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O Isacson

Publications and source records attributed to O Isacson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Neuroimmunophilin ligand enhances neurite outgrowth and effect of fetal dopamine transplants.

Neuroimmunophilin ligands have been shown to enhance neurite outgrowth in several neuronal systems in culture, including primary dopaminergic neurons from fetal ventral mesencephalon. We investigated the ability of neuroimmunophilin ligands to enhance outgrowth of transplanted fetal dopamine neurons in vivo. Rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine system were transplanted with rat embryonic day 14 ventral mesencephalon into the striatum, then treated orally with a neuroimmunophilin ligand (15mg/kg) or vehicle once per day for 14 days. All transplanted animals regained dopamine function over a 10 week behavioral test period, as indicated by decrease and reversal of amphetamine-induced rotation. In addition, neuroimmunophilin ligand-treated animals showed a more pronounced motor response during the first 10min after amphetamine injection, possibly reflecting increased striatal reinnervation or increased functional capacity. At post-mortem analyses, neuroimmunophilin ligand-treated rats showed a significantly higher density of tyrosine hydroxylase-positive fibers reinnervating the lesioned striatum, both immediately surrounding the transplant (92% of unlesioned density in neuroimmunophilin-treated rats vs 67% of unlesioned levels in vehicle-treated rats) and at some distance from the transplant/host interface. The number of tyrosine hydroxylase-positive cells within the transplants was not different between groups. This study demonstrates that short-term oral administration of a neuroimmunophilin ligand can enhance neurite outgrowth from fetal dopamine neuronal transplants.

Animals↗
PubMed2000

Gene therapy in the CNS.

Gene therapy for neurological disorder is currently an experimental concept. The goals for clinical utilization are the relief of symptoms, slowing of disease progression, and correction of genetic abnormalities. Experimental studies are realizing these goals in the development of gene therapies in animal models. Discoveries of the molecular basis of neurological disease and advances in gene transfer systems have allowed focal and global delivery of therapeutic genes for a wide variety of CNS disorders. Limitations are still apparent, such as stability and regulation of transgene expression, and safety of both vector and expressed transgene. In addition, the brain adds several challenges not seen in peripheral gene therapy paradigms, such as post-mitotic cells, heterogeneity of cell types and circuits, and limited access. Moreover, it is likely that several modes of gene delivery will be necessary for successful gene therapies of the CNS. Collaborative efforts between clinicians and basic researchers will likely yield effective gene therapy in the CNS.

Central Nervous System Diseases↗
PubMed2000

Impact of genomics on drug discovery and clinical medicine.

Genomics, particularly high-throughput sequencing and characterization of expressed human genes, has created new opportunities for drug discovery. Knowledge of all the human genes and their functions may allow effective preventive measures, and change drug research strategy and drug discovery development processes. Pharmacogenomics is the application of genomic technologies such as gene sequencing, statistical genetics, and gene expression analysis to drugs in clinical development and on the market. It applies the large-scale systematic approaches of genomics to speed the discovery of drug response markers, whether they act at the level of the drug target, drug metabolism, or disease pathways. The potential implication of genomics and pharmacogenomics in clinical research and clinical medicine is that disease could be treated according to genetic and specific individual markers, selecting medications and dosages that are optimized for individual patients. The possibility of defining patient populations genetically may improve outcomes by predicting individual responses to drugs, and could improve safety and efficacy in therapeutic areas such as neuropsychiatry, cardiovascular medicine, endocrinology (diabetes and obesity) and oncology. Ethical questions need to be addressed and guidelines established for the use of genomics in clinical research and clinical medicine. Significant achievements are possible with an interdisciplinary approach that includes genetic, technological and therapeutic measures.

Alzheimer Disease↗
PubMed1999

Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation.

