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Updated: May 14, 2026

In Vivo Tracking of Edema Development and Microvascular Pathology in a Model of Experimental Cerebral Malaria Using Magnetic Resonance Imaging
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Bradykinin Contributes to Vasogenic Edema in Murine Experimental Cerebral Malaria

Alessandro de Sa Pinheiro, Douglas E Teixeira, Rodrigo P Silva-Aguiar

    Biorxiv : the Preprint Server for Biology
    |May 13, 2026
    PubMed

    Insights

    Bradykinin (BK) contributes to brain swelling and neurological damage in cerebral malaria (CM). Blocking BK pathways or inhibiting plasma kallikrein reduces CM severity and improves survival in mouse models, suggesting new therapeutic targets.

    Area of Science:

    • Neuroscience
    • Immunology
    • Parasitology

    Background:

    • Cerebral malaria (CM), caused by *Plasmodium falciparum*, is a leading cause of death in African children.
    • Bradykinin (BK) is implicated in vasogenic edema and may contribute to CM pathogenesis.
    • Cleaved high molecular weight kininogen (cHK) serves as a biomarker for BK release.

    Purpose of the Study:

    • To investigate the role of the bradykinin system in the pathogenesis of cerebral malaria.
    • To evaluate the therapeutic potential of targeting BK pathways in experimental CM.

    Main Methods:

    • Analysis of plasma cHK levels in children with CM and uncomplicated malaria.
    • Studies in wild-type and genetically modified mice (*Kng1* null, BK receptor null, *Klkb1* null, *Prcp* hypomorph/conditional knockout) infected with *P. berghei* ANKA (PbA).
    • Assessment of neurological deterioration, brain edema, and survival.
    • Evaluation of combined artesunate and plasma kallikrein inhibition treatment in PbA-infected mice.

    Main Results:

    • Elevated plasma cHK levels were observed in children and PbA-infected mice with CM.
    • Mice lacking functional components of the BK system (receptors, kininogen, prekallikrein, prolylcarboxypeptidase) showed protection against CM.
    • Combined inhibition of plasma kallikrein with artesunate reversed neurological deficits and brain edema, prolonging survival in mice.

    Conclusions:

    • Bradykinin-induced vasogenic edema is a significant contributor to the pathophysiology of both human and murine cerebral malaria.
    • Targeting the bradykinin system, particularly plasma kallikrein, represents a promising therapeutic strategy for CM.

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