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A gliotoxin model of occipital seizures in rats
Seyed M Mirsattari1, Bixia Shen, L Stan Leung
1Department of Graduate Studies, University of Western Ontario, London, Ontario, Canada. smirsat2@uwo.ca
Purpose:
Intracortical microinjection of fluorocitrate, a reversible inhibitor of glial tricarboxylic acid (TCA), results in impaired glial metabolism and epileptic seizures. To determine the potential contribution of epileptic activities to the metabolic properties of fluorocitrate, we investigated the seizure-inducing property of fluorocitrate at different doses.
Methods:
Twenty-seven male Sprague Dawley rats (250-400g) were studied with chronically implanted electrodes and cannulae in the occipital cortices. A week after surgery, awake behaving rats were injected with 0.2microl solution containing various concentrations of fluorocitrate or saline in the right occipital cortex; two sham-treated animals did not receive an injection. EEG was recorded with implanted electrodes. Thionin staining was used to verify injection sites. Twenty rats underwent immunohistochemistry for glial fibrilary acidic protein (GFAP) and neuronal nuclear-specific antigen (NeuN) 48h after the injections.
Results:
Seizures developed within an hour of injection in all the rats that received > or =0.8nmol fluorocitrate and 2 of 4 rats that received 0.4nmol fluorocitrate. Five of 12 animals that received > or =1.2nmol fluorocitrate experienced status epilepticus. There was a significant increase in GFAP staining at the injection site in doses > or =0.8nmol fluorocitrate. There was only mild neuronal loss revealed by NeuN staining at the injection site in the animals that had received 1.6nmol flourocitrate.
Conclusion:
This study shows that fluorocitrate results in focal epileptic seizures with secondary generalization in a dose-dependent manner, including low doses of this agent previously used for studies of brain metabolism.
Insights
Fluorocitrate causes dose-dependent epileptic seizures, affecting glial metabolism. This study investigated fluorocitrate
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Fluorocitrate inhibits the glial tricarboxylic acid (TCA) cycle, impairing glial metabolism.
- This inhibition is known to cause epileptic seizures.
- The relationship between seizure activity and metabolic changes induced by fluorocitrate requires further investigation.
Purpose of the Study:
- To investigate the seizure-inducing properties of fluorocitrate at various doses.
- To determine the dose-dependency of fluorocitrate-induced epileptic seizures.
- To understand the contribution of epileptic activities to fluorocitrate's metabolic effects.
Main Methods:
- Intracortical microinjections of varying fluorocitrate concentrations into the occipital cortex of Sprague Dawley rats.
- Electroencephalogram (EEG) recordings to monitor seizure activity.
- Immunohistochemistry for glial fibrillary acidic protein (GFAP) and neuronal nuclear-specific antigen (NeuN) to assess glial and neuronal changes.
Main Results:
- Seizures occurred within an hour in rats receiving ≥0.8 nmol fluorocitrate.
- Status epilepticus was observed in 5 of 12 animals receiving ≥1.2 nmol.
- Increased GFAP staining indicated glial activation at doses ≥0.8 nmol, with minimal neuronal loss at 1.6 nmol.
Conclusions:
- Fluorocitrate induces focal epileptic seizures with secondary generalization in a dose-dependent manner.
- Even low doses of fluorocitrate, previously used in metabolic studies, can trigger seizures.
- These findings highlight the potent epileptogenic nature of fluorocitrate.
