Glutamate Provides Cytoprotective Effect for Astrocytes Against Ischemic Insult and Promotes Astrogliosis.

Glutamate-mediated excitotoxicity has been extensively explored as a therapeutic target for the development of potential treatments of neurological disorders including stroke. However, the effect of glutamate on astrocytes under pathological conditions has been less studied. Using primary astrocyte culture, we determined the effect of glutamate on astrocytes against ischemic insult.

Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy.

Deficiency in human mature frataxin (hFXN-M) protein is responsible for the devastating neurodegenerative and cardiodegenerative disease of Friedreich's ataxia (FRDA). It results primarily through epigenetic silencing of the FXN gene by GAA triplet repeats on intron 1 of both alleles. GAA repeat lengths are most commonly between 600 and 1200 but can reach 1700.

Efficacy and Safety of a Krabbe Disease Gene Therapy.

Krabbe disease is a lysosomal storage disease caused by mutations in the gene that encodes galactosylceramidase, in which galactosylsphingosine (psychosine) accumulation drives demyelination in the central and peripheral nervous systems, ultimately progressing to death in early childhood. Gene therapy, alone or in combination with transplant, has been developed for almost two decades in mouse models, with increasing therapeutic benefit paralleling the improvement of next-generation adeno-associated virus (AAV) vectors. This effort has recently shown remarkable efficacy in the canine model of the disease by two different groups that used either systemic or cerebrospinal fluid (CSF) administration of AAVrh10 or AAV9.

Adeno-Associated Virus-Induced Dorsal Root Ganglion Pathology.

The administration of adeno-associated virus (AAV) vectors to nonhuman primates (NHP) via the blood or cerebrospinal fluid (CSF) can lead to dorsal root ganglion (DRG) pathology. The pathology is minimal to moderate in most cases; clinically silent in affected animals; and characterized by mononuclear cell infiltrates, neuronal degeneration, and secondary axonopathy of central and peripheral axons on histopathological analysis. We aggregated data from 33 nonclinical studies in 256 NHP and performed a meta-analysis of the severity of DRG pathology to compare different routes of administration, dose, time course, study conduct, age of the animals, sex, capsid, promoter, capsid purification method, and transgene.

Standards for Deriving Nonhuman Primate-Induced Pluripotent Stem Cells, Neural Stem Cells and Dopaminergic Lineage.

Humans and nonhuman primates (NHP) are similar in behavior and in physiology, specifically the structure, function, and complexity of the immune system. Thus, NHP models are desirable for pathophysiology and pharmacology/toxicology studies. Furthermore, NHP-derived induced pluripotent stem cells (iPSCs) may enable transformative developmental, translational, or evolutionary studies in a field of inquiry currently hampered by the limited availability of research specimens.

Charting the onset of Parkinson-like motor and non-motor symptoms in nonhuman primate model of Parkinson's disease.

Parkinson's disease is a progressive neurodegenerative disease increasingly affecting our aging population. Remarkable advances have been made in developing novel therapies to control symptoms, halt or cure the disease, ranging from physiotherapy and small molecules to cell and gene therapy. This progress was enabled by the existence of reliable animal models.

Magnetic Resonance Imaging-Guided Delivery of Neural Stem Cells into the Basal Ganglia of Nonhuman Primates Reveals a Pulsatile Mode of Cell Dispersion.

Optimal stem cell delivery procedures are critical to the success of the cell therapy approach. Variables such as flow rate, suspension solution, needle diameter, cell density, and tissue mechanics affect tissue penetration, backflow along the needle, and the dispersion and survival of injected cells during delivery. Most cell transplantation centers engaged in human clinical trials use custom-designed cannula needles, syringes, or catheters, sometimes precluding the use of magnetic resonance imaging (MRI)-guided delivery to target tissue.

Nonhuman primate model in clinical modeling of diseases for stem cell therapy.

