In-vivo visualization of phagocytotic cells in rat brains after transient ischemia by USPIO.
Cerebral ischemia provokes tissue damage by two major patho-physiological mechanisms. Direct cell necrosis is induced by diminished access of neurons and glia to essential nutrients such as glucose and oxygen leading to energy failure. A second factor of cellular loss is related to the activation of immune-competent cells within and around the primary infarct. While granulocytes and presumably monocytes are linked to the no-reflow phenomenon, activated microglia cells and monocytes can release cytotoxic substrates, which cause delayed cell death. As a consequence the infarct volume will increase, despite restoration of cerebral perfusion. In the past, visualization of immune competent cells was only possible by histological analysis of post-mortem tissue. However, contrast agents based on small particles of iron oxide are known to accumulate in organs rich in cells with phagocytotic function. These particles can be tracked in vivo by MRI methods based on their relaxation properties. In the present study, the spatio-temporal distribution of USPIO particles was monitored in a rat model of transient cerebral infarction using T1- and T2-weighted MRI sequences. USPIO were detected in vessels at 24 h after administration. At later time points specific accumulation of USPIO was observed within the infarcted hemisphere, with maximal signal enhancement on day 2. Their detectability based on T1-contrast disappeared between day 4 and day 7. Immuno-histochemically (IHC) stains confirmed the presence of macrophages, presumably blood-derived monocytes within areas of T1 signal enhancement. Direct visualization of iron-burdened macrophages by IHC was only possible later than day 3 after occlusion.
Novartis Pharma AG, Core Technology Area, CH-4002 Basel, Switzerland. martin.rausch@pharma.novartis.com
M
M
Rausch
D
D
Baumann
U
U
Neubacher
M
M
Rudin
D000818:Animals; D002339:Carotid Arteries / Q000473:pathology; D003287:Contrast Media; D003911:Dextrans; D052203:Ferrosoferric Oxide; D007501:Iron; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology*; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles; D008297:Male; D010087:Oxides; D010587:Phagocytosis / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D003287:Contrast Media; D003911:Dextrans; D058185:Magnetite Nanoparticles; D010087:Oxides; C097921:ferumoxtran-10; D007501:Iron; D052203:Ferrosoferric Oxide