Intracerebral Delivery of Brain-Derived Neurotrophic Factor Using HyStem<sup>®</sup>-C Hydrogel Implants Improves Functional Recovery and Reduces Neuroinflammation in a Rat Model of Ischemic Stroke
Ischemic stroke is a leading cause of death and disability worldwide. Potential therapeutics aimed at neural repair and functional recovery are limited in their blood-brain barrier permeability and may exert systemic or off-target effects. We examined the effects of brain-derived neurotrophic factor...
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doaj-0ba317629d49421fb07f945063f441fc2020-11-25T00:56:22ZengMDPI AGInternational Journal of Molecular Sciences1422-00672018-11-011912378210.3390/ijms19123782ijms19123782Intracerebral Delivery of Brain-Derived Neurotrophic Factor Using HyStem<sup>®</sup>-C Hydrogel Implants Improves Functional Recovery and Reduces Neuroinflammation in a Rat Model of Ischemic StrokeKristine Ravina0Denise I. Briggs1Sezen Kislal2Zuha Warraich3Tiffany Nguyen4Rachel K. Lam5Thomas I. Zarembinski6Mehrdad Shamloo7Department of Neurosurgery, Stanford University School of Medicine, 1050 Arastradero Road, Building A, Palo Alto, CA 94304-1334, USADepartment of Neurosurgery, Stanford University School of Medicine, 1050 Arastradero Road, Building A, Palo Alto, CA 94304-1334, USADepartment of Neurosurgery, Stanford University School of Medicine, 1050 Arastradero Road, Building A, Palo Alto, CA 94304-1334, USADepartment of Neurosurgery, Stanford University School of Medicine, 1050 Arastradero Road, Building A, Palo Alto, CA 94304-1334, USADepartment of Neurosurgery, Stanford University School of Medicine, 1050 Arastradero Road, Building A, Palo Alto, CA 94304-1334, USADepartment of Neurosurgery, Stanford University School of Medicine, 1050 Arastradero Road, Building A, Palo Alto, CA 94304-1334, USABioTime Inc., 1010 Atlantic Ave, Suite 102, Alameda, CA 94501-1147, USADepartment of Neurosurgery, Stanford University School of Medicine, 1050 Arastradero Road, Building A, Palo Alto, CA 94304-1334, USAIschemic stroke is a leading cause of death and disability worldwide. Potential therapeutics aimed at neural repair and functional recovery are limited in their blood-brain barrier permeability and may exert systemic or off-target effects. We examined the effects of brain-derived neurotrophic factor (BDNF), delivered via an extended release HyStem<sup>®</sup>-C hydrogel implant or vehicle, on sensorimotor function, infarct volume, and neuroinflammation, following permanent distal middle cerebral artery occlusion (dMCAo) in rats. Eight days following dMCAo or sham surgery, treatments were implanted directly into the infarction site. Rats received either vehicle, BDNF-only (0.167 µg/µL), hydrogel-only, hydrogel impregnated with 0.057 µg/µL of BDNF (hydrogel + BDNF<sub>LOW</sub>), or hydrogel impregnated with 0.167 µg/µL of BDNF (hydrogel + BDNF<sub>HIGH</sub>). The adhesive removal test (ART) and 28-point Neuroscore (28-PN) were used to evaluate sensorimotor function up to two months post-ischemia. The hydrogel + BDNF<sub>HIGH</sub> group showed significant improvements on the ART six to eight weeks following treatment and their behavioral performance was consistently greater on the 28-PN. Infarct volume was reduced in rats treated with hydrogel + BDNF<sub>HIGH</sub> as were levels of microglial, phagocyte, and astrocyte marker immunoexpression in the corpus striatum. These data suggest that targeted intracerebral delivery of BDNF using hydrogels may mitigate ischemic brain injury and restore functional deficits by reducing neuroinflammation.https://www.mdpi.com/1422-0067/19/12/3782brain-derived neurotrophic factorfunctional recoveryhydrogelischemic strokeneuroinflammation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kristine Ravina Denise I. Briggs Sezen Kislal Zuha Warraich Tiffany Nguyen Rachel K. Lam Thomas I. Zarembinski Mehrdad Shamloo |
