Novel molecular imaging of cell death in experimental cerebral stroke.
Cell death is the basic neuropathological substrate in cerebral ischemia, and its non-invasive imaging may improve diagnosis and treatment for stroke patients. ApoSense is a novel family of low-molecular weight compounds for detection and imaging of cell death in vivo. We now report on imaging of cell death and monitoring of efficacy of neuroprotective treatment in vivo by intravenous administration of the ApoSense compound DDC (didansylcystine), in experimental stroke in rodents. Rats and mice were subjected to a short-term (2 h) or permanent occlusion of the middle cerebral artery (MCA) and injected with DDC or 3H-labeled DDC. Fluorescent and autoradiographic studies, respectively, were performed ex vivo, comprising assessment of DDC uptake in the infarct region, in correlation with tissue histopathology. Neuroprotection was induced by a caspase inhibitor (Q-VD-OPH), and its effect was monitored by DDC. Following its intravenous administration, DDC accumulated selectively in injured neurons within the region of infarct. Caspase inhibition exerted a 45% reduction in infarct volume, which was well reported by DDC. This is the first report on a small molecule probe for detection in vivo of cell death in cerebral stroke. DDC may potentially assist in addressing the current "neuroimaging/neurohistology gap", for molecular assessment of the extent of stroke-related cell death.
Reshef
Ayelet
A
NST NeuroSurvival Technologies, Ltd., 5 Odem St., PO Box 7119, Petach-Tiqva 49170, Israel. ayelet@nst.co.il
Shirvan
Anat
A
Grimberg
Hagit
H
Levin
Galit
G
Cohen
Avi
A
Mayk
Adi
A
Kidron
Debora
D
Djaldetti
Ruth
R
Melamed
Eldad
E
Ziv
Ilan
I
D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use; D000818:Animals; D001345:Autoradiography / Q000379:methods; D016923:Cell Death; D003553:Cystine / Q000031:analogs & derivatives*; D053938:DNA Fragmentation / Q000187:drug effects; D003619:Dansyl Compounds; D003952:Diagnostic Imaging / Q000379:methods*; D004195:Disease Models, Animal; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000473:pathology* / Q000517:prevention & control; D013997:Time Factors; D014316:Tritium
D000590:Amino Acid Chloromethyl Ketones; D003619:Dansyl Compounds; D018696:Neuroprotective Agents; D011804:Quinolines; C468548:quinoline-val-asp(OMe)-CH2-OPH; D014316:Tritium; C038494:di(dansyl)cystine; D003553:Cystine