Nonhuman primates (NHPs) are alike humans in size, behavior, physiology, biochemistry, and immunology. Given close similarities to humans, the NHP model offers exceptional opportunities to understand the biological mechanisms and translational applications with direct relevance to human conditions. Here, we evaluate the opportunities and limitations of NHPs as animal models for translational regenerative medicine.

Impaired Arm Function and Finger Dexterity in a Nonhuman Primate Model of Stroke: Motor and Cognitive Assessments.

Background And Purpose: Ischemic stroke is the leading cause of upper extremity motor impairments. Although several well-characterized experimental stroke models exist, modeling of upper extremity motor impairments, which are unique to primates, is not well established. Cortical representation of dexterous movements in nonhuman primates is functionally and topographically similar to that in humans.

Reactive astrocytes and therapeutic potential in focal ischemic stroke.

Astrocytes are specialized and the most abundant cell type in the central nervous system (CNS). They play important roles in the physiology of the brain. Astrocytes are also critically involved in many CNS disorders including focal ischemic stroke, the leading cause of brain injury and death in patients.

Methylene blue promotes quiescence of rat neural progenitor cells.

Neural stem cell-based treatment holds a new therapeutic opportunity for neurodegenerative disorders. Here, we investigated the effect of methylene blue on proliferation and differentiation of rat neural progenitor cells (NPCs) both in vitro and in vivo. We found that methylene blue inhibited proliferation and promoted quiescence of NPCs in vitro without affecting committed neuronal differentiation.

Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10.

Forkhead box P3 (Foxp3)(+) regulatory T (Treg) cells maintain the immune tolerance and prevent inflammatory responses in the periphery. However, the presence of Treg cells in the CNS under steady state has not been studied. Here, for the first time, we show a substantial TCRαβ (+) CD4(+) Foxp3(+) T-cell population (cerebral Treg cells) in the rat cerebrum, constituting more than 15% of the cerebral CD4(+) T-cell compartment.

Pyruvate minimizes rtPA toxicity from in vitro oxygen-glucose deprivation and reoxygenation.

Clinical application of recombinant tissue plasminogen activator (rtPA) for stroke is limited by hemorrhagic transformation, which narrows rtPA's therapeutic window. In addition, mounting evidence indicates that rtPA is potentially neurotoxic if it traverses a compromised blood brain barrier. Here, we demonstrated that pyruvate protects cultured HT22 neuronal and primary microvascular endothelial cells co-cultured with primary astrocytes from oxygen glucose deprivation (OGD)/reoxygenation stress and rtPA cytotoxicity.

Astroglial PTEN Loss Disrupts Neuronal Lamination by Dysregulating Radial Glia-guided Neuronal Migration.

PTEN plays an important role not only in tumorigenesis but also in the normal development of central nervous system. PTEN loss in neural progenitor cells during embryogenesis disrupts migration and proper formation of the brain laminar structure. We generated a conditional PTEN knockout mouse by crossing mice that express Cre recombinase driven by the human GFAP promoter to a floxed PTEN gene to investigate the role of astroglial PTEN signaling pathway in neuronal patterning and lamination.

Reversing the Warburg effect as a treatment for glioblastoma.

Glioblastoma multiforme (GBM), like most cancers, possesses a unique bioenergetic state of aerobic glycolysis known as the Warburg effect. Here, we documented that methylene blue (MB) reverses the Warburg effect evidenced by the increasing of oxygen consumption and reduction of lactate production in GBM cell lines. MB decreases GBM cell proliferation and halts the cell cycle in S phase.

Embolic middle cerebral artery occlusion model using thrombin and fibrinogen composed clots in rat.

Ischemic stroke accounts for over 80% in total human stroke which mostly affect middle cerebral artery (MCA) territory. Embolic stroke models induced by injection of homologous clots into the internal carotid artery and MCA closely mimic human stroke and have been commonly used in stroke research. Studies indicate that the size and composition of clots are critical for the reproducibility of the stroke model.