Comparative study between gadobenate dimeglumine and gadobutrol in rats with brain ischemia: evaluation of somatosensory evoked potentials.
OBJECTIVE
The present study had two main objectives: to validate a rat model of brain ischemia in terms of somatosensory evoked potentials (SEPs) and to compare, using the validated model, the potential activity on the somatosensory function of the new, approved contrast agent gadobenate dimeglumine with that of gadobutrol, a specific contrast agent, for magnetic resonance imaging of the brain.


METHODS
Rats were prepared for SEP recording at least 5 days before ischemia induction. Ischemia was induced by 30-minute right middle cerebral artery occlusion and 3-day reperfusion. The SEP responses, evoked contralaterally to the stimulated upper limb, were recorded from the primary somatosensory cortical area. Model validation, on day 3 after occlusion, was performed using iopromide, an iodinated contrast agent poorly neurotolerated in rats, intravenously injected at 7 g I/kg. The comparative study between gadobenate dimeglumine and gadobutrol was performed at an intravenously injected dose of 2 mmol/kg. Somatosensory evoked potential responses were measured as peak latencies (P2 and N2) and peak-to-peak amplitude (P2N2). The brain concentration of iopromide was measured by high-performance liquid chromatography, whereas that of the gadolinium contrast agent was measured by inductively coupled plasma-atomic emission spectrometry analysis; given the absence of metabolism for both contrast agents, the gadolinium content values can be interpreted as representing unmetabolized contrast agent.


RESULTS
In the ischemic rats, the SEP responses of the lesioned hemisphere showed significant increases in P2, N2, and interpeak N2-P2 latencies and a significant reduction in peak-to-peak (P2N2) amplitude. In the validation experiments, iopromide dramatically increased the P2N2 amplitude of the SEP responses recorded from both hemispheres of ischemic rats without affecting the P2, N2, and interpeak N2-P2 latencies. The iopromide effect was coupled with high concentrations of the contrast agent in the brain. Iopromide had no effect on healthy rats. In the comparative study, gadobenate dimeglumine did not induce any alteration in SEP components of either the lesioned or unlesioned hemisphere of ischemic rats. In fact, no significant difference was found between responses obtained before and after gadobenate dimeglumine injection. Gadobutrol, administered at the same dose, on the whole showed the same behavior as gadobenate dimeglumine, although a slight but significant decrease in the P2 latency, a sign of excitatory activity, was observed 2 hours after injection. Analytic data indicated higher levels of contrast agent in the lesioned hemisphere versus the unlesioned hemisphere 2 hours after injection.


CONCLUSIONS
Based on these results, three conclusions can be drawn: (1) the evaluation of SEPs in ischemic rats is a useful tool for assessing the potential neurological effects of a new contrast agent because ischemic and contrast agent effects can be clearly differentiated; (2) the experimental conditions used allow the contrast agents to penetrate into the brain, where their activity can be manifested and evaluated; and (3) the complete absence of neurological activity of gadobenate dimeglumine shows its safety profile and confirms its suitability for use in neurological diseases for which contrast-enhanced magnetic resonance imaging is indicated.
Frigeni
V
V
Milano Research Centre, Bracco Imaging SpA, Milan, Italy. vfrigeni@bracco.it
Miragoli
L
L
Grotti And
A
A
Lorusso
V
V
D000818:Animals; D002545:Brain Ischemia / Q000175:diagnosis / Q000503:physiopathology*; D003287:Contrast Media / Q000493:pharmacokinetics; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects*; D005682:Gadolinium; D007472:Iohexol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D003287:Contrast Media; D009942:Organometallic Compounds; C064572:gadobenic acid; C090600:gadobutrol; D007472:Iohexol; D008536:Meglumine; C038192:iopromide; D005682:Gadolinium