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Ronald M. Lindsay - One of the best experts on this subject based on the ideXlab platform.
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brain derived Neurotrophic Factor transgenic mice exhibit passive avoidance deficits increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex
Neuroscience, 1999Co-Authors: Susan D Croll, John S. Rudge, Ronald M. Lindsay, George D. Yancopoulos, Chitra Suri, Debra L Compton, Mary V Simmons, Stanley J Wiegand, Helen E ScharfmanAbstract:Transgenic mice overexpressing brain-derived Neurotrophic Factor from the β-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived Neurotrophic Factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived Neurotrophic Factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived Neurotrophic Factor transcripts decreased. In addition, the brain-derived Neurotrophic Factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived Neurotrophic Factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived Neurotrophic Factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived Neurotrophic Factor could be pro-convulsant in the limbic system.
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Changes in Neurotrophic Factor expression and receptor activation following exposure of hippocampal neuron/astrocyte cocultures to kainic acid
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1995Co-Authors: John S. Rudge, Elizabeth Pasnikowski, P Holst, Ronald M. LindsayAbstract:Neurotrophic Factor expression in the adult mammalian CNS is largely neuronal. However, upon traumatic injury reactive astrocytes express a number of Neurotrophic Factors including ciliary Neurotrophic Factor (CNTF), fibroblast growth Factor (FGF), and NGF. In this study, we examined whether the upregulation of Neurotrophic Factors in reactive astrocytes and cultured astrocytes is a consequence of separation from their neuronal counterparts, and whether Neurotrophic Factor levels can be regulated by placing astrocytes into coculture with neurons. We show that reintroduction of rat hippocampal neurons to rat hippocampal astrocytes in vitro leads to a time dependent downregulation in astrocytes of the Neurotrophic Factors CNTF, NGF, and neurotrophin 3 (NT-3). In contrast, brain-derived Neurotrophic Factor (BDNF) mRNA, which is only expressed in neurons in these cultures is slightly increased. Once Neurotrophic Factor levels in cocultures had reached a steady state in the neuron/glia cocultures, we initiated a traumatic event with the excitotoxin kainic acid. BDNF protein was rapidly upregulated within 24 hr after lesion, whereas CNTF protein upregulation was delayed reaching maximal levels by 3 d. Despite the endogenous upregulation of both of these trophic Factors, no activation of their respective receptors, as measured by tyrosine phosphorylation, was detectable following kainate administration. However, following addition of exogenous CNTF at any time point up to 24 hr after kainate administration, the beta components of the CNTF receptor (LIFR beta and gp130) could be phosphorylated. Furthermore, although activation of neuronal LIFR beta and gp130 by exogenous CNTF declined during the period of neuronal death, these receptors reappeared on astrocytes and could be activated by CNTF. In contrast, phosphorylation of TrkB by exogenous BDNF was undetectable by 24 hr and could not be reactivated after this point. These data suggest that the intimate association of astrocytes and neurons in the CNS serves to suppress astrocyte-derived Neurotrophic Factor expression and that neuronal loss leads to a derepression of Neurotrophic Factor synthesis in astrocytes. However, the upregulation of endogenous BDNF and CNTF observed after excitotoxic lesion in this culture model are insufficient to activate signal transduction and protect against neuronal loss.
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histometric effects of ciliary Neurotrophic Factor in wobbler mouse motor neuron disease
Annals of Neurology, 1995Co-Authors: Ken Ikeda, Ronald M. Lindsay, Vivien Wong, Thomas H Holmlund, Tom Greene, Jesse M Cedarbaum, Hiroshi MitsumotoAbstract:We investigated the histological effects of ciliary Neurotrophic Factor on degenerating motor neurons, their axons, and skeletal muscles in 68 wobbler mice with motor neuron disease. Treatment consisted of recombinant rat or human ciliary Neurotrophic Factor (or a vehicle solution), 1-mg/kg subcutaneous injection, three times per week for 4 weeks after the clinical diagnosis. The number of motor neurons immunoreactive for calcitonin gene--related peptide was higher in mice receiving rat ciliary Neurotrophic Factor (p < 0.03), although the number of choline acetyltransferase-reactive neurons was the same in both treated and untreated control groups. Treatment did not prevent vacuolar degeneration of motor neurons. In mice treated with human ciliary Neurotrophic Factor, the percentage of axons undergoing acute axonal degeneration (myelin ovoids) was smaller in the entire C5 ventral root (p < 0.02) and in the musculocutaneous nerve (p < 0.04), and the number of myelinated nerve fibers was 30% higher in both nerves (p < 0.01 and p < 0.04, respectively) than in controls. In ciliary Neurotrophic Factor-treated mice, the biceps muscle weight was 20% greater, the mean muscle fiber diameter was 30% larger, and the number of atrophied muscle fibers was 75% lower than that in the vehicle-treated wobbler mice (p < 0.001 for all three results). The number of terminal axonal branching points and the mean length of motor end-plates were also higher in the ciliary Neurotrophic Factor-treated mice (p < 0.001 and p < 0.02, respectively). Our study thus suggests that ciliary Neurotrophic Factor slowed neuronal degeneration, enhanced axonal regeneration at both the proximal and distal motor axons, and reduced muscle atrophy in this motor neuron disease.
