Heterotopic Mucosal Grafting Enables the Delivery of Therapeutic Neuropeptides Across the Blood Brain Barrier

Neurosurgery ◽  
2015 ◽  
Vol 78 (3) ◽  
pp. 448-457 ◽  
Author(s):  
Benjamin S. Bleier ◽  
Richie E. Kohman ◽  
Kevin Guerra ◽  
Angela L. Nocera ◽  
Shreshtha Ramanlal ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Parkinson Disease ◽  
Blood Brain Barrier ◽  
Disease Model ◽  
Brain Barrier ◽  
Saline Control ◽  
Skull Base Reconstruction ◽  
Blood Brain ◽  
Behavioral Assays ◽  
Intrastriatal Injection

Abstract BACKGROUND: The blood-brain barrier represents a fundamental limitation in treating neurological disease because it prevents all neuropeptides from reaching the central nervous system (CNS). Currently, there is no efficient method to permanently bypass the blood-brain barrier. OBJECTIVE: To test the feasibility of using nasal mucosal graft reconstruction of arachnoid defects to deliver glial-derived neurotrophic factor (GDNF) for the treatment of Parkinson disease in a mouse model. METHODS: The Institutional Animal Care and Use Committee approved this study in an established murine 6-hydroxydopamine Parkinson disease model. A parietal craniotomy and arachnoid defect was repaired with a heterotopic donor mucosal graft. The therapeutic efficacy of GDNF (2 μg/mL) delivered through the mucosal graft was compared with direct intrastriatal GDNF injection (2 μg/mL) and saline control through the use of 2 behavioral assays (rotarod and apomorphine rotation). An immunohistological analysis was further used to compare the relative preservation of substantia nigra cell bodies between treatment groups. RESULTS: Transmucosal GDNF was equivalent to direct intrastriatal injection at preserving motor function at week 7 in both the rotarod and apomorphine rotation behavioral assays. Similarly, both transmucosal and intrastriatal GDNF demonstrated an equivalent ratio of preserved substantia nigra cell bodies (0.79 ± 0.14 and 0.78 ± 0.09, respectively, P = NS) compared with the contralateral control side, and both were significantly greater than saline control (0.53 ± 0.21; P = .01 and P = .03, respectively). CONCLUSION: Transmucosal delivery of GDNF is equivalent to direct intrastriatal injection at ameliorating the behavioral and immunohistological features of Parkinson disease in a murine model. Mucosal grafting of arachnoid defects is a technique commonly used for endoscopic skull base reconstruction and may represent a novel method to permanently bypass the blood-brain barrier.

107 DETECTION OF BIOTINYLATED-OVULATION-INDUCING FACTOR (OIF) IN CEREBROSPINAL FLUID AND ITS ABILITY TO INDUCE OVULATION

2013 ◽  
Vol 25 (1) ◽  
pp. 201 ◽  
Author(s):  
M. Berland ◽  
M. Guerra ◽  
O. A. Bogle ◽  
K. Vio ◽  
G. P. Adams ◽  
...  
Keyword(s):  
Corpus Luteum ◽  
Blood Brain Barrier ◽  
Model Experiment ◽  
Rabbit Model ◽  
Brain Barrier ◽  
Saline Control ◽  
Dot Blot ◽  
Engineering Research ◽  
Blood Brain ◽  
Streptavidin Peroxidase

