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Measles virus-induced hippocampal neurodegeneration in the mouse: a novel, subacute model for testing neuroprotective
T Andersson1, R Schwarcz, A Löve
1Clinical Research Center, Karolinska Institutet, Huddinge Hospital, Sweden.
Abstract:
The hamster neurotropic (HNT) strain of measles virus causes non-inflammatory encephalopathy in Balb/c mice, associated with neurodegeneration in hippocampal CA1 and CA3 regions. This loss of pyramidal cells can be prevented by twice daily systemic treatment with 1 mg/kg dizocilpine (5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclo-hepten-5,10-imine maleate; MK-801) for 7 days. By varying the MK-801 treatment protocol, we now found that drug administration during the last 4 days prior to sacrifice (i.e. days 4-7 post inoculation, p.i.) is essential for neuroprotection. In contrast, MK-801 treatment during the first days (days 0-4 p.i.) did not prevent the neuronal necrosis. These data suggest that the concentration of an excitotoxic factor in the mouse brain increases after virus inoculation, reaching toxic levels by days 4-5 p.i. This novel 'subacute' mouse model of neurodegeneration therefore constitutes an attractive tool for mechanistic and interventional studies in excitotoxicity research.
Insights
Neuroprotection against measles virus-induced brain damage in mice requires dizocilpine (MK-801) treatment during the later stages of infection. Early treatment does not prevent neuronal loss, suggesting a delayed increase in excitotoxicity.
Area of Science:
- Neuroscience
- Virology
- Pharmacology
Background:
- Measles virus infection can cause non-inflammatory encephalopathy and neurodegeneration in specific brain regions.
- Pyramidal cell loss in the hippocampus is a key feature of this neurodegeneration.
- Dizocilpine (MK-801) has previously shown neuroprotective effects in this model.
Purpose of the Study:
- To determine the critical timing of dizocilpine (MK-801) administration for neuroprotection.
- To investigate the temporal dynamics of excitotoxicity in a viral neurodegeneration model.
- To establish a subacute mouse model for studying excitotoxicity.
Main Methods:
- Balb/c mice were inoculated with the hamster neurotropic (HNT) strain of measles virus.
- Varying treatment protocols of dizocilpine (MK-801) were administered at different time points post-inoculation.
- Neuroprotection was assessed by evaluating neuronal survival in hippocampal regions.
Main Results:
- Treatment with dizocilpine (MK-801) during the last 4 days (days 4-7 post-inoculation) was essential for preventing neuronal necrosis.
- Early treatment (days 0-4 post-inoculation) did not confer neuroprotection.
- These findings suggest an increase in brain excitotoxic factors after day 4-5 post-inoculation.
Conclusions:
- The timing of intervention is critical for neuroprotection in this viral encephalopathy model.
- This model demonstrates a delayed onset of excitotoxicity following viral infection.
- The developed subacute mouse model is valuable for research into excitotoxicity mechanisms and interventions.