PPARγ Agonists Improve Survival and Neurocognitive Outcomes in Experimental Cerebral Malaria and Induce Neuroprotective Pathways in Human Malaria

English version České info

Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that is associated with long-term neurocognitive impairment in about a third of survivors even when optimal anti-malarial therapy is used. Since both the parasite and the host immune response to infection play a role in the development of CM, adjunctive therapies that modulate the host response, given in conjunction with anti-parasitic therapy, may improve survival and prevent neurocognitive injury. Here we examine the effects of PPARγ agonists on neurocongitive injury using a mouse model of CM. We demonstrate that PPARγ agonists, when administered with anti-malarials, protected mice from developing brain atrophy and neurocognitive impairment. This was associated with induction of anti-oxidant and neuroprotective pathways in the brains of infected mice. We also observed the same neuroprotective pathways induced in patients with falciparum malaria that received PPARγ adjunctive therapy. Our findings suggest that PPARγ agonists may be valuable in the treatment and prevention of CM-induced neurocognitive injury, and support the testing of PPARγ agonists in patients with CM.

Vyšlo v časopise: PPARγ Agonists Improve Survival and Neurocognitive Outcomes in Experimental Cerebral Malaria and Induce Neuroprotective Pathways in Human Malaria. PLoS Pathog 10(3): e32767. doi:10.1371/journal.ppat.1003980
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003980

Souhrn

Zdroje

1. DondorpA, NostenF, StepniewskaK, DayN, WhiteN, et al. (2005) Artesunate versus quinine for treatment of severe falciparum malaria, a randomised trial. Lancet 366: 717–725.

2. DondorpAM, FanelloCI, HendriksenIC, GomesE, SeniA, et al. (2010) Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT), an open-label, randomised trial. Lancet 376: 1647–1657.

3. JohnCC, KutambaE, MugaruraK, OpokaRO (2010) Adjunctive therapy for cerebral malaria and other severe forms of Plasmodium falciparum malaria. Expert Rev Anti Infect Ther 8: 997–1008.

4. JohnCC, BangiranaP, ByarugabaJ, OpokaRO, IdroR, et al. (2008) Cerebral malaria in children is associated with long-term cognitive impairment. Pediatrics 122: e92–99.

5. BoivinMJ, BangiranaP, ByarugabaJ, OpokaRO, IdroR, et al. (2007) Cognitive impairment after cerebral malaria in children, a prospective study. Pediatrics 119: e360–366.

6. BirbeckG, MolyneuxME, KaplanPW, SeydelKB, ChimalizeniYF, et al. (2010) Blantyre Malaria Project Epilepsy Study (BMPES) of neurological outcomes in retinopathy-positive paediatric cerebral malaria survivors: a prospective cohort study. Lancet Neurol 9: 1173–1181.

7. FernandoSD, RodrigoC, RajapakseS (2010) The hidden burden of malaria, cognitive impairment following infection. Malaria J 9: 366.

8. TaylorTE, FuWJ, CarrRA, WhittenRO, MuellerJS, et al. (2004) Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med 10: 143–145.

9. WhiteVA, LewallenS, BeareN, KayiraK, CarrRA, et al. (2001) Correlation of retinal haemorrhages with brain haemorrhages in children dying of cerebral malaria in Malawi. Trans R Soc Trop Med Hyg 95: 618–621.

10. MedanaIM, DayNP, HienTT, MaiNT, BethellD, et al. (2002) Axonal injury in cerebral malaria. Am J Pathol 160: 655–666.

11. NacerA, MovillaA, BaerK, MikolajczakSA, KappeSH, et al. (2012) Neuroimmunological blood brain opening in experimental cerebral malaria. PloS Pathog 8: e1002982.

12. BergerJ, MollerDE (2002) The mechanism of action of PPARs. Ann Rev Med 53: 409–435.

13. LehrkeM, LazarMA (2005) The many faces of PPARgamma. Cell 123: 993–999.

14. KapadiaR, YiJH, VemugantiR (2008) Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Front Biosci 13: 1813–1826.

15. JinJ, AlbertzJ, GuoZ, PengQ, RudowG, et al. (2013) Neuroprotective effects of PPAR-γ agonist rosiglitazone in N171-82Q mouse model of Huntington's disease. J Neurochem 125: 410–419.

16. SerghidesL, PatelSN, AyiK, LuZ, GowdaDC, et al. (2009) Rosiglitazone modulates the innate immune response to Plasmodium falciparum infection and improves outcome in experimental cerebral malaria. J Infect Dis 199: 1536–1545.

17. BoggildAK, KrudsoodS, PatelSN, SerghidesL, TangpukdeeN, et al. (2009) Use of peroxisome proliferator-activated receptor gamma agonists as adjunctive treatment for Plasmodium falciparum malaria, a randomized, double-blind, placebo-controlled trial. Clin Infect Dis 49: 841–849.