A number of in vitro studies have shown that activation of muscarinic receptors by cholinergic agonists stimulates the nonamyloidogenic, alpha-secretase-processing pathway of amyloid precursor protein (APP). To determine whether increased cholinergic neurotransmission can modify the APP processing in vivo, we administered a muscarinic receptor agonist (RS86) to normal or aged rats and rats with severe basal forebrain cholinergic deficits (induced by 192 IgG-saporin). The levels of the cell-associated APP in neocortex, hippocampus, and striatum, as well as the secreted form of APP (APPs) in cerebrospinal fluid, were examined by Western blots. Additionally, we investigated the association between the altered APP levels and behavioral deficits caused by cholinergic lesions. We found that treatment with muscarinic receptor agonist resulted in decreased APP levels in neocortex and hippocampus and increased levels of APPs in cerebrospinal fluid. Regulation of APP processing by the muscarinic agonist treatment occurred not only in normal rats, but also in aged and cholinergic denervated rats that model this aspect of Alzheimer's disease. Interestingly, we found that elevation of APP in neocortex correlated with the cognitive deficits in water-maze testing of rats with cholinergic dysfunction. These data indicate that increased cholinergic neurotransmission can enhance nonamyloidogenic APP processing in intact and lesioned rats and that APP may be involved in cognitive performance.

Aging↗
PubMed1999

Gene transfer to the nigrostriatal system by hybrid herpes simplex virus/adeno-associated virus amplicon vectors.

To improve gene transfer to CNS neurons, critical elements of herpes simplex virus 1 (HSV-1) amplicons and recombinant adeno-associated virus (AAV) vectors were combined to construct a hybrid amplicon vector, and then packaged via a helper virus-free system. We tested the HSV/AAV hybrid amplicon vectors for transduction efficiency and stability of transgene expression (green fluorescent protein) in primary neuronal cultures from rat fetal ventral mesencephalon, in comparison with traditional HSV amplicon, AAV, or adenovirus (Ad) vectors at the same multiplicity of infection. The HSA/AAV hybrid vectors transduced the highest number of primary neurons in culture 2 days after infection. As compared with all other vectors tested, only hybrid vectors containing the AAV rep gene maintained the 2-day level of transgene expression over 12 days in culture. This rep-containing hybrid vector was then tested for efficiency and safety in the brain. One month after injection into adult rat striatum (1 x 10(6) transducing units injected), transgene expression was observed within the striatum (ranging from 564 to 8610 cells) and the substantia nigra (via retrograde transport, ranging from 130 to 809 neurons). The HSV/AAV hybrid amplicon vectors transduced predominantly neurons within the striatum, and showed transduction efficacy similar to and in many cases higher than that of HSV amplicon vectors. No immune response was observed in the HSA/AAV hybrid vector-injected brains, as determined by immune markers specific for helper T lymphocytes, cytotoxic T lymphocytes, and microglia. This HSV/AAV hybrid system shows high transduction efficiency and stability in culture. The effective and safe transgene delivery into the nigrostriatal system illustrates its potential for therapeutic application for neurologic disorders, such as Parkinson and Huntington disease.

Animals↗
PubMed1999

Detection of dopaminergic cell loss and neural transplantation using pharmacological MRI, PET and behavioral assessment.

We demonstrate the use of magnetic resonance imaging (MRI) for detection of neurotransmitter stimulation using the dopamine transporter ligands amphetamine and CFT (2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane) as pharmacological challenges. We demonstrate that the unilateral loss of a hemodynamic response to either amphetamine or CFT challenge by unilateral 6-hydroxydopamine lesioning is restored by transplantation of fetal dopamine neurons in the striatum. The time course for the hemodynamic changes parallels the time courses for dopamine release, measured by prior microdialysis studies, and also for the rotational behavior in the unilaterally lesioned animals. Transplantation of the fetal cells results in hemodynamic time courses after CFT or amphetamine challenges at the graft site that are identical to those induced both before transplantation and on the intact contralateral side. The transplantation also results in complete behavioral recovery. The spatial extent of the dopaminergic recovery in the lesioned striatum is the same when measured using either PET of tracer levels of [11C]CFT binding or MRI. These results show great promise for the application of pharmacological MRI for application to studies of dopamine cell loss and potential recovery in Parkinson's disease.

Amphetamine↗
PubMed1999

Apoptosis in neuronal development and transplantation: role of caspases and trophic factors.

