C activity of standard anti-malarial drugs and, as such, present a valuable tool in the management bmjopen-2016-011824 of CM and limit the emergence 2-Chloro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one of resistant parasites. This review highlights the potential benefits that the plant-based natural product curcumin may have PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/14960617 as an immunomodulator and as an adjunctive therapy for CM.Rationale for the use of immunomodulators for the treatment of cerebral malariaCerebral malaria, one of the most severe complications of Plasmodium falciparum infections, is associated with various pathophysiological processes [6]. CM is mostly characterized by hyper-parasitaemia and by an excessive production of type 1 pro-inflammatory cytokines followed by up-regulation of endothelial cell adhesion molecule expression which contributes to the sequestration of PE in the brain microvasculature [7]. Understanding the molecular events implicated in the onset of CM would pave the way for the development of adjunctive therapies that may reduce cerebral damage by modulation of the pathological processes involved in its development, and thus prevent subsequent mortality and neurological sequalae. The association of immunomodulators with anti-malarial drugs could prove to be beneficial for the management of this condition [8]. This approach has already been tested using a variety of compounds in animal models of experimental cerebral malaria (ECM) [9-13] as well as in humans [14,15]. One of the strategies currently being investigated is to target the peroxisome proliferator activated receptor gamma (PPARg), a nuclear receptor involved in the regulation of the scavenger receptor CD36, which mediates nonopsonic phagocytosis of PE [16]. Pharmacological upregulation of CD36 in monocytes/macrophages by PPARg agonists increases CD36 dependant phagocytosis of PE in vitro [17]. In a murine model of malaria, administration of the PPARg agonist rosiglitazone, to Plasmodium chabaudi-infected mice, significantly decreased parasitaemia levels in wild type compared to CD36 knock-out mice and improved survival in Plasmodium bergheiANKA infected groups [12]. These findings warranted a randomized, double-blind, placebo-controlled trial to assess the efficacy of rosiglitazone, as an adjunctive therapy for the treatment of P. falciparum malaria. That trial showed a reduction in parasite clearance time and inflammatory markers in patients with uncomplicated malaria under a treatment regimen consisting of atovaquone + rosiglitazone compared to patients treated with atovaquone + placebo [18]. This evidence, together with a recent genome-wide association study linking a locus containing PPARg with improved survival in a rodent malaria model [19], led us to speculate thatpharmacologically targeting the signalling pathways involved in PPARg/CD36 expression during a malarial infection might improve CM treatment outcome. Erythropoietin (Epo), a hormone produced by the kidneys which modulates the survival of developing PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/6967774 erythroid precursors and production of new erythrocytes in the bone marrow, has been explored for the management of CM in animals and humans [9]. N-BOC-3-Fluoro-D-phenylalanine In the P. berghei-ANKA murine model of ECM, injection of high doses of Epo at the beginning of symptoms, significantly reduced the expression of pro-inflammatory cytokines (TNF and Interferon-g) and improved the survival of mice with ECM compared to untreated mice [20]. Furthermore, in the same murine model of ECM, the doses of Epo were decreased six fold and its administration combined with artesunate was.