Shoushu Jiao

Glial cell line-derived neurotrophic factor attenuates behavioural deficits and regulates nigrostriatal dopaminergic and peptidergic markers in 6-hydroxydopamine-lesioned adult rats: comparison of intraventricular and intranigral delivery

The effects of intranigrally- or intraventricularly-administered glial cell line-derived neurotrophic factor were tested on low dose (0.05 mg/kg) apomorphine-induced rotations and tyrosine hydroxylase activity in the substantia nigra and striatum of stable 6-hydroxydopamine-lesioned rats. In addition, we determined if 6-hydroxydopamine lesions in the absence or presence of treatment affected neuropeptide (substance P, met-enkephalin, dynorphin) content in the striatum. Glial cell line-derived neurotrophic factor, when administered intranigrally, prevented apomorphine-induced rotational behaviour for 11 weeks following a single injection. In comparison, intraventricularly-administered glial cell line-derived neurotrophic factor produced a transient reduction in rotational behaviour that lasted for two to three weeks following a single injection. We also show that rotational behaviour is reduced following each subsequent intraventricular injection of glial cell line-derived neurotrophic factor given every six weeks, a time-point when baseline rotation deficits were re-established. Intranigrally- or intraventricularly-administered glial cell line-derived neurotrophic factor significantly reduced weight gain in all 6-hydroxydopamine-lesioned rats in this study. Following behavioural analysis where a confirmed improvement of behaviour was established, tissues were dissected for neurochemical analysis. In lesioned rats with intranigral injections of administered glial cell line-derived neurotrophic factor, significant increases of nigral, but not striatal tyrosine hydroxylase activity were measured. Additionally, 6-hydroxydopamine lesions significantly increased striatal dynorphin (61-139%) and met-enkephalin (81-139%), but not substance P levels. In these rats, intranigrally-administered glial cell line-derived neurotrophic factor injections reversed lesion-induced increases in nigral dynorphin A levels and increased nigral dopamine levels, but did not alter nigral met-enkephalin or substance P levels nor striatal dopamine levels. In lesioned rats with intraventricular injections of glial cell line-derived neurotrophic factor, tyrosine hydroxylase ispilateral to the lesion was increased in the substantia nigra, but not in the striatum. Intraventricularly-administered glial cell line-derived neurotrophic factor did not reverse lesion-induced increases in nigral dynorphin A or met-enkephalin levels nor did glial cell line-derived neurotrophic factor affect substance P levels in the striatum. These results suggest that in an animal model of Parkinsons disease, the neurotrophic factor glial cell line-derived neurotrophic factor reverses behavioural consequences of 6-hydroxydopamine administration, an effect that may involve both dopaminergic and peptidergic neurotransmission.

Adenoviral vector-mediated GDNF gene therapy in a rodent lesion model of late stage Parkinson's disease

A recombinant adenoviral vector encoding the human glial cell line-derived neurotrophic factor (GDNF) gene (Ad-GDNF) was used to express the neurotrophic factor GDNF in the unilaterally 6-hydroxydopamine (6-OHDA) denervated substantia nigra (SN) of adult rats ten weeks following the 6-OHDA injection. 6-OHDA lesions significantly increased apomorphine-induced (contralateral) rotations and reduced striatal and nigral dopamine (DA) levels by 99% and 70%, respectively. Ad-GDNF significantly (P < 0.01) decreased (by 30-40%) apomorphine-induced rotations in lesioned rats for up to two weeks following a single injection. Locomotor activity, assessed 7 days following the Ad-GDNF injection, was also significantly (P < 0.05) increased (by 300-400%). Two weeks after the Ad-GDNF injection, locomotor activity was still significantly increased compared to the Ad-beta-gal-injected 6-OHDA lesioned (control) group. Additionally, in Ad-GDNF-injected rats, there was a significant decrease (10-13%) in weight gain which persisted for approximately two weeks following the injection. Consistent with the behavioral changes, levels of DA and the metabolite dihydroxyphenylacetic acid (DOPAC) were elevated (by 98% and 65%, respectively) in the SN, but not the striatum of Ad-GDNF-injected rats. Overall, a single Ad-GDNF injection had significant effects for 2-3 weeks following administration. These results suggest that virally delivered GDNF promotes the recovery of nigral dopaminergic tone (i.e.: increased DA and DOPAC levels) and improves behavioral performance (i.e.: decreased rotations, increased locomotion) in rodents with extensive nigrostriatal dopaminergic denervation. Moreover, our results suggest that viral delivery of trophic factors may be used eventually to treat neurodegenerative diseases such as Parkinsons disease.

