Intracarotid Infusion of Redox-Active Manganese Porphyrin, MnTnBuOE-2-PyP<sup>5+</sup>, following Reperfusion Improves Long-Term, 28-Day Post-Stroke Outcomes in Rats
Endovascular mechanical thrombectomy, combined with a tissue plasminogen activator (t-PA), is efficacious as a standard care for qualifying ischemic stroke patients. However, > 50% of thrombectomy patients still have poor outcomes. Manganese porphyrins, commonly known as mimics of superoxide dism...
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| Format: | Article |
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MDPI AG
2023-10-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/10/1861 |
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| author | Xuan Li Weina Duan Li Du Dongmei Chu Peng Wang Zhong Yang Xingguang Qu Zhenxing Yang Ines Batinic-Haberle Ivan Spasojevic David S. Warner James D. Crapo Miriam M. Treggiari Huaxin Sheng |
| author_facet | Xuan Li Weina Duan Li Du Dongmei Chu Peng Wang Zhong Yang Xingguang Qu Zhenxing Yang Ines Batinic-Haberle Ivan Spasojevic David S. Warner James D. Crapo Miriam M. Treggiari Huaxin Sheng |
| author_sort | Xuan Li |
| collection | DOAJ |
| description | Endovascular mechanical thrombectomy, combined with a tissue plasminogen activator (t-PA), is efficacious as a standard care for qualifying ischemic stroke patients. However, > 50% of thrombectomy patients still have poor outcomes. Manganese porphyrins, commonly known as mimics of superoxide dismutases, are potent redox-active catalytic compounds that decrease oxidative/nitrosative stress and in turn decrease inflammatory responses, mitigating therefore the secondary injury of the ischemic brain. This study investigates the effect of intracarotid MnTnBuOE-2-PyP<sup>5+</sup> (BMX-001) administration on long-term, 28-day post-stroke recovery in a clinically relevant setting. The 90 min of transient middle cerebral artery occlusion was performed in young, aged, male, female, and spontaneous hypertension rats. All physiological parameters, including blood pressure, blood gas, glucose, and temperature, were well controlled during ischemia. Either BMX-001 or a vehicle solution was infused through the carotid artery immediately after the removal of filament, mimicking endovascular thrombectomy, and was followed by 7 days of subcutaneous injection. Neurologic deficits and infarct volume were assessed at 28 days in a blinded manner. The effects of BMX-001 on the carotid arterial wall and blood–brain barrier permeability and its interaction with t-PA were assessed in normal rats. There were no intra-group differences in physiological variables. BMX-001-treated stroke rats regained body weight earlier, performed better in behavioral tests, and had smaller brain infarct size compared to the vehicle-treated group. No vascular wall damage and blood–brain barrier permeability changes were detected after the BMX-001 infusion. There was no drug interaction between BMX-001 and t-PA. Intracarotid BMX-001 infusion was safe, and it significantly improved stroke outcomes in rats. These findings indicate that BMX-001 is a candidate drug as an adjunct treatment for thrombectomy procedure to further improve the neurologic outcomes of thrombectomy patients. This study warrants further clinical investigation of BMX-001 as a new stroke therapy. |
| first_indexed | 2024-03-10T21:29:46Z |
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| id | doaj.art-cd7bd498d53b459a86835b675ccfbd52 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T21:29:46Z |
| publishDate | 2023-10-01 |
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| spelling | doaj.art-cd7bd498d53b459a86835b675ccfbd522023-11-19T15:28:13ZengMDPI AGAntioxidants2076-39212023-10-011210186110.3390/antiox12101861Intracarotid Infusion of Redox-Active Manganese Porphyrin, MnTnBuOE-2-PyP<sup>5+</sup>, following Reperfusion Improves Long-Term, 28-Day Post-Stroke Outcomes in RatsXuan Li0Weina Duan1Li Du2Dongmei Chu3Peng Wang4Zhong Yang5Xingguang Qu6Zhenxing Yang7Ines Batinic-Haberle8Ivan Spasojevic9David S. Warner10James D. Crapo11Miriam M. Treggiari12Huaxin Sheng13Multidisciplinary Neuroprotection Laboratories, Center of Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USAMultidisciplinary Neuroprotection Laboratories, Center of Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USAMultidisciplinary Neuroprotection Laboratories, Center of Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USAMultidisciplinary Neuroprotection Laboratories, Center of Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USAMultidisciplinary Neuroprotection Laboratories, Center of Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USAMultidisciplinary Neuroprotection Laboratories, Center of Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USAMultidisciplinary Neuroprotection