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the effects of ciliary Neurotrophic Factor on motor dysfunction in wobbler mouse motor neuron disease
Annals of Neurology, 1994Co-Authors: Hiroshi Mitsumoto, Ken Ikeda, Vivien Wong, Tom Greene, Jesse M Cedarbaum, Tomas Holmlund, Ronald M. LindsayAbstract:Ciliary Neurotrophic Factor is the first Neurotrophic Factor to show survival-promoting effects in developing motor neurons in vitro, in ovo, and in vivo. In the present study we tested the effects of recombinant rat or human ciliary Neurotrophic Factor in the wobbler mouse model of motor neuron disease. Mice received 1 mg/kg of the Factor or a vehicle solution subcutaneously three times a week for 4 weeks, after the disease was diagnosed between the ages of 3 and 4 weeks. Although treatment with rat ciliary Neurotrophic Factor (n=6) resulted in delayed weight gain (p<0.001), grip strength normalized to body weight in the Factor-treated mice was significantly greater (p<0.02) and declined at a slower rate (p<0.05) compared to that in vehicle-treated animals
Hiroshi Mitsumoto - One of the best experts on this subject based on the ideXlab platform.
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histometric effects of ciliary Neurotrophic Factor in wobbler mouse motor neuron disease
Annals of Neurology, 1995Co-Authors: Ken Ikeda, Ronald M. Lindsay, Vivien Wong, Thomas H Holmlund, Tom Greene, Jesse M Cedarbaum, Hiroshi MitsumotoAbstract:We investigated the histological effects of ciliary Neurotrophic Factor on degenerating motor neurons, their axons, and skeletal muscles in 68 wobbler mice with motor neuron disease. Treatment consisted of recombinant rat or human ciliary Neurotrophic Factor (or a vehicle solution), 1-mg/kg subcutaneous injection, three times per week for 4 weeks after the clinical diagnosis. The number of motor neurons immunoreactive for calcitonin gene--related peptide was higher in mice receiving rat ciliary Neurotrophic Factor (p < 0.03), although the number of choline acetyltransferase-reactive neurons was the same in both treated and untreated control groups. Treatment did not prevent vacuolar degeneration of motor neurons. In mice treated with human ciliary Neurotrophic Factor, the percentage of axons undergoing acute axonal degeneration (myelin ovoids) was smaller in the entire C5 ventral root (p < 0.02) and in the musculocutaneous nerve (p < 0.04), and the number of myelinated nerve fibers was 30% higher in both nerves (p < 0.01 and p < 0.04, respectively) than in controls. In ciliary Neurotrophic Factor-treated mice, the biceps muscle weight was 20% greater, the mean muscle fiber diameter was 30% larger, and the number of atrophied muscle fibers was 75% lower than that in the vehicle-treated wobbler mice (p < 0.001 for all three results). The number of terminal axonal branching points and the mean length of motor end-plates were also higher in the ciliary Neurotrophic Factor-treated mice (p < 0.001 and p < 0.02, respectively). Our study thus suggests that ciliary Neurotrophic Factor slowed neuronal degeneration, enhanced axonal regeneration at both the proximal and distal motor axons, and reduced muscle atrophy in this motor neuron disease.
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the effects of ciliary Neurotrophic Factor on motor dysfunction in wobbler mouse motor neuron disease
Annals of Neurology, 1994Co-Authors: Hiroshi Mitsumoto, Ken Ikeda, Vivien Wong, Tom Greene, Jesse M Cedarbaum, Tomas Holmlund, Ronald M. LindsayAbstract:Ciliary Neurotrophic Factor is the first Neurotrophic Factor to show survival-promoting effects in developing motor neurons in vitro, in ovo, and in vivo. In the present study we tested the effects of recombinant rat or human ciliary Neurotrophic Factor in the wobbler mouse model of motor neuron disease. Mice received 1 mg/kg of the Factor or a vehicle solution subcutaneously three times a week for 4 weeks, after the disease was diagnosed between the ages of 3 and 4 weeks. Although treatment with rat ciliary Neurotrophic Factor (n=6) resulted in delayed weight gain (p<0.001), grip strength normalized to body weight in the Factor-treated mice was significantly greater (p<0.02) and declined at a slower rate (p<0.05) compared to that in vehicle-treated animals
Marta Agudobarriuso - One of the best experts on this subject based on the ideXlab platform.
