ArticleParasites & vectors2025
Hemozoin induces neuronal injury primarily characterized by axon rupture and mitochondrial damage in experimental cerebral malaria.
Article in Parasites & vectors, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Mangiferin in combination with primaquine reduces disease progression and transmission potential while alleviating cerebral pathology through suppression of neural cell apoptosis in experimental cerebral malaria.Inflammopharmacology · 2026Article
- Microglial tunneling nanotubes: an intercellular transfer facilitating mitochondrial dysfunction and neuroinflammation in experimental cerebral malaria.Apoptosis : an international journal on programmed cell death · 2026Article
- Research progress of OTUD7B: from structural function and disease mechanisms to clinical translation.Frontiers in immunology · 2026Review
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14 authors.
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Abstract
backgroundCerebral malaria (CM) is the most serious and fatal neurological complication of Plasmodium falciparum infection, which can cause death or long-term neurological sequelae. Neuronal injury is a primary cause of these sequelae in patients with CM; however, the underlying mechanisms remain incompletely elucidated. Hemozoin (Hz), the metabolic byproduct of hemoglobin digested by Plasmodium parasites, is closely associated with the severity of CM. However, it is not clear whether Hz is a direct contributor to neuronal injury.
methodsC57BL/6 J mice were infected with the Plasmodium berghei ANKA (PbA) strain to induce experimental cerebral malaria (ECM). Hz deposition and neuronal injury in ECM mice brain tissues were assessed using histopathological staining. In vitro, primary cortical neurons were stimulated with purified hemozoin (pHz). Neuronal morphology, pHz internalization, and injury severity were assessed via transmission electron microscopy (TEM), live-cell imaging, and lactate dehydrogenase (LDH) assays, respectively. Furthermore, Mito-Tracker and JC-1 probes were used to analyze mitochondrial content and membrane potential, respectively. ATP assay kits were used to quantify cellular energy metabolism levels, while reactive oxygen species (ROS)/neuronal nitric oxide synthase (nNOS) fluorescent probes were used to assess oxidative stress and inflammatory response. Neurotransmitter alterations were analyzed by measuring glutamate (Glu) levels.
resultsIn the cerebral cortex of ECM mice, significant Hz deposition and reduced neuronal nuclei (NeuN) expression levels were observed. Immunofluorescence (IF) staining demonstrated that pHz adhered to primary neurons in vitro, causing reduced dendritic arborization, axon rupture, and plasma membrane disruption. TEM and live-cell imaging confirmed that pHz was internalized into the cytoplasm of neurons. Furthermore, pHz induced mitochondrial structural damage and reduced mitochondrial content. Concurrently, pHz triggered mitochondrial dysfunction, characterized by diminished mitochondrial membrane potential (MMP), reduced ATP levels, and elevated ROS. In addition, pHz upregulated intraneuronal nNOS activity and caused a decrease in neurotransmitter levels.
conclusionsThis study provided the first evidence to our knowledge that Hz directly adhered to neurons and underwent internalization into its cytoplasm, thereby leading to neuronal injury. These findings elucidate a potential mechanism underlying neuronal injury in ECM and inform the development of adjuvant therapies targeting Hz.
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