Brain redox imaging using blood-brain barrier-permeable nitroxide MRI contrast agent

Area of Science:

• Neuroscience
• Biochemistry
• Medical Imaging

Background:

• Reactive oxygen species (ROS) and impaired antioxidant defenses are implicated in neurological disorders like stroke.
• Nitroxides serve as dual-action agents, functioning as both redox-sensitive contrast agents and antioxidants.

Purpose of the Study:

• To evaluate the efficacy of a blood-brain barrier (BBB)-permeable nitroxide, methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (MC-P), as a contrast agent for brain tissue redox imaging using magnetic resonance imaging (MRI).

Main Methods:

• Quantified MC-P relaxation in rodent brain using fast Look-Locker T(1)-mapping MRI sequences.
• Compared MRI signal changes with a BBB-impermeable nitroxide (3CxP).
• Validated brain tissue and blood concentrations using ex vivo electron paramagnetic resonance (EPR) spectroscopy.

Main Results:

• MC-P injection increased MRI signal intensity by up to 50% in the cerebral cortex and thalamus, significantly more than the BBB-impermeable nitroxide (2.7%).
• Maximum MC-P concentrations in brain tissue were determined to be 1.9+/-0.35 mmol/L (thalamus) and 3.0+/-0.50 mmol/L (cerebral cortex).
• Reduced MC-P reduction rates were observed after reperfusion in a middle cerebral artery occlusion (MCAO) model, indicating altered redox status.

Conclusions:

• BBB-permeable nitroxides like MC-P are effective MRI contrast agents for brain tissue redox imaging.
• These agents can quantify changes in redox status associated with oxidative damage in neurological conditions.
• MC-P holds potential as both an MRI contrast agent and an antioxidant for studying ROS in neurologic diseases.