Theranostics 2020; 10(12):5341-5356. doi:10.7150/thno.42077 This issue Cite
1. MTA-ELTE Motor Pharmacology Research Group, Eötvös Loránd University, Department of Biochemistry, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary
2. Department of Biophysics and Radiation Biology, Nanobiotechnology and In Vivo Imaging Centre, Semmelweis University, Tűzoltó utca 37-47, 1094 Budapest, Hungary
3. Department of Neurosurgery, University of Pécs, Medical School, Szigeti út 12, 7624 Pécs, Hungary
4. MTA-PTE Clinical Neuroscience MR Research Group-Pécs Diagnostic Center, Pécs, Hungary
5. Cognitive Neuroimaging Centre (CoNiC), Lee Kong Chian School of Medicine, 59, Nanyang Drive, Nanyang Technological University, Singapore-636921
6. MTA-ELTE Laboratory of Molecular and Systems Neurobiology, Department of Physiology and Neurobiology, Eötvös Loránd University and the Hungarian Academy of Sciences, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary
7. Hungarian Defense Forces Military Hospital, Róbert Károly körút 44, 1134 Budapest, Hungary
#These authors contributed equally to this work
Acute ischemic stroke treatment faces an unresolved obstacle as capillary reperfusion remains insufficient after thrombolysis and thrombectomy causing neuronal damage and poor prognosis. Hypoxia-induced capillary constriction is mediated by actomyosin contraction in precapillary smooth muscle cells (SMCs) therefore smooth muscle myosin-2 could be an ideal target with potentially high impact on reperfusion of capillaries.
Methods: The myosin-2 inhibitor para-aminoblebbistatin (AmBleb) was tested on isolated human and rat arterioles to assess the effect of AmBleb on vasodilatation. Transient middle cerebral artery occlusion (MCAO) was performed on 38 male Wistar rats followed by local administration of AmBleb into the ischemic brain area. Development of brain edema and changes in cerebrovascular blood flow were assessed using MRI and SPECT. We also tested the neurological deficit scores and locomotor asymmetry of the animals for 3 weeks after the MCAO operation.
Results: Our results demonstrate that AmBleb could achieve full relaxation of isolated cerebral arterioles. In living animals AmBleb recovered cerebral blood flow in 32 out of the 65 affected functional brain areas in MCAO operated rats, whereas only 8 out of the 67 affected areas were recovered in the control animals. Animals treated with AmBleb also showed significantly improved general and focal deficit scores in neurological functional tests and showed significantly ameliorated locomotor asymmetry.
Conclusion: Direct inhibition of smooth muscle myosin by AmBleb in pre-capillary SMCs significantly contribute to the improvement of cerebral blood reperfusion and brain functions suggesting that smooth muscle myosin inhibition may have promising potential in stroke therapies as a follow-up treatment of physical or chemical removal of the occluding thrombus.
Keywords: MCAO, reperfusion, myosin, smooth muscle cell, SPECT