Abstract
The development of a diagnostic technology that can accurately determine the pathological progression of ischemic stroke and evaluate the therapeutic effects of cerebroprotective agents has been desired. We previously developed a novel PET probe, 2-tert-butyl-4-chloro-5-{6-[2-(2-18F-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([18F]BCPP-EF) for detecting activity of mitochondrial complex I (MC-I). This probe was shown to visualize neuronal damage in the living brain of rodent and primate models of neurodegenerative diseases. In the present study, [18F]BCPP-EF was applied to evaluate the therapeutic effects of a neuroprotectant, liposomal FK506 (FK506-liposomes), on cerebral ischemia/reperfusion (I/R) injury in transient middle cerebral artery occlusion rats. The PET imaging using [18F]BCPP-EF showed a prominent reduction in the MC-I activity in the ischemic brain hemisphere. Treatment with FK506-liposomes remarkably increased the uptake of [18F]BCPP-EF in the ischemic side corresponding to the improvement of blood flow disorders and motor function deficits throughout the 7 days after I/R. Additionally, the PET scan could diagnose the extent of the brain damage accurately and showed the neuroprotective effect of FK506-liposomes at Day 7, at which 2, 3, 5-triphenyltetrazolium chloride staining couldn’t visualize them. Our study demonstrated that the PET technology using [18F]BCPP-EF has a potent capacity to evaluate the therapeutic effect of drug candidates in living brain.
Highlights
Ischemic stroke is the leading cause of long-term disability in adults worldwide[1]
Our previous study revealed that liposomalization of FK506 enhances its neuroprotective effect against cerebral I/R injury in transient middle cerebral artery occlusion (t-MCAO) rats, which procedure could lead to decreased rates of side effects by allowing a reduction in the dose of the drug[13]
We examined the therapeutic effect of FK506-liposomes on cerebral I/R injury in t-MCAO rats at both acute and subacute phases, by chronologically assessing the mitochondrial complex I (MC-I) activity by PET analysis using [18F]BCPP-EF, the motor functional behavior, and the cerebral blood flow
Summary
Ischemic stroke is the leading cause of long-term disability in adults worldwide[1]. Cerebral ischemia-reperfusion (I/R) injury, which often results from thrombolytic therapy, is strongly related to the disability in stroke patients and remains an important clinical problem[2]. Advanced evaluation methods are required to precisely assess the therapeutic effect of candidate drugs on ischemic brain damage. We examined the therapeutic effect of FK506-liposomes on cerebral I/R injury in t-MCAO rats at both acute and subacute phases, by chronologically assessing the MC-I activity by PET analysis using [18F]BCPP-EF, the motor functional behavior, and the cerebral blood flow. Through these analyses, we investigated the potential of [18F]BCPP-EF as a novel diagnostic probe for non-invasively evaluating the neuroprotective effect of drug candidates on cerebral injury
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