenuates neurological deficit and neuroinflammation following intracerebral hemorrhage. Exp Ther Med. 15:4131–4138. 2018.PubMed/NCBI
11	Block ML: Neuroinflammation: Modulating mighty microglia. Nat Chem Biol. 10:988–989. 2014. View Article : Google Scholar : PubMed/NCBI
12	Liu H, Huang F, Wu H, Zhang B, Shi H, Wu X and Hu Z: Isoastragaloside I inhibits NF-κB activation and inflammatory responses in BV-2 microglial cells stimulated with lipopolysaccharide. Int J Mol Med. 40:1270–1276. 2017. View Article : Google Scholar : PubMed/NCBI
13	Jin M, Park SY, Shen Q, Lai Y, Ou X, Mao Z, Lin D, Yu Y and Zhang W: Anti-neuroinflammatory effect of curcumin on Pam3CSK4-stimulated microglial cells. Int J Mol Med. 41:521–530. 2018.PubMed/NCBI
14	Zhang Z, Yuan H, Zhao H, Qi B, Li F and An L: PPARγ activation ameliorates postoperative cognitive decline probably through suppressing hippocampal neuroinflammation in aged mice. Int Immunopharmacol. 43:53–61. 2017. View Article : Google Scholar : PubMed/NCBI
15	Gagnon K, Baril AA, Gagnon JF, Fortin M, Décary A, Lafond C, Desautels A, Montplaisir J and Gosselin N: Cognitive impairment in obstructive sleep apnea. Pathol Biol (Paris). 62:233–240. 2014. View Article : Google Scholar : PubMed/NCBI
16	Jin F, Liu J and Zhang X, Cai W, Zhang Y, Zhang W, Yang J, Lu G and Zhang X: Effect of continuous positive airway pressure therapy on inflammatory cytokines and atherosclerosis in patients with obstructive sleep apnea syndrome. Mol Med Rep. 16:6334–6339. 2017. View Article : Google Scholar : PubMed/NCBI
17	Sforza E and Roche F: Chronic intermittent hypoxia and obstructive sleep apnea: An experimental and clinical approach. Hypoxia (Auckl). 4:99–108. 2016. View Article : Google Scholar : PubMed/NCBI
18	Yaffe K, Laffan AM, Harrison SL, Redline S, Spira AP, Ensrud KE, Ancoli-Israel S and Stone KL: Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA. 306:613–619. 2011. View Article : Google Scholar : PubMed/NCBI
19	Moore-Carrasco R, Poblete Bustamante M, González Guerra O, Leiva Madariaga E, Mujica Escudero V, Aranguez Arellano C and Palomo I: Peroxisome proliferator-activated receptors: Targets for the treatment of metabolic illnesses (Review). Mol Med Rep. 1:317–324. 2008.PubMed/NCBI
20	Martin H: Role of PPAR-gamma in inflammation. Prospects for therapeutic intervention by food components. Mutat Res. 690:57–63. 2010. View Article : Google Scholar : PubMed/NCBI
21	Zhang T, Shao B and Liu GA: Rosuvastatin promotes the differentiation of peripheral blood monocytes into M2 macrophages in patients with atherosclerosis by activating PPAR-γ. Eur Rev Med Pharmacol Sci. 21:4464–4471. 2017.PubMed/NCBI
22	Wang Q, Su YY, Li YQ, Zhang YF, Yang S, Wang JL and Li HY: Atorvastatin alleviates renal ischemia-reperfusion injury in rats by promoting M1-M2 transition. Mol Med Rep. 15:798–804. 2017. View Article : Google Scholar : PubMed/NCBI
23	Culman J, Zhao Y, Gohlke P and Herdegen T: PPAR-gamma: Therapeutic target for ischemic stroke. Trends Pharmacol Sci. 28:244–249. 2007. View Article : Google Scholar : PubMed/NCBI
24	Kapadia R, Yi JH and Vemuganti R: Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Front Biosci. 13:1813–1826. 2008. View Article : Google Scholar : PubMed/NCBI
25	Nicolakakis N and Hamel E: The nuclear receptor PPARgamma as a therapeutic target for cerebrovascular and brain dysfunction in Alzheimer's disease. Front Aging Neurosci. 2:212010. View Article : Google Scholar : PubMed/NCBI
26	Domi E, Uhrig S, Soverchia L, Spanagel R, Hansson AC, Barbier E, Heilig M, Ciccocioppo R and Ubaldi M: Genetic deletion of neuronal PPARγ enhances the emotional response to acute stress and exacerbates anxiety: An effect reversed by rescue of amygdala PPARγ Function. J Neurosci. 36:12611–12623. 2016. View Article : Google Scholar : PubMed/NCBI
27	Bernardo A and Minghetti L: Regulation of glial cell functions by PPAR-gamma natural and synthetic agonists. PPAR Res. 2008:8641402008. View Article : Google Scholar : PubMed/NCBI