Fetal ventral mesencephalic (VM) transplants have been studied in the context of dopaminergic (DA) replacement therapy for Parkinson's disease (PD). DA neurons from VM transplants will grow axons and form functional synapses in the adult host central nervous system (CNS). Recently, studies have demonstrated that most of the transplanted DA neurons die in grafts within the first week after implantation. An important feature of neural development, also in transplanted developing fetal neural tissue, is cell death. However, while about 50% of cells born in the CNS will die naturally, up to 99% of fetal cells die after neural transplantation. It has been shown that VM grafts contain many apoptotic cells even at 14 days after transplantation. The interleukin-1beta converting enzyme (ICE) cysteine protease and 11 other ICE-like-related proteases have been identified, now named caspases. Activation of caspases is one of the final steps before a neuron is committed to die by apoptosis. Here we review this cell death process in detail: Since the growth of fetal neural grafts placed in the adult brain in many ways mimics normal development, it is likely that the caspases also play a functional role in transplants. Pharmacological inhibitors of caspases and genetically modified mice are now available for the study of neuronal death in fetal neuronal transplants. Understanding cell death mechanisms involved in acute cellular injury, necrosis, and programmed cell death (PCD) is useful in improving future neuronal transplantation methodology, as well as in neuroprotection, for patients with neurodegenerative diseases.

Animals↗
PubMed1999

Cellular delivery of trophic factors for the treatment of Huntington's disease: is neuroprotection possible?

The elucidation of the genetic defect in patients with Huntington's disease (HD) has allowed for the detection of individuals at risk for HD prior to the onset of symptoms. Thus "neuroprotection strategies" aimed at preventing the neuropathological and behavioral sequelae of this disease might be powerful therapeutically since they could be introduced to healthy patients before the initiation of a massive degenerative cascade principally localized to the striatum. A variety of trophic factors potently protect vulnerable striatal neurons in animal models of HD. A number of experimental variables are critical in determining the success of trophic factors in animal models. In this regard, the method of trophic factor delivery may be crucial, as delivery via genetically modified cells often produces greater and more widespread effects on striatal neurons than infusions of that same factor. The mechanisms by which cellularly delivered trophic factors forestall degeneration and prevent behavioral deficits are complex and often appear to be unrelated to the trophic factor binding to its cognate receptor. In this regard, cells genetically modified to secrete nerve growth factor (NGF) or ciliary neurotrophic factor (CNTF) protect degenerating striatal neurons which do not express either NGF or CNTF receptors. This review will discuss some of the non-receptor-based events that might underlie these effects and present the hypothesis that cellular delivery of certain trophic factors using genetically modified cells may be ready for clinical testing in HD patients.

Animals↗
PubMed1999

Factors intrinsic to the neuron can induce and maintain its ability to promote axonal outgrowth: a role for BCL2?

The adult CNS provides a poor environment for axonal growth and regeneration. The question of to what extent the loss of axonal growth occurring as the brain matures is dependent on factors intrinsic or extrinsic to the growing neuron is still unanswered. Examination of axonal growth from neural transplants provides insight into the roles of growth factors, inhibitory molecules, growth-promoting substrates and the differences between CNS and PNS environments in the regulation of neurite extension. The data that imply a role for BCL2 and related molecules in such processes are reviewed in this article, which analyzes the factors intrinsic to the neuron that control its capacity for axonal growth.

Animals↗
PubMed1999

Dopamine imaging markers and predictive mathematical models for progressive degeneration in Parkinson's disease.

We conducted PET imaging studies of modulation of dopamine transporter function and MRS studies of neurochemicals in idiopathic primate Parkinson's disease (PD) model induced by long-term, low-dose administration of MPTP. MR spectra showed striking similarities of the control spectrum of the primate and human striatum as well as MPTP-treated primate (six months after cessation of MPTP), and Parkinson's disease patient striatum (68 year old male; Hoehn-Yahr scale II; 510 mg/d L-DOPA). The choline/creatine ratio was similar in the MPTP model and human parkinsonism, suggesting a possible glial abnormality. The progressive degeneration of dopamine re-uptake sites observed in our PD model can be expressed by a time dependent exponential equation N(t) = N0 exp (-(0.072 +/- 0.016) t), where N0 represents intact entities (dopamine re-uptake sites before MPTP) and 0.072 per month is the rate of degeneration. When the signs of PD appear, N(t) is about 0.3-0.4 times N0. Interestingly, this biological degenerative phenomena has similar progression to that observed in cell survival theory. According to this theory and calculated degeneration rate, predictive models can be produced for regeneration and protective treatments.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Chronic cognitive deficits and amyloid precursor protein elevation after selective immunotoxin lesions of the basal forebrain cholinergic system.

