Neurotolerability of Contrast Agents in Rats with Brain Ischemia Induced by Transient Middle Cerebral Artery Occlusion

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Abstract
Because contrast agent (CA) formulations are injected intravenously to patients who may have a disrupted blood-brain barrier, their neurotolerability should be tested by using appropriate animal models. In the present study, a model of rat brain ischemia evaluated in terms of the electroencephalogram (EEG) was validated and then used to compare the neurotolerability of gadobenate dimeglumine to that of gadodiamide, a well-documented CA for brain MRI. Rats were prepared for EEG recording about 15 days before ischemia induction. Ischemia was induced in the right hemisphere by 2-hour middle cerebral artery (MCA) occlusion and 3-day reperfusion. Model validation in terms of EEG, on day 3 after MCA occlusion, was performed by using iopromide, a poorly neurotolerated iodinated CA in rats, intravenously injected at 7 g iodine/kg. The EEG recording was analyzed for pathological tracings and for changes in spectral content in terms of the frequency index (FI) at 1, 2, and 3 hours after test compound injection. The comparative study between gadobenate dimeglumine and gadodiamide was performed at 2.0 mmol/kg. d-Mannitol was used as a control compound. The presence of CA in the rat brain was verified by measuring the total gadolinium content by using inductively coupled plasma-atomic emission spectrometry analysis. Given the absence of metabolism for both CAs, the values of gadolinium content can be interpreted as representing unmetabolized CA. On days 1, 2, and 3 after transient MCA occlusion, the lesioned hemisphere of rats presented a decreased FI value with respect to the basal value. The unlesioned hemisphere, after a slight, nonsignificant decrease in the FI value on the first 2 days, presented a normal FI value on day 3. Thus, ischemic rats on day 3 after transient MCA occlusion were chosen for these neurotolerability studies. Iopromide injected intravenously into ischemic rats at a dose 10 times higher than the maximum clinical dose caused bilateral spikes on the EEG and increases in FI values for the unlesioned hemisphere without affecting the lesioned hemisphere. Gadobenate dimeglumine, like gadodiamide when injected into ischemic rats, did not cause spikes or further changes in the FI value of the lesioned hemisphere and did not modify the normal FI value of the unlesioned hemisphere. Furthermore, no significant differences between gadobenate dimeglumine, gadodiamide, and d-mannitol were found when postinjection FI values were compared. Finally, higher levels of gadolinium were found in the lesioned hemisphere with respect to the unlesioned hemisphere after both gadobenate dimeglumine and gadodiamide administration. We can therefore conclude that (1) on the EEG, ischemia induced by transient MCA occlusion is an appropriate model for evaluating CA neurotolerability because ischemic and CA effects can be clearly differentiated; (2) the higher level of CA in the lesioned hemisphere compared with the unlesioned one (two to three times), even 3 hours after injection, demonstrates that the CA effectively penetrated the brain; if it were neurotoxic, any negative effects would have been detected; and (3) gadobenate dimeglumine, like gadodiamide, injected intravenously at a dose 20 times higher than the intended clinical dose for brain MRI is well tolerated and, also like gadodiamide, is suitable for use in neurological diseases for which contrast-enhanced MRI is indicated.