28	Dong P, Zhao J, Li N, Lu L, Li L, Zhang X, Yang B, Zhang L and Li D: Sevoflurane exaggerates cognitive decline in a rat model of chronic intermittent hypoxia by aggravating microglia-mediated neuroinflammation via downregulation of PPAR-γ in the hippocampus. Behav Brain Res. 347:325–331. 2018. View Article : Google Scholar : PubMed/NCBI
29	Callaway JK, Jones NC, Royse AG and Royse CF: Sevoflurane anesthesia does not impair acquisition learning or memory in the Morris water maze in young adult and aged rats. Anesthesiology. 117:1091–1101. 2012. View Article : Google Scholar : PubMed/NCBI
30	Li D, Liu L, Li L, Li X, Huang B, Zhou C, Zhang Z, Wang C, Dong P, Zhang X, et al: Sevoflurane induces exaggerated and persistent cognitive decline in a type II diabetic rat model by aggregating hippocampal inflammation. Front Pharmacol. 8:8862017. View Article : Google Scholar : PubMed/NCBI
31	Cippitelli A, Domi E, Ubaldi M, Douglas JC, Li HW, Demopulos G, Gaitanaris G, Roberto M, Drew PD, Kane CJ and Ciccocioppo R: Protection against alcohol-induced neuronal and cognitive damage by the PPARγ receptor agonist pioglitazone. Brain Behav Immun. 64:320–329. 2017. View Article : Google Scholar : PubMed/NCBI
32	Zhao Q, Wu X, Yan S, Xie X, Fan Y, Zhang J, Peng C and You Z: The antidepressant-like effects of pioglitazone in a chronic mild stress mouse model are associated with PPARγ-mediated alteration of microglial activation phenotypes. J Neuroinflammation. 13:2592016. View Article : Google Scholar : PubMed/NCBI
33	Grommes C, Karlo JC, Caprariello A, Blankenship D, Dechant A and Landreth GE: The PPARγ agonist pioglitazone crosses the blood-brain barrier and reduces tumor growth in a human xenograft model. Cancer Chemother Pharmacol. 71:929–936. 2013. View Article : Google Scholar : PubMed/NCBI
34	Garvey JF, Pengo MF, Drakatos P and Kent BD: Epidemiological aspects of obstructive sleep apnea. J Thorac Dis. 7:920–929. 2015.PubMed/NCBI
35	Liu M, Bachstetter AD, Cass WA, Lifshitz J and Bing G: Pioglitazone attenuates neuroinflammation and promotes dopaminergic neuronal survival in the nigrostriatal system of rats after diffuse brain injury. J Neurotrauma. 34:414–422. 2017. View Article : Google Scholar : PubMed/NCBI
36	Collino M, Aragno M, Mastrocola R, Gallicchio M, Rosa AC, Dianzani C, Danni O, Thiemermann C and Fantozzi R: Modulation of the oxidative stress and inflammatory response by PPAR-gamma agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion. Eur J Pharmacol. 530:70–80. 2006. View Article : Google Scholar : PubMed/NCBI
37	Chen F, Wang M, O'Connor JP, He M, Tripathi T and Harrison LE: Phosphorylation of PPARgamma via active ERK1/2 leads to its physical association with p65 and inhibition of NF-kappabeta. J Cell Biochem. 90:732–744. 2003. View Article : Google Scholar : PubMed/NCBI
38	Ruan H, Pownall HJ and Lodish HF: Troglitazone antagonizes tumor necrosis factor-alpha-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-kappaB. J Biol Chem. 278:28181–28192. 2003. View Article : Google Scholar : PubMed/NCBI
39	Wang W, Chen X, Zhang J, Zhao Y, Li S, Tan L, Gao J, Fang X and Luo A: Glycyrrhizin attenuates isoflurane-induced cognitive deficits in neonatal rats via its anti-inflammatory activity. Neuroscience. 316:328–336. 2016. View Article : Google Scholar : PubMed/NCBI
40	Zhang L, Zhang J, Yang L, Dong Y, Zhang Y and Xie Z: Isoflurane and sevoflurane increase interleukin-6 levels through the nuclear factor-kappa B pathway in neuroglioma cells. Br J Anaesth. 110 (Suppl 1):i82–i91. 2013. View Article : Google Scholar : PubMed/NCBI
41	Warden A, Truitt J, Merriman M, Ponomareva O, Jameson K, Ferguson LB, Mayfield RD and Harris RA: Localization of PPAR isotypes in the adult mouse and human brain. Sci Rep. 6:276182016. View Article : Google Scholar : PubMed/NCBI