Neurotolerability of Gadobenate Dimeglumine in a Rat Model of Focal Brain Ischemia:

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Abstract
The neurologic pathologies for which contrast-enhanced MRI is indicated are often accompanied by a disruption of the blood-brain barrier (BBB), which allows the contrast agent to come into contact with the nervous tissue. Thus, assessment of the neurologic safety for a new contrast agent is of crucial importance. The objective of this study was to assess the neurotolerability of the new MRI contrast agent gadobenate dimeglumine using EEG in the presence of focal lesions of the BBB. Lesions of the BBB were obtained inducing a photochemical ischemia in rats. Gadobenate dimeglumine was intravenously administered at 4.0 mmol/kg. An EEG was recorded during sleep/awake behavior and was analyzed for pathologic tracing and for changes in spectral content in terms of total power and frequency index. The presence of the BBB lesions was verified using high-performance liquid chromatography measurement of the gadobenate ion content in the brain. Gadobenate dimeglumine did not have any epileptogenic effect in ischemic rats. However, it caused a transitory shift of the EEG power spectrum toward the 0.5 to 9 Hz frequency bands of the lesioned hemisphere during quiet wake. In the lesioned cortex, higher levels of gadobenate ion were found until 3 hours after administration. In experimental conditions of focal brain ischemia associated with BBB lesions, gadobenate dimeglumine was well tolerated up to doses even 10 times higher than the maximum clinical dose (0.3 mmol/kg) intended for brain imaging procedures.