Stroke is a leading cause of death and disability. Free radical generation is a well-documented mechanism of ischemia/reperfusion injury, blood brain barrier (BBB) disruption and hemorrhage in ischemic stroke. However, free radicals are difficult to study due to lack of non-invasive tools for in vivo assessment. Conventional MRI is widely used for diagnostic imaging;however, it offers no window into the fundamental processes of oxidative stress following reperfusion injury. There are currently no NMR contrast mechanisms that can detect endogenous production of destructive free radicals. MRI-based biomarkers for visualizing and quantifying the BBB disruption at very early (hyperacute) stages of stroke are similarly unavailable as MRI contrast agents such as Gd-DTPA can only probe ischemic BBB disruption several hours after stroke onset. Free radical sensitive Overhauser-enhanced MRI (OMRI) is a promising technique for imaging the distribution and dynamics of free radicals. We have recently demonstrated a novel, fast and high-resolution OMRI method that offers new perspectives for the free radicals imaging in living organisms. We propose here two complementary aims to implement this novel MRI-based method for non-invasive 3D free radical imaging in ischemic stroke:
Aim 1 : Detect endogenous free radical production by OMRI as a novel and direct measure of oxidative stress associated with ischemia/reperfusion injury.
Aim 2 : Detect hyperacute BBB breakdown by making use of a stable free radical probe (TEMPOL) as an exogenously administered contrast agent for OMRI. We will use a rat model of cerebral ischemia/reperfusion to test and refine the ability of our technique to detect endogenous and exogenous free radicals.
Both aims have direct clinical relevance. In vivo OMRI of endogenous free radical production will open a non-invasive window into oxidative stress and reperfusion injury, a critical mechanism of cell death in stroke and other forms of brain injury. OMRI will provide an in-depth understanding of spatiotemporal patterns of endogenous free radical production in ischemic brain. Moreover, timely detection of oxidative stress will help tailor interventions to mitigate free radical-induced brain injury in individual patients. Additionally, the use of TEMPOL as a small, exogenous OMRI agent will allow monitoring BBB disruption in stroke at the hyperacute stage, much earlier than the traditional relaxation-based MRI contrast agents that rely on the leakage of larger molecules (such as Gd-DTPA) across the BBB. Altogether, the OMRI technology is a tool that may transform the diagnostic, therapeutic and prognostic approach to acute stroke.
Each year, about 15 million people worldwide and 795,000 people in United States experience a new or recurrent stroke. The production of free radicals is well documented in stroke, and is associated with reperfusion injury, blood brain barrier rupture, and further risk of hemorrhage;despite their importance free radicals are difficult to study due t the profound absence of non-invasive tools for in vivo assessment. This work seeks to develop a new MRI-based method for imaging free radicals in vivo as a powerful new tool to clarify the mechanisms involved in reperfusion damage, and may revolutionize the use of MRI for the clinical assessment, pharmacological intervention and treatment of acute stroke.