18. KimH, HigginsS, LilesWC, KainKC (2011) Endothelial activation and dysregulation in malaria, a potential target for novel therapeutics. Curr Opion Hematol 18: 177–185.

19. Franke-FayardB, WatersAP, JanseCJ (2006) Real-time in vivo imaging of transgenic bioluminescent blood stages of rodent malaria parasites in mice. Nat Protoc 1: 476–485.

20. JeanssonM, GawlikA, AndersonG, LiC, KerjaschkiD, et al. (2011) Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. J Clin Invest 121: 2278–2289.

21. CarrollRW, WainwrightMS, KimKY, KidambiT, GomezND, et al. (2010) A rapid murine coma and behavior scale for quantitative assessment of murine cerebral malaria. PLoS One 5: e13124.

22. ReisPA, ComimCM, HermaniF, SilvaB, BarichelloT, et al. (2010) Cognitive dysfunction is sustained after rescue therapy in experimental cerebral malaria, and is reduced by additive antioxidant therapy. PLoS Pathog 24: e1000963.

23. PabonA, CarmonaJ, BurgosLC, BlairS (2003) Oxidative stress in patients with non-complicated malaria. Clin Biochem 36: 71–78.

24. SkaperSD (2012) The neurotrophin family of neurotrophic factors: an overview. Methods Mol Biol 846: 1–12.

25. LinaresM, Marin-GarciaP, Perez-BenaventeS, Sanchez-NogueiroJ, PuyetA, et al. (2013) Brain-derived neurotrophic factor and the course of experimental cerebral malaria. Brain Res 1490: 210–224.

26. Huang EJ, Reichardt LF (2003) Trk receptors, roles in neuronal signal transduction. Annu Rev Biochem 72, 609–642.

27. DaiM, ReznikSE, SprayDC, WeissLM, TanowitzHB, et al. (2010) Persistent cognitive and motor deficits after successful antimalarial treatment in murine cerebral malaria. Microbes Infect 12: 1198–1207.

28. LerchJP, YiuAP, Martinez-CanabalA, PekarT, BohbotVD, et al. (2011) Maze training in mice induces MRI-detectable brain shape changes specific to the type of learning. Neuroimage 54: 2086–2095.

29. PotchenMJ, BirbeckGL, DemarcoJK, KampondeniSD, BeareN, et al. (2010) Neuroimaging findings in children with retinopathy-confirmed cerebral malaria. Eur J Radiol 74: 262–268.

30. KampondeniSD, PotchenMJ, BeareNA, SeydelKB, GloverSJ, et al. (2013) MRI findings in a cohort of brain injured survivors of pediatric cerebral malaria. Am J Trop Med Hyg 88: 542–546.

31. LerchJP, SledJG, HenkelmanRM (2011) MRI phenotyping of genetically altered mice. Methods Mol Biol 711: 349–361.

32. DorrAE, LerchJP, SpringS, KabaniN, HenkelmanRM (2008) High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice. Neuroimage 42: 60–69.

33. BoivinMJ, GladstoneMJ, VokhiwaM, BirbeckGL, MagenJG, et al. (2011) Developmental outcomes in Malawian children with retinopathy-positive cerebral malaria. Trop Med Int Health 16: 263–271.

34. KiharaM, CarterJA, HoldingPA, Vargha-KhademF, ScottRC, et al. (2009) Impaired everyday memory associated with encephalopathy of severe malaria, the role of seizures and hippocampal damage. Malaria J 8: 273.

35. CarterJA, Mung'ala-OderaV, NevilleBG, MuriraB, MturiN, et al. (2005) Persistent neurocognitive impairments associated with severe falciparum malaria in Kenyan children. J Neurol Neurosurg Psychiatry 76: 476–481.

36. MasiG, BrovedaniP (2011) The hippocampus, neurotrophic factors and depression, possible implications for the pharmacotherapy of depression. CNS Drugs 25: 913–931.

37. Van der Werf YD, Witter MP, Uylings HB, Jolles J (2000) Neuropsychology of infarctions in the thalamus, a review. Neuropsychologia 38, 613–627.

38. PozzilliC, BastianelloS, PadovaniA, PassafiumeD, MillefioriniE, et al. (1991) Anterior corpus callosum atrophy and verbal fluency in multiple sclerosis. Cortex 27: 441–445.

39. HinesM, ChiuL, McAdamsLA, BentlerPM, LipcamonJ (1992) Cognition and the corpus callosum, verbal fluency, visuospatial ability, and language lateralization related to midsagittal surface areas of callosal subregions. Behav Neurosci 106: 3–14.

40. AggletonJP, O'MaraSM, VannSD, WrightNF, TsanovM, et al. (2010) Hippocampal-anterior thalamic pathways for memory, uncovering a network of direct and indirect actions. Eur J Neurosci 31: 2292–2307.