Ovulation-inducing factor (OIF) is a protein in the seminal plasma of llamas that induces a preovulatory LH surge by acting directly or indirectly on the hypothalamic GnRH neurons (Silva et al. 2011 Reprod. Biol. Endocr. 9, 74). We hypothesize that OIF crosses the blood–brain barrier and reaches the hypothalamus via secretion into the cerebro-spinal fluid (CSF) through the choroid plexus. Two experiments were designed to determine whether biotinylation of OIF (as a tracer) alters its bioactivity in a llama model (Experiment 1) and whether it crosses the blood–brain barrier in a rabbit model (Experiment 2). In Experiment 1, llamas with a follicle ≥8 mm in diameter that had grown for 3 consecutive days were assigned randomly to 5 groups (n = 2/group) and given an IV dose of 1) 800 µg of OIF, 2) 800 µg of OIF biotinylated at the amino end; 3) 1600 µg of OIF biotinylated at the amino end, 4) 800 µg of OIF biotinylated at the carboxyl end, or 5) phosphate buffered saline (control). The ovaries were examined daily by transrectal ultrasonography on Day 3 and 8 after treatment (Day 0 = treatment) to detect ovulation and corpus luteum formation. In Experiment 2, adult female rabbits were assigned randomly to 3 groups and given an IV dose of (1) 250 µg of OIF, (2) 250 µg of OIF biotinylated at the amino end, or (3) 250 µg of OIF biotinylated at the carboxyl end. A 50-µL sample of CSF was collected from the cisterna magna under general anesthesia before (0 min) and 10, 20, 30, and 45 min after treatment. The presence of biotinylated OIF in CSF samples was determined by dot blot, using streptavidin-peroxidase and diaminobenzidine. In Experiment 1, the diameter of the follicle at the time of the treatment did not differ among groups (9.7 ± 0.2, 9.4 ± 0.0, 10.5 ± 1.0, 10.1 ± 0.2, 10.3 ± 0.4). Ovulation was detected in all llamas except one llama treated with 800 µg OIF biotinylated at the carboxyl end and both llamas given PBS. The diameter of the corpus luteum did not differ among OIF-treated groups. In Experiment 2, OIF biotinylated at both amino and carboxyl ends was detected in CSF samples at 10, 20, 30, and 45 min after IV administration. No signal was recorded before IV administration (0 min) or in samples from rabbits that were given nonbiotinylated OIF. We conclude that the biotinylation process did not affect OIF bioactivity, and OIF crosses the blood–brain barrier and reaches the CSF in rabbits. Research supported by FONDECYT 1120518, the Natural Sciences and Engineering Research Council of Canada, and the Alpaca Research Foundation.

scholarly journals Endonasal CNS Delivery System for Blood-Brain Barrier Impermeant Therapeutic Oligonucleotides Using Heterotopic Mucosal Engrafting

2021 ◽  
Vol 12 ◽  
Author(s):  
Grishma Pawar ◽  
Neha N. Parayath ◽  
Aditya A. Sharma ◽  
Carlos Coito ◽  
Olga Khorkova ◽  
...  
Keyword(s):  
Rat Brain ◽  
Blood Brain Barrier ◽  
Transfection Efficiency ◽  
Neuroprotective Effect ◽  
Brain Barrier ◽  
Saline Control ◽  
Bdnf Expression ◽  
Endoscopic Surgical Procedures ◽  
Blood Brain

The most significant obstacle in the treatment of neurological disorders is the blood-brain barrier (BBB), which prevents 98% of all potential neuropharmaceuticals from reaching the central nervous system (CNS). Brain derived neurotrophic factor (BDNF) is one of the most intensely studied targets in Parkinson’s disease (PD) as it can reverse disease progression. BDNF AntagoNAT’s (ATs) are synthetic oligonucleotide-like compounds capable of upregulating endogenous BDNF expression. Despite the significant promise of BDNF AT therapies for PD, they cannot cross the blood-brain barrier (BBB). Our group has developed an innovative endonasal heterotopic mucosal grafting technique to provide a permanent method of permeabilizing the BBB. This method is based on established endoscopic surgical procedures currently used in routine clinical practice. Our overall goal for the study was to investigate the distribution and efficacy of BDNF AT’s using an extra-cranial graft model in naïve rats using the innovative heterotopic mucosal engrafting technique. BDNF AT cationic liposomes (ideal size range 200–250 nm) were developed and characterized to enhance the delivery to rat brain. Uptake, distribution and transfection efficiency of BDNF AntagoNAT’s in saline and liposomes were evaluated qualitatively (microscopy) and quantitatively (ELISA and AT hybridization assays) in RT4-D6P2T rat schwannoma cells and in naïve rats. In vivo therapeutic efficacy of BDNF AT’s encapsulated in liposomes was evaluated in a 6-OHDA toxin model of PD using western blot and tyrosine hydroxylase immunohistochemistry. Using complimentary in vitro and in vivo techniques, our results demonstrate that grafts are capable of delivering therapeutic levels of BDNF ATs in liposomes and saline formulation throughout the brain resulting in significant BDNF upregulation in key end target regions relevant to PD. BDNF AT liposomes resulted in a better distribution in rat brain as compared to saline control. The delivered BDNF AT’s encapsulated in liposomes also conferred a neuroprotective effect in a rat 6-OHDA model of PD. As a platform technique, these results further suggest that this approach may be utilized to deliver other BBB impermeant oligonucleotide-based therapeutics thereby opening the door to additional treatment options for CNS disease.

