ABSTRACT
Detection and protection of apoptosis, autophagy and neurovascular unit (NVU) are essentially important in understanding and treatment for ischemic stroke patients. In this study, we have conducted an in vivo optical imaging for detecting apoptosis and activation of matrix metalloproteinases (MMPs), then evaluated the protective effect of 2 package types of free radical scavenger edaravone (A and B) on apoptosis, autophagy and NVU in mice after transient middle cerebral artery occlusion (tMCAO). As compared to vehicle treatment, edaravones A and B showed a significant improvement of clinical scores and infarct size at 48 h after 90 min of tMCAO with great reductions of in vivo fluorescent signal for MMPs and early apoptotic annexin V activations. Ex vivo imaging of MMPSense 680 or annexin V-Cy5.5 showed a fluorescent signal, while which was remarkably different between vehicle and edaravone groups, and colocalized with antibody for MMP-9 or annexin V. Edaravone A and B ameliorated the apoptotic neuronal cell death in immunohistochemistry, and activations of MMP-9 and aquaporin 4 with reducing autophagic activations of microtubule-associated protein 1 light chain 3 (LC3) in Western blot. In this study, edaravone in both packages showed a similar strong neuroprotection after cerebral ischemia, which was confirmed with in vivo and ex vivo optical imagings for MMPs and annexin V as well as reducing cerebral infarct, inhibiting apoptotic/autophagic mechanisms, and protecting a part of neurovascular unit.
Subject(s)
Antipyrine/analogs & derivatives , Free Radical Scavengers/therapeutic use , Ischemic Attack, Transient/drug therapy , Ischemic Attack, Transient/pathology , Animals , Annexin A5/metabolism , Antipyrine/therapeutic use , Apoptosis , Autophagy , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/pathology , Blotting, Western , Cerebral Infarction/pathology , Diagnostic Imaging , Edaravone , Fluorescence , Fluorescent Antibody Technique , Fluorescent Antibody Technique, Indirect , Immunohistochemistry , In Situ Nick-End Labeling , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/pathology , Male , Matrix Metalloproteinases/metabolism , Mice , Mice, Inbred ICRABSTRACT
BACKGROUND: The sonodynamically-induced in vitro and in vivo antitumor effects of mono-l-aspartyl chlorin e6 (NPe6) was investigated. MATERIALS AND METHODS: Both in vitro and in vivo antitumor effects were tested in combination with ultrasound at 2 MHz. RESULTS: The rate of ultrasonically-induced damage on isolated sarcoma 180 cells in air-saturated suspension was enhanced two-fold with 80 µM NPe6. The co-administration of 25 mg/kg NPe6 followed by ultrasonic exposure at 2 MHz suppressed the growth of implanted colon 26 cell tumors at an intensity at which ultrasound alone showed only a slight antitumor effect. CONCLUSION: These in vitro and in vivo results suggest that NPe6 is a potential sensitizer for sonodynamic tumor treatment. The enhancement of cell damage by NPe6 was significantly inhibited by histidine, which may suggest reactive oxygen species plays a primary role in sonodynamically-induced antitumor effect.
Subject(s)
Antineoplastic Agents/pharmacology , Porphyrins/pharmacology , Sarcoma 180/therapy , Animals , Combined Modality Therapy , Male , Mice , Mice, Inbred BALB C , Mice, Inbred ICR , Sarcoma 180/drug therapy , Ultrasonic TherapyABSTRACT
A series of 5-phenyl-substituted-N-alkyl-imidazolin-2-ones with potent radical-scavenging activity and lipid peroxidation inhibitory activity was synthesized. Many of the compounds showed memory-improving effect in animal models independent of the inhibitory activity on lipid peroxidation.
Subject(s)
Antioxidants/chemistry , Antioxidants/pharmacology , Imidazolines/chemistry , Imidazolines/pharmacology , Memory/drug effects , Animals , Antioxidants/chemical synthesis , Free Radical Scavengers/chemical synthesis , Free Radical Scavengers/chemistry , Free Radical Scavengers/pharmacology , Imidazolines/chemical synthesis , Lipid Peroxidation/drug effects , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
This paper describes the discovery of a novel free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone, 1), as a potent antioxidant agent against lipid peroxidation. The structure-activity relationship of edaravone indicated that lipophilic substituents were essential to show its lipid peroxidation-inhibitory activity. In vivo studies revealed that edaravone showed brain-protective activity in a transient ischemia model.
