Perillyl Alcohol Reduces Parasite Sequestration and Cerebrovascular Dysfunction during Experimental Cerebral Malaria

Author(s)

Marin, Adriana A. ^[1] ; Murillo, Oscar ^{[1, 2]} ; Sussmann, Rodrigo A. ^{[1, 3]} ; Ortolan, Luana S. ^{[4, 5]} ; Battagello, Daniella S. ^[6] ; Quirino, Thatyane de Castro ^[7] ; Bittencourt, Jackson C. ^[6] ; Epiphanio, Sabrina ^[7] ; Katzin, Alejandro M. ^[1] ; Carvalho, Leonardo J. M. ^[8]

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Sao Paulo - Brazil

^[2] Univ Texas Tyler, Hlth Sci Ctr, Tyler, TX - USA

^[3] Fed Univ Southern Bahia, Inst Humanities Arts & Sci, Salvador - Brazil

^[4] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil

^[5] Ctr Global & Infect Dis Res, Seattle Childrens Res Inst, Seattle, WA - USA

^[6] Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Sao Paulo - Brazil

^[7] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo - Brazil

^[8] Oswaldo Cruz Inst, Lab Malaria Res, Rio De Janeiro - Brazil

• Document type: Journal article
• Source: Antimicrobial Agents and Chemotherapy; v. 65, n. 5 MAY 2021.
• Web of Science Citations: 0

Abstract

Cerebral malaria (CM) is a severe immune vasculopathy which presents a high mortality rate (15 to 20%), despite the availability of artemisinin-based therapy. More effective immunomodulatory and/or antiparasitic therapies are urgently needed. Experimental cerebral malaria (ECM) in mice is used to elucidate aspects involved in this pathology because it manifests many of the neurological features of CM. In the present study, we evaluated the potential mechanisms involved in the protection afforded by perillyl alcohol (POH) in mouse strains susceptible to CM caused by Plasmodium berghei ANKA (PbA) infection through intranasal preventive treatment. Additionally, we evaluated the interaction of POH with the cerebral endothelium using an in vitro model of human brain endothelial cells (HBEC). Pharmacokinetic approaches demonstrated constant and prolonged levels of POH in the plasma and brain after a single intranasal dose. Treatment with POH effectively prevented vascular dysfunction. Furthermore, treatment with POH reduced the endothelial cell permeability and PbA parasitized red blood cells in the brain and spleen. Finally, POH treatment decreased the accumulation of macrophages and T and B cells in the spleen and downregulated the expression of endothelial adhesion molecules (ICAM- 1, VCAM-1, and CD36) in the brain. POH is a potent monoterpene that prevents cerebrovascular dysfunction in vivo and in vitro, decreases parasite sequestration, and modulates different processes related to the activation, permeability, and integrity of the blood-brain barrier (BBB), thereby preventing cerebral edema and inflammatory infiltrates. (AU)

• FAPESP's process: 17/22452-1 - Biosynthesis of isoprenoids in Plasmodium falciparum: evaluation of possible targets to obtain new anti-malarial drugs
• Grantee: Alejandro Miguel Katzin
• Support Opportunities: Research Projects - Thematic Grants