scholarly journals Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Iosif Pediaditakis ◽  
Konstantia R. Kodella ◽  
Dimitris V. Manatakis ◽  
Christopher Y. Le ◽  
Chris D. Hinojosa ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Human Brain ◽  
Blood Brain Barrier ◽  
Dopaminergic Neurons ◽  
Alpha Synuclein ◽  
Brain Barrier ◽  
Blood Brain

AbstractParkinson’s disease and related synucleinopathies are characterized by the abnormal accumulation of alpha-synuclein aggregates, loss of dopaminergic neurons, and gliosis of the substantia nigra. Although clinical evidence and in vitro studies indicate disruption of the Blood-Brain Barrier in Parkinson’s disease, the mechanisms mediating the endothelial dysfunction is not well understood. Here we leveraged the Organs-on-Chips technology to develop a human Brain-Chip representative of the substantia nigra area of the brain containing dopaminergic neurons, astrocytes, microglia, pericytes, and microvascular brain endothelial cells, cultured under fluid flow. Our αSyn fibril-induced model was capable of reproducing several key aspects of Parkinson’s disease, including accumulation of phosphorylated αSyn (pSer129-αSyn), mitochondrial impairment, neuroinflammation, and compromised barrier function. This model may enable research into the dynamics of cell-cell interactions in human synucleinopathies and serve as a testing platform for target identification and validation of novel therapeutics.

scholarly journals Modeling Alpha-Synuclein Pathology in a Human Brain-Chip to Assess Blood-Brain Barrier Disruption in Parkinson’s Disease

2020 ◽  
Author(s):  
Iosif Pediaditakis ◽  
Konstantia R. Kodella ◽  
Dimitris V. Manatakis ◽  
Chris D. Hinojosa ◽  
Elias S. Manolakos ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Human Brain ◽  
Blood Brain Barrier ◽  
Dopaminergic Neurons ◽  
Alpha Synuclein ◽  
Therapeutic Interventions ◽  
Brain Barrier ◽  
Blood Brain

AbstractParkinson’s disease and related synucleinopathies are characterized by the abnormal accumulation of alpha-synuclein aggregates, loss of dopaminergic neurons, and gliosis in the substantia nigra. Although clinical evidence and in vitro studies indicate disruption of the Blood-Brain Barrier in Parkinson’s disease, the mechanisms mediating the endothelial dysfunction remain elusive. Lack of relevant models able to recapitulate the order of events driving the development of the disease in humans has been a significant bottleneck in the identification of specific successful druggable targets. Here we leveraged the Organs-on-Chips technology to engineer a human Brain-Chip representative of the substantia nigra area of the brain containing dopaminergic neurons, astrocytes, microglia, pericytes, and microvascular brain endothelial cells, cultured under fluid flow. Our αSyn fibril-induced model was capable of reproducing several key aspects of Parkinson’s disease, including accumulation of phosphorylated αSyn (pSer129-αSyn), mitochondrial impairment, neuroinflammation, and compromised barrier function. This model is poised to enable research into the dynamics of cell-cell interactions in human synucleinopathies and to serve as testing platform for novel therapeutic interventions, including target identification and target validation.

scholarly journals The Role of P-Glycoprotein in Transport of Danshensu across the Blood-Brain Barrier

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Peng-Fei Yu ◽  
Wen-Yan Wang ◽  
Gaowa Eerdun ◽  
Tian Wang ◽  
Lei-Ming Zhang ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Salvia Miltiorrhiza ◽  
Water Soluble ◽  
Brain Barrier ◽  
Saline Control ◽  
Control Group ◽  
P Glycoprotein ◽  
Blood Brain ◽  
The Brain

Danshensu (3-(3, 4-dihydroxyphenyl) lactic acid), a water-soluble active component isolated from the root ofSalvia miltiorrhizaBunge, is widely used for the treatment of cerebrovascular diseases. The present study aims to investigate the role of P-glycoprotein in transport of Danshensu across the blood-brain barrier. Sprague-Dawley rats were pretreated with verapamil at a dose of 20 mg kg−1(verapamil group) or the same volume of normal saline (control group). Ninety minutes later, the animals were administrated with Danshensu (15 mg kg−1) by intravenous injection. At 15 min, 30 min, and 60 min after Danshensu administration, the levels of Danshensu in the blood and brain were detected by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). The results showed that Danshensu concentrations in the brain of the rats pretreated with verapamil were significantly increased. In addition, the brain-plasma ratios of the group pretreated with verapamil were much higher than that of the control group. There was no difference in Danshensu level in plasma between the verapamil group and control group. The findings indicated that Danshensu can pass the blood-brain barrier, and P-glycoprotein plays an important role in Danshensu transportation in brain.

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