spellingShingle |
Kristine Ravina Denise I. Briggs Sezen Kislal Zuha Warraich Tiffany Nguyen Rachel K. Lam Thomas I. Zarembinski Mehrdad Shamloo Intracerebral Delivery of Brain-Derived Neurotrophic Factor Using HyStem<sup>®</sup>-C Hydrogel Implants Improves Functional Recovery and Reduces Neuroinflammation in a Rat Model of Ischemic Stroke International Journal of Molecular Sciences brain-derived neurotrophic factor functional recovery hydrogel ischemic stroke neuroinflammation |
author_facet |
Kristine Ravina Denise I. Briggs Sezen Kislal Zuha Warraich Tiffany Nguyen Rachel K. Lam Thomas I. Zarembinski Mehrdad Shamloo |
author_sort |
Kristine Ravina |
title |
Intracerebral Delivery of Brain-Derived Neurotrophic Factor Using HyStem<sup>®</sup>-C Hydrogel Implants Improves Functional Recovery and Reduces Neuroinflammation in a Rat Model of Ischemic Stroke |
title_short |
Intracerebral Delivery of Brain-Derived Neurotrophic Factor Using HyStem<sup>®</sup>-C Hydrogel Implants Improves Functional Recovery and Reduces Neuroinflammation in a Rat Model of Ischemic Stroke |
title_full |
Intracerebral Delivery of Brain-Derived Neurotrophic Factor Using HyStem<sup>®</sup>-C Hydrogel Implants Improves Functional Recovery and Reduces Neuroinflammation in a Rat Model of Ischemic Stroke |
title_fullStr |
Intracerebral Delivery of Brain-Derived Neurotrophic Factor Using HyStem<sup>®</sup>-C Hydrogel Implants Improves Functional Recovery and Reduces Neuroinflammation in a Rat Model of Ischemic Stroke |
title_full_unstemmed |
Intracerebral Delivery of Brain-Derived Neurotrophic Factor Using HyStem<sup>®</sup>-C Hydrogel Implants Improves Functional Recovery and Reduces Neuroinflammation in a Rat Model of Ischemic Stroke |
title_sort |
intracerebral delivery of brain-derived neurotrophic factor using hystem<sup>®</sup>-c hydrogel implants improves functional recovery and reduces neuroinflammation in a rat model of ischemic stroke |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2018-11-01 |
description |
Ischemic stroke is a leading cause of death and disability worldwide. Potential therapeutics aimed at neural repair and functional recovery are limited in their blood-brain barrier permeability and may exert systemic or off-target effects. We examined the effects of brain-derived neurotrophic factor (BDNF), delivered via an extended release HyStem<sup>®</sup>-C hydrogel implant or vehicle, on sensorimotor function, infarct volume, and neuroinflammation, following permanent distal middle cerebral artery occlusion (dMCAo) in rats. Eight days following dMCAo or sham surgery, treatments were implanted directly into the infarction site. Rats received either vehicle, BDNF-only (0.167 µg/µL), hydrogel-only, hydrogel impregnated with 0.057 µg/µL of BDNF (hydrogel + BDNF<sub>LOW</sub>), or hydrogel impregnated with 0.167 µg/µL of BDNF (hydrogel + BDNF<sub>HIGH</sub>). The adhesive removal test (ART) and 28-point Neuroscore (28-PN) were used to evaluate sensorimotor function up to two months post-ischemia. The hydrogel + BDNF<sub>HIGH</sub> group showed significant improvements on the ART six to eight weeks following treatment and their behavioral performance was consistently greater on the 28-PN. Infarct volume was reduced in rats treated with hydrogel + BDNF<sub>HIGH</sub> as were levels of microglial, phagocyte, and astrocyte marker immunoexpression in the corpus striatum. These data suggest that targeted intracerebral delivery of BDNF using hydrogels may mitigate ischemic brain injury and restore functional deficits by reducing neuroinflammation. |
topic |
brain-derived neurotrophic factor functional recovery hydrogel ischemic stroke neuroinflammation |
url |
https://www.mdpi.com/1422-0067/19/12/3782 |
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