Glial cell line-derived neurotrophic factor: distribution and pharmacology in the rat following a bolus intraventricular injection

Glial cell line-derived neurotrophic factor (GDNF) has been shown to increase dopaminergic parameters in vitro and in vivo and can reduce parkinsonian behaviors in animal models of the disease. This study determined the potential of the lateral ventricle as an administration route for GDNF by examining the distribution and neurochemical consequences of a single intraventricular injection. Autoradiographic analysis showed that intraventricularly administered [125I]GDNF was distributed throughout the ventricular system at 1 and 24 h following injection. The cerebral cortex, septum, diagonal band, fimbria, striatum, hippocampus, hypothalamus, substantia nigra/ventral tegmental area, and cerebellum were also labeled. At 7 days, there was still labeling throughout the ventricular system, hypothalamus, substantia nigra, and cerebellum. Twenty-four hours following an intrastriatal injection of [125I]GDNF, label was observed in the substantia nigra/ventral tegmental area, demonstrating retrograde transport. The neurochemical effects of intraventricularly administered GDNF (0.1-100 micrograms) at 7 days post injection were also examined. GDNF significantly increased striatal (approximately 28%) and nigral (up to 40%) dopamine, as well as regulated the dopamine metabolites homovanillic acid and dihydroxyphenylacetic acid. Dopamine levels were unchanged in the frontal cortex. Dopamine content was significantly increased in the hypothalamus (up to 35%), an increase which may contribute to the inhibition of weight gain seen after administration of GDNF. Additionally, dopamine turnover was decreased or unchanged across the brain regions analyzed, which may indicate that in unlesioned rats, intraventricularly administered GDNF stimulates the synthesis and storage of dopamine. This study shows that intraventricularly injected GDNF can access basal ganglia structures, most notably the midbrain dopamine cell body region, and remains present in this area for at least 7 days following a single administration. GDNF differentially increases dopaminergic tone within a variety of brain structures, including the nigrostriatal pathway. These data support the potential effectiveness of intraventricular administered GDNF as a treatment for Parkinsons disease.

Glial cell line-derived neurotrophic factor induces the dopaminergic and cholinergic phenotype and increases locomotor activity in aged Fischer 344 rats.

Glial cell line-derived neurotrophic factor has been shown to affect dopaminergic and cholinergic neuron markers and functions in young rats. However, it is not known if the response to exogenous glial cell line-derived neurotrophic factor is augmented during normal aging. Thus, the effects of chronic intraventricular infusions of glial cell line-derived neurotrophic factor were determined in young adult (three-months-old) and aged (24-months-old) Fischer 344 (F344) male rats. The effects of glial cell line-derived neurotrophic factor were compared to the effects of the neurotrophin nerve growth factor. Growth factors were administered at a dose of 10 mg/day for 14 days. Locomotor activity and weight changes were also examined in all rats. Aged F344 rats showed significantly reduced (by 75-80%) locomotor activity compared to young rats. In glial cell line-derived neurotrophic factor-treated aged and young rats there was significantly increased (242% and 149%, respectively) locomotor activity measured at seven days. There was also a significant increase in locomotor activity measured 14 days after the start of infusion. Both glial cell line-derived neurotrophic factor and nerve growth factor reduced weight gain by 10% in young and old F344 rats. Two weeks following the start of nerve growth factor or glial cell line-derived neurotrophic factor administration the brains were used for neurochemical analyses. Glial cell line-derived neurotrophic factor significantly increased tyrosine hydroxylase activity in the substantia nigra and striatum of aged rats and in the substantia nigra of young rats. Nerve growth factor treatment did not significantly affect tyrosine hydroxylase activity. However, glial cell line-derived neurotrophic factor and nerve growth factor increased choline acetyltransferase activity in the septum, hippocampus, striatum and cortex of aged rats and in the hippocampus and striatum of young rats to a comparable degree. These findings indicate that specific dopaminergic and cholinergic neuron populations remain responsive to glial cell line-derived neurotrophic factor during the life span of the rat and may be involved in maintaining phenotypic expression within multiple neuronal populations. Additionally, the glial cell line-derived neurotrophic factor-induced up-regulation of brain neurotransmitter systems may be responsible for increased locomotor activity in F344 rats.

Adrenal medullary autografts into the basal ganglia of Cebus monkeys: Graft viability and fine structure

Based largely upon studies done in rats, a number of medical centers are now performing autografts of adrenal medullary tissue in consenting patients with Parkinsons disease. However, a systematic experimental evaluation of adrenal medullary autografts in nonhuman primates is necessary. This study provides a detailed analysis of the implant site at the fine structural level 30 days post-transplantation in the Cebus monkey. Five normal and two 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-treated Cebus monkeys received adrenal medullary autografts using an open microsurgical approach (n = 3) or via stereotactic placement with a tissue carrier (n = 4). Analysis of preimplant samples of the adrenal medulla confirmed that viable chromaffin cells were implanted into the basal ganglia. However, 30 days later, the implant site resembled a chronic inflammatory focus, with grafted chromaffin cells identified ultrastructurally in only two of the seven transplanted monkeys. The grafted cells showed overt signs of cellular degeneration and were surrounded by phagocytic macrophages. All of the implant sites, regardless of the surgical approach, were filled with macrophages, cells of hematogenous origin, and fibrous astrocytes. The vasculature of the implant site was of the nonfenestrated type, characteristic of the host striatum. Despite the poor survival of implanted chromaffin cells, robust sprouting of tyrosine hydroxylase-like immunoreactive fibers was evident in the striatum adjacent to the implant site (see accompanying manuscript, M.S. Fiandaca, J. H. Kordower, J.T. Hansen, S.-S. Jiao, and D.M. Gash, 1988, Exp. Neurol. 102: 76-91), suggesting that implantation may have precipitated a host response that was beneficial to the transplanted animal. Additional studies that provide a better understanding of the cellular elements residing in the implant site and their potential for trophic influence seem warranted.

