Treatment with afobazole at delayed time points following ischemic stroke improves long-term functional and histological outcomes
There is currently a significant lack of therapeutic options for acute ischemic stroke, and no drug has been approved for treating patients at delayed time points (≥6 h post-stroke). Afobazole, an anxiolytic currently used clinically in Russia, has been shown to reduce neuronal and glial cell injury...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2014-02-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996113002866 |
| _version_ | 1818610522687275008 |
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| author | C. Katnik A. Garcia A.A. Behensky I.E. Yasny A.M. Shuster S.B. Seredenin A.V. Petrov S. Seifu J. McAleer A. Willing J. Cuevas |
| author_facet | C. Katnik A. Garcia A.A. Behensky I.E. Yasny A.M. Shuster S.B. Seredenin A.V. Petrov S. Seifu J. McAleer A. Willing J. Cuevas |
| author_sort | C. Katnik |
| collection | DOAJ |
| description | There is currently a significant lack of therapeutic options for acute ischemic stroke, and no drug has been approved for treating patients at delayed time points (≥6 h post-stroke). Afobazole, an anxiolytic currently used clinically in Russia, has been shown to reduce neuronal and glial cell injury in vitro following ischemia. Experiments using the permanent middle cerebral artery occlusion (MCAO) rat model were carried out to determine if afobazole can reduce ischemic stroke damage in vivo and expand the therapeutic window for stroke treatment. Post-stroke (24 h) application of afobazole (0.3–3 mg/kg) significantly decreased infarct volume at 96 h post-surgery, as determined by Fluoro-Jade and NeuN staining of brain sections. Moreover, afobazole helped preserve both the levels and normal histological distribution of myelin basic protein, indicating a reduction in white matter injury. A time-dependence study showed that either pre-treatment or treatment started 6 to 48 h post-stroke with the drug yields improved outcomes at 96 h. The decrease in infarct volume produced by afobazole was blocked by the application of either a σ-1 (BD 1063, 30 mg/kg) or a σ-2 (SM-21, 1 mg/kg) antagonist, indicating that both receptor subtypes are involved in the effects of afobazole. Treatment with afobazole starting at 24 h post-stroke resulted in enhanced survival one month following surgery. Behavioral testing of animals 28–32 days post-surgery using the elevated body swing and forelimb grip-strength tests revealed that treatment with afobazole starting 24 h post-stroke significantly reduces behavioral deficits caused by ischemic stroke. The increase in survival and improved functional outcomes are accompanied by a reduction in infarct volume, as determined by thionin staining of brain sections. Taken together, our data support the use of afobazole as a post-stroke pharmacological agent to expand the current therapeutic window. |
| first_indexed | 2024-12-16T15:15:47Z |
| format | Article |
| id | doaj.art-29ae9393d7c04a8a848876bad9b141be |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T15:15:47Z |
| publishDate | 2014-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-29ae9393d7c04a8a848876bad9b141be2022-12-21T22:26:47ZengElsevierNeurobiology of Disease1095-953X2014-02-0162354364Treatment with afobazole at delayed time points following ischemic stroke improves long-term functional and histological outcomesC. Katnik0A. Garcia1A.A. Behensky2I.E. Yasny3A.M. Shuster4S.B. Seredenin5A.V. Petrov6S. Seifu7J. McAleer8A. Willing9J. Cuevas10Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC78, Tampa, FL 33612, USADepartment of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC78, Tampa, FL 33612, USADepartment of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC78, Tampa, FL 33612, USAIBC Generium, 27 Al. Soljenitsyna, Moscow 109004, RussiaIBC Generium, 27 Al. Soljenitsyna, Moscow 109004, RussiaState Foundation Institute of Pharmacology, Russian Academy of Medical Sciences, 8 Baltiyskaya, Moscow 125315, RussiaIBC Generium, 27 Al. Soljenitsyna, Moscow 109004, RussiaDepartment of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC78, Tampa, FL 33612, USACenter for Excellence in Aging & Brain Repair, Morsani College of Medicine, USA; Department of Neurosurgery and Brain Repair, Morsani College of Medicine, USADepartment of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC78, Tampa, FL 33612, USA; Center for Excellence in Aging & Brain Repair, Morsani College of Medicine, USA; Department of Neurosurgery and Brain Repair, Morsani College of Medicine, USADepartment of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC78, Tampa, FL 33612, USA; Corresponding author at: Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., MDC-9, Tampa, FL 33612-4799, USA. Fax: +1 813 974 3079.There is currently a significant lack of therapeutic options for acute ischemic stroke, and no drug has been approved for treating patients at delayed time points (≥6 h post-stroke). Afobazole, an anxiolytic currently used clinically in Russia, has been shown to reduce neuronal and glial cell injury in vitro following ischemia. Experiments using the permanent middle cerebral artery occlusion (MCAO) rat model were carried out to determine if afobazole can reduce ischemic stroke damage in vivo and expand the therapeutic window for stroke treatment. Post-stroke (24 h) application of afobazole (0.3–3 mg/kg) significantly decreased infarct volume at 96 h post-surgery, as determined by Fluoro-Jade and NeuN staining of brain sections. Moreover, afobazole helped preserve both the levels and normal histological distribution of myelin basic protein, indicating a reduction in white matter injury. A time-dependence study showed that either pre-treatment or treatment started 6 to 48 h post-stroke with the drug yields improved outcomes at 96 h. The decrease in infarct volume produced by afobazole was blocked by the application of either a σ-1 (BD 1063, 30 mg/kg) or a σ-2 (SM-21, 1 mg/kg) antagonist, indicating that both receptor subtypes are involved in the effects of afobazole. Treatment with afobazole starting at 24 h post-stroke resulted in enhanced survival one month following surgery. Behavioral testing of animals 28–32 days post-surgery using the elevated body swing and forelimb grip-strength tests revealed that treatment with afobazole starting 24 h post-stroke significantly reduces behavioral deficits caused by ischemic stroke. The increase in survival and improved functional outcomes are accompanied by a reduction in infarct volume, as determined by thionin staining of brain sections. Taken together, our data support the use of afobazole as a post-stroke pharmacological agent to expand the current therapeutic window.http://www.sciencedirect.com/science/article/pii/S0969996113002866Ischemic strokeAfobazoleMiddle cerebral artery occlusionSigma receptorBehaviorNeuroprotection |
| spellingShingle | C. Katnik A. Garcia A.A. Behensky I.E. Yasny A.M. Shuster S.B. Seredenin A.V. Petrov S. Seifu J. McAleer A. Willing J. Cuevas Treatment with afobazole at delayed time points following ischemic stroke improves long-term functional and histological outcomes Neurobiology of Disease Ischemic stroke Afobazole Middle cerebral artery occlusion Sigma receptor Behavior Neuroprotection |
| title | Treatment with afobazole at delayed time points following ischemic stroke improves long-term functional and histological outcomes |
| title_full | Treatment with afobazole at delayed time points following ischemic stroke improves long-term functional and histological outcomes |
| title_fullStr | Treatment with afobazole at delayed time points following ischemic stroke improves long-term functional and histological outcomes |
| title_full_unstemmed | Treatment with afobazole at delayed time points following ischemic stroke improves long-term functional and histological outcomes |
| title_short | Treatment with afobazole at delayed time points following ischemic stroke improves long-term functional and histological outcomes |
| title_sort | treatment with afobazole at delayed time points following ischemic stroke improves long term functional and histological outcomes |
| topic | Ischemic stroke Afobazole Middle cerebral artery occlusion Sigma receptor Behavior Neuroprotection |
| url | http://www.sciencedirect.com/science/article/pii/S0969996113002866 |
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