41. PotchenMJ, KampondeniSD, SeydelKB, BirbeckGL, HammondCA, et al. (2012) Acute brain MRI findings in 120 Malawian children with cerebral malaria, new insights into an ancient disease. AJNR Am J Neuroradiol 33: 1740–1746.

42. ComimCM, ReisPA, FrutusoVS, FriesGR, FragaDB, et al. (2012) Effects of experimental cerebral malaria in memory, brain-derived neurotrophic factor and acetylcholinesterase activity in the hippocampus of survivor mice. Neurosci Lett 523: 104–107.

43. Gomez-Palacio-SchjetnanA, EscobarML (2013) Neurotrophins and synaptic plasticity. Curr Top Behav Neurosci 15: 117–136.

44. ShiQ, ZhangP, ZhangJ, ChenX, LuH, et al. (2009) Adenovirus-mediated brain-derived neurotrophic factor expression regulated by hypoxia response element protects brain from injury of transient middle cerebral artery occlusion in mice. Neurosci Lett 465: 220–225.

45. BarichelloT, BelarminoEJr, ComimCM, CiprianoAL, GenerosoJS, et al. (2010) Correlation between behavioral deficits and decreased brain-derived neurotrophic factor in neonatal meningitis. J Neuroimmunol 223: 73–76.

46. BekinschteinP, CammarotaM, KatcheC, SlipczukL, RossatoJI, et al. (2008) BDNF is essential to promote persistence of long-term memory storage. Proc. Natl Acad Sci USA 105: 2711–2716.

47. CanalsJM, PinedaJR, Torres-PerazaJF, BoschM, Martin-IbanezR, et al. (2004) Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease. J Neurosci 24: 7727–7739.

48. KleinAB, WilliamsonR, SantiniMA, ClemmensenC, EttrupA, et al. (2011) Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychopharmacol 14: 347–353.

49. SofroniewMV, HoweCL, MobleyWC (2001) Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 24: 1217–1281.

50. LovegroveFE, TangpukdeeN, OpokaRO, LaffertyEI, RajwansN, et al. (2009) Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children. PLoS One 4: e4912.

51. ConroyAL, GloverSJ, HawkesM, ErdmanLK, SeydelKB, et al. (2012) Angiopoietin-2 levels are associated with retinopathy and predict mortality in Malawian children with cerebral malaria, a retrospective case-control study. Crit Care Med 40: 952–959.

52. YeoTW, LampahDA, GitawatiR, TjitraE, KenangalemE, et al. (2008) Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. Proc Natl Acad Sci U S A 105: 17097–17102.

53. NarsariaN, MohantyC, DasBK, MishraSP, PrasadR (2012) Oxidative stress in children with severe malaria. J Trop Pediatr 58: 147–150.

54. DrewPD, XuJ, RackeMK (2008) PPAR-gamma, therapeutic potential for multiple sclerosis. PPAR Res 2008: 627463.

55. VemugantiR (2008) Therapeutic potential of PPARγ activation in stroke. PPAR Res 2008: 461981.

56. BrightJJ, KanakasabaiS, ChearwaeW, ChakrabortyS (2008) PPAR regulation of inflammation signaling in CNS diseases. PPAR Res 2008: 658520.

57. Mandrekar-ColucciS, KarloJC, LandrethGE (2012) Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease. J Neurosci 32: 10117–10128.

58. EscribanoL, SimónAM, Pérez-MediavillaA, Salazar-ColochoP, RíoJD, et al. (2009) Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer's disease mouse model. Biochem Biophys Res Commun 379: 406–410.

59. SchintuN, FrauL, IbbaM, CaboniP, GarauA, et al. (2009) PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson's disease. Eur J Neurosci 29: 954–963.

60. WatsonGS, CholertonBA, RegerMA, BakerLD, PlymateSR, et al. (2005) Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone, a preliminary study. Am J Geriatr Psychiatry 13: 950–958.

61. KaiserCC, ShuklaDK, StebbinsGT, SkiasDD, JefferyDR, et al. (2009) A pilot test of pioglitazone as an add-on in patients with relapsing remitting multiple sclerosis. J Neuroimmunol 211: 124–130.

62. SerghidesL, KimH, LuZ, KainDC, MillerC, et al. (2011) Inhaled nitric oxide reduces endothelial activation and parasite accumulation in the brain, and enhances survival in experimental cerebral malaria. PLoS One 6: e27714.

63. FrancisBM, KimJ, BarakatME, FraenkiS, YucelYH, et al. (2012) Object recognition memory and BDNF expression are reduced in young TgCRND8 mice. Neurobiol Aging 33: 555–563.

64. CahillLS, LaliberteCL, EllegoodJ, SpringS, GleaveJA, et al. (2012) Preparation of fixed mouse brains for MRI. Neuroimage 60: 933–939.