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Updated: May 14, 2026
Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines
Published on: September 21, 2021
Experimental models of disseminated scedosporiosis with cerebral involvement
Bénédicte Lelièvre1, Pierre Legras, Charlotte Godon
1Groupe d'Etude des Interactions Hôte-Pathogène, Institut de Biologie en Santé-PBH, CHU, 4 rue Larrey, 49933 ANGERS cedex 9, France. belelievre@chu-angers.fr
Abstract:
Scedosporium apiospermum is a soil fungus which can cause severe and often fatal cerebral infections in both immunocompetent patients in the event of near drowning and immunosuppressed patients such as lung transplant recipients. Because of the low susceptibility of this fungus to antifungal drugs, and the low permeability of the blood-brain barrier (BBB), therapeutic drug monitoring is necessary to reach an effective tissue concentration with limited side effects. Indeed, diffusion of the drug in the brain is dependent on several parameters, such as the integrity of the BBB and the activity of efflux pumps. To evaluate drug diffusion, two experimental models were developed in immunocompetent and immunosuppressed rats. Inocula were administered via the penile vein and a clinical scale (0-9) was established, based on weight and clinical and neurologic signs evaluated by the tail suspension test. Cerebral involvement was confirmed by magnetic resonance imaging and histologic examination of brain sections after hematoxylin-eosin-safran or silver staining. Voriconazole or posaconazole was given to the rats at doses ranging from 10 to 75 mg/kg/day via i.v. or oral routes, respectively. Whatever the immune status, the effective doses (defined by a doubling of the survival time and the absence of neurologic sequelae) were 30 mg/kg/day for voriconazole and 50 mg/kg/day for posaconazole. Overall, the results demonstrated that these models may constitute valuable tools for the performance of pharmacokinetic and pharmacodynamic studies for pharmacokinetic-pharmacodynamic modeling.
Insights
Scedosporium apiospermum causes severe brain infections. Effective voriconazole and posaconazole doses were determined in rat models to improve therapeutic drug monitoring for cerebral infections.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- Scedosporium apiospermum causes severe, often fatal, cerebral infections in immunocompetent and immunosuppressed individuals.
- Low antifungal drug susceptibility and poor blood-brain barrier (BBB) penetration necessitate therapeutic drug monitoring for effective treatment.
- Drug diffusion into the brain is influenced by BBB integrity and efflux pump activity.
Purpose of the Study:
- To develop and validate experimental rat models for evaluating antifungal drug diffusion across the BBB.
- To determine effective doses of voriconazole and posaconazole for treating Scedosporium apiospermum cerebral infections in vivo.
- To establish a basis for pharmacokinetic-pharmacodynamic (PK/PD) studies in cerebral mycoses.
Main Methods:
- Developed immunocompetent and immunosuppressed rat models for Scedosporium apiospermum cerebral infections.
- Administered fungal inocula via penile vein; monitored clinical and neurological signs using a 0-9 scale and tail suspension test.
- Confirmed cerebral involvement via MRI and histological examination; treated rats with voriconazole or posaconazole (10-75 mg/kg/day).
Main Results:
- Effective doses were established as 30 mg/kg/day for voriconazole and 50 mg/kg/day for posaconazole, regardless of immune status.
- Effective doses doubled survival time and prevented neurological sequelae.
- The developed rat models proved valuable for PK/PD studies of antifungal agents targeting the central nervous system.
Conclusions:
- The study successfully established and validated rat models for investigating Scedosporium apiospermum cerebral infections.
- Effective therapeutic doses for voriconazole and posaconazole were identified, crucial for guiding clinical treatment strategies.
- These models provide a robust platform for future PK/PD research to optimize antifungal therapy for brain infections.