Laboratories, Center of Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USADepartment of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USADepartment of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USAPharmacokinetics and Pharmacodynamics Core, Duke Cancer Institute, and Department of Medicine, Duke University Medical Center, Durham, NC 27710, USAMultidisciplinary Neuroprotection Laboratories, Center of Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USABioMimetix JV LLC, Greenwood Village, CO 80111, USAMultidisciplinary Neuroprotection Laboratories, Center of Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USAMultidisciplinary Neuroprotection Laboratories, Center of Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USAEndovascular mechanical thrombectomy, combined with a tissue plasminogen activator (t-PA), is efficacious as a standard care for qualifying ischemic stroke patients. However, > 50% of thrombectomy patients still have poor outcomes. Manganese porphyrins, commonly known as mimics of superoxide dismutases, are potent redox-active catalytic compounds that decrease oxidative/nitrosative stress and in turn decrease inflammatory responses, mitigating therefore the secondary injury of the ischemic brain. This study investigates the effect of intracarotid MnTnBuOE-2-PyP<sup>5+</sup> (BMX-001) administration on long-term, 28-day post-stroke recovery in a clinically relevant setting. The 90 min of transient middle cerebral artery occlusion was performed in young, aged, male, female, and spontaneous hypertension rats. All physiological parameters, including blood pressure, blood gas, glucose, and temperature, were well controlled during ischemia. Either BMX-001 or a vehicle solution was infused through the carotid artery immediately after the removal of filament, mimicking endovascular thrombectomy, and was followed by 7 days of subcutaneous injection. Neurologic deficits and infarct volume were assessed at 28 days in a blinded manner. The effects of BMX-001 on the carotid arterial wall and blood–brain barrier permeability and its interaction with t-PA were assessed in normal rats. There were no intra-group differences in physiological variables. BMX-001-treated stroke rats regained body weight earlier, performed better in behavioral tests, and had smaller brain infarct size compared to the vehicle-treated group. No vascular wall damage and blood–brain barrier permeability changes were detected after the BMX-001 infusion. There was no drug interaction between BMX-001 and t-PA. Intracarotid BMX-001 infusion was safe, and it significantly improved stroke outcomes in rats. These findings indicate that BMX-001 is a candidate drug as an adjunct treatment for thrombectomy procedure to further improve the neurologic outcomes of thrombectomy patients. This study warrants further clinical investigation of BMX-001 as a new stroke therapy.https://www.mdpi.com/2076-3921/12/10/1861ischemic strokethrombectomyBMX-001manganese porphyrinintracarotidlong-term, 28-day post-stroke outcome |
| spellingShingle | Xuan Li Weina Duan Li Du Dongmei Chu Peng Wang Zhong Yang Xingguang Qu Zhenxing Yang Ines Batinic-Haberle Ivan Spasojevic David S. Warner James D. Crapo Miriam M. Treggiari Huaxin Sheng Intracarotid Infusion of Redox-Active Manganese Porphyrin, MnTnBuOE-2-PyP<sup>5+</sup>, following Reperfusion Improves Long-Term, 28-Day Post-Stroke Outcomes in Rats Antioxidants ischemic stroke thrombectomy BMX-001 manganese porphyrin intracarotid long-term, 28-day post-stroke outcome |
| title | Intracarotid Infusion of Redox-Active Manganese Porphyrin, MnTnBuOE-2-PyP<sup>5+</sup>, following Reperfusion Improves Long-Term, 28-Day Post-Stroke Outcomes in Rats |
| title_full | Intracarotid Infusion of Redox-Active Manganese Porphyrin, MnTnBuOE-2-PyP<sup>5+</sup>, following Reperfusion Improves Long-Term, 28-Day Post-Stroke Outcomes in Rats |
| title_fullStr | Intracarotid Infusion of Redox-Active Manganese Porphyrin, MnTnBuOE-2-PyP<sup>5+</sup>, following Reperfusion Improves Long-Term, 28-Day Post-Stroke Outcomes in Rats |
| title_full_unstemmed | Intracarotid Infusion of Redox-Active Manganese Porphyrin, MnTnBuOE-2-PyP<sup>5+</sup>, following Reperfusion Improves Long-Term, 28-Day Post-Stroke Outcomes in Rats |
| title_short | Intracarotid Infusion of Redox-Active Manganese Porphyrin, MnTnBuOE-2-PyP<sup>5+</sup>, following Reperfusion Improves Long-Term, 28-Day Post-Stroke Outcomes in Rats |
| title_sort | intracarotid infusion of redox active manganese porphyrin mntnbuoe 2 pyp sup 5 sup following reperfusion improves long term 28 day post stroke outcomes in rats |
| topic | ischemic stroke thrombectomy BMX-001 manganese porphyrin intracarotid long-term, 28-day post-stroke outcome |
| url | https://www.mdpi.com/2076-3921/12/10/1861 |
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