PMID- 24603727 OWN - NLM STAT- MEDLINE DCOM- 20141104 LR - 20211021 IS - 1553-7374 (Electronic) IS - 1553-7366 (Print) IS - 1553-7366 (Linking) VI - 10 IP - 3 DP - 2014 Mar TI - PPARgamma agonists improve survival and neurocognitive outcomes in experimental cerebral malaria and induce neuroprotective pathways in human malaria. PG - e1003980 LID - 10.1371/journal.ppat.1003980 [doi] LID - e1003980 AB - 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. PPARgamma agonists have been reported to have immunomodulatory effects in a variety of disease models. Here we report that adjunctive therapy with PPARgamma agonists improved survival and long-term neurocognitive outcomes in the Plasmodium berghei ANKA experimental model of CM. Compared to anti-malarial therapy alone, PPARgamma 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 PPARgamma adjunctive therapy were completely protected from neurocognitive impairment and from PbA-infection induced brain atrophy. In humans with P. falciparum malaria, PPARgamma 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 PPARgamma agonists in human CM. FAU - Serghides, Lena AU - Serghides L AD - 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. FAU - McDonald, Chloe R AU - McDonald CR AD - 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. FAU - Lu, Ziyue AU - Lu Z AD - 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. FAU - Friedel, Miriam AU - Friedel M AD - Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada. FAU - Cui, Cheryl AU - Cui C AD - Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. FAU - Ho, Keith T AU - Ho KT AD - Department of Physiology, University of Toronto, Toronto, Ontario, Canada. FAU - Mount, Howard T J AU - Mount HT AD - Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. FAU - Sled, John G AU - Sled JG AD - Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. FAU - Kain, Kevin C AU - Kain KC AD - 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. LA - eng GR - 244701/Canadian Institutes of Health Research/Canada GR - MOP-13721/Canadian Institutes of Health Research/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140306 PL - United States TA - PLoS Pathog JT - PLoS pathogens JID - 101238921 RN - 0 (Antimalarials) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Neuroprotective Agents) RN - 0 (PPAR gamma) RN - 0 (Thiazolidinediones) RN - 05V02F2KDG (Rosiglitazone) RN - EC 3.1.27.- (angiogenin) RN - EC 3.1.27.5 (Ribonuclease, Pancreatic) SB - IM MH - Animals MH - Antimalarials/*pharmacology MH - Brain/*drug effects/metabolism/pathology MH - Brain-Derived Neurotrophic Factor/analysis MH - Disease Models, Animal MH - Enzyme-Linked Immunosorbent Assay MH - Female MH - Humans MH - Malaria, Cerebral/*complications/metabolism/pathology MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Neuroprotective Agents/pharmacology MH - PPAR gamma/*antagonists & inhibitors MH - Randomized Controlled Trials as Topic MH - Real-Time Polymerase Chain Reaction MH - Ribonuclease, Pancreatic/analysis MH - Rosiglitazone MH - Thiazolidinediones/pharmacology PMC - PMC3946361 COIS- I have read the journal's policy and have the following conflicts: The University Health Network holds intellectual property pertaining to the use of PPARgamma agonists for the treatment of severe malaria. The authors have no other financial interests related to this work. This does not alter our adherence to all PLOS Pathogens policies on sharing data and materials. EDAT- 2014/03/08 06:00 MHDA- 2014/11/05 06:00 PMCR- 2014/03/06 CRDT- 2014/03/08 06:00 PHST- 2013/06/29 00:00 [received] PHST- 2014/01/22 00:00 [accepted] PHST- 2014/03/08 06:00 [entrez] PHST- 2014/03/08 06:00 [pubmed] PHST- 2014/11/05 06:00 [medline] PHST- 2014/03/06 00:00 [pmc-release] AID - PPATHOGENS-D-13-01743 [pii] AID - 10.1371/journal.ppat.1003980 [doi] PST - epublish SO - PLoS Pathog. 2014 Mar 6;10(3):e1003980. doi: 10.1371/journal.ppat.1003980. eCollection 2014 Mar.