Pharmacological characterization of glial cell line-derived neurotrophic factor (GDNF): implications for GDNF as a therapeutic molecule for treating neurodegenerative diseases

Abstract.This review presents a comprehensive survey of the recently described pharmacological activities of glial cell line-derived neurotrophic factor on the central nervous system.

Glial Cell Line-Derived Neurotrophic Factor: A Novel Therapeutic Approach to Treat Motor Dysfunction in Parkinson's Disease

The discovery of the novel neurotrophic factor glial cell-line derived neurotrophic factor (GDNF) in 1993 sparked the interest of basic neuroscientists and clinicians alike. Since that time, many aspects of GDNFs physiology and pharmacology have been studied in great detail. GDNF has been shown to be a potent survival factor for dopaminergic neurons during development. GDNF also has been shown to be a survival factor and neurotrophic factor for nigrostriatal dopaminergic neurons in the adult. The factor also reverses behavioral deficits in a rodent and primate model of Parkinsons disease. The overall goal will be to discuss the pharmacology of GDNF in the context of a potential therapeutic use to treat Parkinsons disease. Thus, the following report presents a comprehensive review of the development of GDNFs pharmacology and evidence which supports the clinical use of GDNF to treat dopaminergic deficits and motor dysfunctions in Parkinsons disease.

Topographical distribution of [125I]-glial cell line-derived neurotrophic factor in unlesioned and MPTP-lesioned rhesus monkey brain following a bolus intraventricular injection

The present study determined the topographical distribution profile for [125I]-glial cell line-derived neurotrophic factor in unlesioned and MPTP-lesioned (unilateral intracarotid injection) rhesus monkeys following an intraventricular injection. Autoradiographic analysis showed that following a bolus intraventricular injection, there was widespread distribution of [125I]-glial cell line-derived neurotrophic factor throughout the ventricular system (walls of lateral, third, and fourth ventricles and aqueduct), with some accumulation at the lateral ventricle injection site, possibly associated with the ependymal cell layer. In both unlesioned and MPTP-lesioned monkeys, there was labelling of the cerebral cortex, substantia nigra/ventral tegmental area and sequestration of [125I]-glial cell line-derived neurotrophic factor adjacent to the hippocampal formation, globus pallidus, ventral to and in the substantia nigra. However, [125I]-glial cell line-derived neurotrophic factor did not appear to diffuse readily or accumulate in the caudate-putamen even though there was some penetration away from the ventricular walls. Throughout the brain, there was also substantial non-parenchymal labelling of [125I]-glial cell line-derived neurotrophic factor, possibly associated with extracellular matrix components, meninges and vasculature due to the heparin binding properties of glial cell line-derived neurotrophic factor. In addition to the extensive loss of tyrosine hydroxylase immunoreactivity within the substantia nigra, there was also decreased accumulation of [125I]-glial cell line-derived neurotrophic factor and reduced glial cell line-derived neurotrophic factor immunoreactivity ipsilateral to the lesion. Microscopic analysis showed that glial cell line-derived neurotrophic factor immunoreactivity was associated with upper cortical layers including a high density of immunoreactivity at the surface of the cortex (meningeal, pial layer, vasculature) and around the ventricular walls (with some cellular labelling and labelling of vasculature). Moderate staining was observed in nigral cells contralateral to the MPTP-lesion, whereas only minimal levels of that glial cell line-derived neurotrophic factor immunoreactivity were detected ipsilateral to the lesion. This study shows that intraventricularly injected glial cell line-derived neurotrophic factor accumulates not only around the ventricular walls, but also in specific brain regions in which sub-populations of cells are more readily accessible than others. The presence of cells labelled with [125I] and immunopositive for glial cell line-derived neurotrophic factor in the substantia nigra indicates that these cells are a target for the trophic factor following intraventricular administration. Thus, the behavioral improvement observed in MPTP-lesioned monkeys following an intraventricular injection of glial cell line-derived neurotrophic factor is likely the result of activation of nigral cells.

Enhanced delivery of [125I]glial cell line-derived neurotrophic factor to the rat CNS following osmotic blood-brain barrier modification.

Subsequent to osmotic (mannitol-induced) blood-brain barrier (BBB) opening, [125I]glial cell line-derived neurotrophic factor (GDNF) was detected throughout the ventricular system, associated with the ependymal cell layer and extracellular matrix and to some extent penetrated into the cerebral cortex, subcortical gray matter, substantia nigra, septum, eye and optic nerve at 1 and 24 h following an intracarotid administration. Our study indicates that osmotic opening of the BBB allows for extensive distribution of GDNF throughout the central nervous system (CNS).