Neurotolerability of Gadobenate Dimeglumine

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Abstract
Magnetic resonance imaging with contrast agents (CAs) is a procedure currently used for the diagnosis of neurologic pathologies. These pathologies are often characterized by blood-brain barrier disruptions, which determines a direct contact between CA and brain tissue. For this reason, an accurate assessment of neurotolerability is useful for the development of new CAs. The present study was designed to evaluate the neurotolerability of a new CA for MRI, gadobenate dimeglumine, employing a neurochemical method. The effect of gadobenate dimeglumine on the striatal levels of neurotransmitters was determined. In particular, the brain concentrations of dopamine and dopamine metabolites, 3,4-dihydroxyphenylacetic and homovanillic acid, were measured using microdialysis, after the direct application of gadobenate dimeglumine into the rat corpus striatum. Gadopentetate dimeglumine and gadoteridol were employed as reference compounds. A microdialysis probe for brain extracellular fluid sampling and a stainless-steel cannula for CA application were chronically inserted into the right corpus striatum of rats. All CAs were administered at a dose of 5.4 nmol/rat. Dopamine and metabolite concentrations were analyzed using high-performance liquid chromatography. Gadobenate dimeglumine did not induce any significant changes in the extracellular levels of dopamine or dopamine metabolites up to 2 hours after administration. Gadoteridol produced similar results. Gadopentetate dimeglumine caused a moderate but not significant increase in dopamine levels throughout the duration of the experiments. Gadobenate dimeglumine directly administered into the corpus striatum of freely moving rats did not affect the dopaminergic system. This result demonstrates the safety of gadobenate dimeglumine under the experimental conditions used, thus confirming previous behavioral and electrophysiologic findings.