Alzheimer's disease (AD) is the most common neurodegenerative disorder that causes cognitive deficits in the elderly. Its neuropathology is characterized by amyloid deposition and specific cholinergic degeneration. To address the link between amyloid formation and cholinergic loss, we examined histologically the amyloid precursor protein (APP) changes following selective immunolesion of the basal forebrain cholinergic system with 192 IgG-saporin in rats at 6 months post-lesion. In such rats with cognitive deficits observed in Morris water maze tests, we found increased levels of APP by optical density measurements in regions of cholinergic denervation. APP elevation and performance in the water maze task correlate with reduction of acetyl-cholinesterase (AChE) activity in the frontal cortex and CA3 subfield of hippocampus. The data indicate that loss of cholinergic innervation can affect APP expression.

Acetylcholinesterase↗
PubMed1998

In vivo PET imaging in rat of dopamine terminals reveals functional neural transplants.

Positron emission tomography (PET) and carbon-11-labeled 2B-carbomethoxy-3B-(4-fluorophenyl)tropane (11C-CFT or 11-WIN 35,428) were used as molecular markers for striatal presynaptic dopamine (DA) transporters in a unilateral Parkinson's disease rat neurotransplantation model. In the lesioned striatum, the binding ratio measured by the DA presynaptic marker was reduced to 15% to 35% of the intact side (or unoperated control). After grafting with non-DA cells (from dorsal mesencephalon), the DA binding ratio remained reduced to levels observed before transplantation and rats showed no behavioral recovery. In contrast, after DA neuronal transplantation, behavioral recovery occurred only after the 11C-CFT binding ratio had increased to 75% to 85% of the intact side. This study provides direct in vivo evidence for the dopaminergic molecular basis of functional recovery in the lesioned nigrostriatal system after neural transplantation.

Animals↗
PubMed1998

Blastula-stage stem cells can differentiate into dopaminergic and serotonergic neurons after transplantation.

In order to assess the potential of embryonic stem cells to undergo neuronal differentiation in vivo, totipotent stem cells from mouse blastocysts (D3 and E14TG2a; previously expanded in the presence of leukemia inhibitory factor) were transplanted, with or without retinoic acid pretreatment, into adult mouse brain, adult lesioned rat brain, and into the mouse kidney capsule. Intracerebral grafts survived in 61% of cyclosporine immunosuppressed rats and 100% of mouse hosts, exhibited variable size and morphology, and both intracerebral and kidney capsule grafts developed large numbers of cells exhibiting neuronal morphology and immunoreactivity for neurofilament, neuron-specific enolase, tyrosine hydroxylase (TH), 5-hydroxytryptamine (5-HT), and cells immunoreactive for glial fibrillary acidic protein. Though graft size and histology were variable, typical grafts of 5-10 mm3 contained 10-20,000 TH+ neurons, whereas dopamine-beta-hydroxylase+ cells were rare. Most grafts also included nonneuronal regions. In intracerebral grafts, large numbers of astrocytes immunoreactive for glial fibrillary acidic protein were present. Both TH+ and 5-HT+ axons from intracerebral grafts grew into regions of the dopamine-lesioned host striatum. TH+ axons grew preferentially into striatal gray matter, while 5-HT+ axons showed no white/gray matter preference. These findings demonstrate that transplantation to the brain or kidney capsule can induce a significant fraction of totipotent embryonic stem cells to become putative dopaminergic or serotonergic neurons and that when transplanted to the brain these neurons are capable of innervating the adult host striatum.

Animals↗
PubMed1998

A novel immunophilin ligand: distinct branching effects on dopaminergic neurons in culture and neurotrophic actions after oral administration in an animal model of Parkinson's disease.

Protection or regeneration of the dopaminergic (DA) system would be of significant therapeutic value for Parkinson's disease. Immunophilin ligands, such as FK506, can produce neurotrophic effects in vitro and in vivo, but their immunosuppressive effects make them unsuitable for neurological application. This study demonstrates that a novel, nonimmunosuppressive immunophilin ligand (V-10,367) increased the number of neurites extended by tyrosine hydroxylase positive (TH+) DA neurons in embryonic day 14 primary DA neuronal cultures. In contrast, the immunosuppressive immunophilin ligand FK506 increased the length of TH+ neurites. After oral administration in MPTP-treated mice, V-10,367 completely protected against MPTP-induced loss of striatal TH+ axonal density, while FK506 did not. These experiments demonstrate that nonimmunosuppressive immunophilin ligands specifically increase neurite branching in primary DA neuronal culture and possess neurotrophic actions in vivo with potential application to neurodegenerative disease.

Administration, Oral↗