title: PPARγ agonists improve survival and neurocognitive outcomes in experimental cerebral malaria and induce neuroprotective pathways in human malaria.
abstract: Cerebral malaria (CM) is associated with a high mortality rate, and long-term neurocognitive impairment in approximately one third of survivors. Adjunctive therapies that modify the pathophysiological processes involved in CM may improve outcome over anti-malarial therapy alone. PPARγ agonists have been reported to have immunomodulatory effects in a variety of disease models. Here we report that adjunctive therapy with PPARγ agonists improved survival and long-term neurocognitive outcomes in the Plasmodium berghei ANKA experimental model of CM. Compared to anti-malarial therapy alone, PPARγ adjunctive therapy administered to mice at the onset of CM signs, was associated with reduced endothelial activation, and enhanced expression of the anti-oxidant enzymes SOD-1 and catalase and the neurotrophic factors brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brains of infected mice. Two months following infection, mice that were treated with anti-malarials alone demonstrated cognitive dysfunction, while mice that received PPARγ adjunctive therapy were completely protected from neurocognitive impairment and from PbA-infection induced brain atrophy. In humans with P. falciparum malaria, PPARγ therapy was associated with reduced endothelial activation and with induction of neuroprotective pathways, such as BDNF. These findings provide insight into mechanisms conferring improved survival and preventing neurocognitive injury in CM, and support the evaluation of PPARγ agonists in human CM.
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; SA Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network, Toronto, Ontario, Canada; Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.
authors.forename: Lena
authors.initials: L
authors.lastname: Serghides
authors.affiliation: SA Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network, Toronto, Ontario, Canada; Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Chloe R
authors.initials: CR
authors.lastname: McDonald
authors.affiliation: SA Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network, Toronto, Ontario, Canada; Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ziyue
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Miriam
authors.initials: M
authors.lastname: Friedel
authors.affiliation: Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Cui
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Ho
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Howard T J
authors.initials: HT
authors.lastname: Mount
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: John G
authors.initials: JG
authors.lastname: Sled
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; SA Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network, Toronto, Ontario, Canada; Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016779:Malaria, Cerebral / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D016032:Randomized Controlled Trials as Topic; D060888:Real-Time Polymerase Chain Reaction; D012259:Ribonuclease, Pancreatic / Q000032:analysis; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C046366:angiogenin; D012259:Ribonuclease, Pancreatic