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brain derived Neurotrophic Factor maintains brn3a expression in axotomized rat retinal ganglion cells
Experimental Eye Research, 2011Co-Authors: M C Sanchezmigallon, Francisco M Nadalnicolas, Manuel Jimenezlopez, Paloma Sobradocalvo, Manuel Vidalsanz, Marta AgudobarriusoAbstract:The transcription Factor Brn3a has been reported to be a good marker for adult rat retinal ganglion cells in control and injured retinas. However, it is still unclear if Brn3a expression declines progressively by the injury itself or otherwise its expression is maintained in retinal ganglion cells that, though being injured, are still alive, as might occur when assessing neuroprotective therapies. Therefore, we have automatically quantified the whole population of surviving Brn3a positive retinal ganglion cells in retinas subjected to intraorbital optic nerve transection and treated with either brain derived Neurotrophic Factor or vehicle. Brain derived Neurotrophic Factor is known to delay retinal ganglion cell death after axotomy. Thus, comparison of both groups would inform of the suitability of Brn3a as a retinal ganglion cell marker when testing neuroprotective molecules. As internal control, retinal ganglion cells were, as well, identified in all retinas by retrogradely tracing them with fluorogold. Our data show that at all the analyzed times post-lesion, the numbers of Brn3a positive retinal ganglion cells and of fluorogold positive retinal ganglion cells are significantly higher in the brain derived Neurotrophic Factor-treated retinas compared to the vehicle-treated ones. Moreover, detailed isodensity maps of the surviving Brn3a positive retinal ganglion cells show that a single injection of brain derived Neurotrophic Factor protects retinal ganglion cells throughout the entire retina. In conclusion, Brn3a is a reliable retinal ganglion cell marker that can be used to accurately measure the potential effect of a given neuroprotective therapy.
Luigi Aloe - One of the best experts on this subject based on the ideXlab platform.
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Neurotrophic Factor expression in three infants with Ondine's curse.
Pediatric neurology, 2005Co-Authors: Antonio Chiaretti, Giulia Zorzi, Concezio Di Rocco, Orazio Genovese, A. Antonelli, Marco Piastra, Giancarlo Polidori, Luigi AloeAbstract:This study investigates the expression of some Neurotrophic Factors (brain-derived Neurotrophic Factor, glial-derived Neurotrophic Factor, and nerve growth Factor) in the cerebrospinal fluid of infants suffering from idiopathic congenital central hypoventilation syndrome and determines their correlations with this syndrome. Cerebrospinal fluid samples were collected from three infants suffering from idiopathic congenital central hypoventilation syndrome and 15 control subjects with obstructive hydrocephalus to measure the expression of brain-derived Neurotrophic Factor, glial-derived Neurotrophic Factor, and nerve growth Factor using an immunoenzymatic assay. In the cerebrospinal fluid of patients, analysis of Neurotrophic Factors expression indicated a reduction, not statistically significant, of brain-derived Neurotrophic Factor compared with the mean level of the control group (1554 pg/mL, 1509 pg/mL, and 1582 pg/mL respectively, in comparison to 1954 ± 103 pg/mL), whereas nerve growth Factor and glial-derived Neurotrophic Factor did not undergo significant variations in either group. Neurotrophic Factors, namely brain-derived Neurotrophic Factor, regulate the maturation and differentiation of respiratory neurons. The reduced expression of brain-derived Neurotrophic Factor in the cerebrospinal fluid samples of infants with Ondine's curse, although not statistically significant, is suggestive of a dysregulation in the brain-derived Neurotrophic Factor synthesis that could play an important role in the breathing disorders observed in patients with idiopathic congenital central hypoventilation syndrome.
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Neurotrophic Factor expression in childhood low-grade astrocytomas and ependymomas
Child's Nervous System, 2004Co-Authors: Antonio Chiaretti, Alessia Antonelli, Marco Piastra, Luigi Aloe, Antonio Ruggiero, Riccardo Riccardi, Giampiero Tamburrini, Concezio Di RoccoAbstract:Background Neurotrophic Factors (nerve growth Factor [NGF], brain-derived Neurotrophic Factor [BDNF] and glial-derived Neurotrophic Factor [GDNF]) are growth Factors implicated in the growth and differentiation of brain nerve cells. An involvement of these Factors in the biology and progression of some specific tumours has been suggested. In accordance with the role of Neurotrophic Factors in tumour behaviour the aim of the present study was to investigate their expression in two childhood brain neoplasms, namely low-grade astrocytomas and ependymomas. Materials and methods We investigated the NGF, BDNF, GDNF and NGF receptors (TrkA and p75) expression in the tumour tissues, cerebrospinal fluid (CSF) and plasma of ten children affected by low-grade astrocytomas and ependymomas. Control tissue samples (together with CSF and plasma samples) were obtained from patients who underwent surgery for cerebral vascular or epileptogenic lesions. Results The expression of NGF decreases both in tumour samples and in the CSF of affected children compared with controls. BDNF instead increases in CSF, while the expression of GDNF remains unchanged both in tissues and in CSF. No differences were found in Neurotrophic Factor plasma levels in patients or in controls. Gene expression of NGF and its high-affinity receptor (TrkA) are reduced in tumour tissues, whereas the number of cells immunopositive to the low-affinity NGF receptor (p75) is increased. Conclusion Reduced expression of NGF and TrkA has been shown in low-grade astrocytomas and ependymomas. These findings may be related to the role of this neurotrophin in cell differentiation and apoptosis. The different expression of NGF, BDNF, and GDNF in low-grade astrocytomas and ependymomas suggests that a different degree of redundancy exists among members of the Neurotrophic Factor family and that their expression may be correlated with the biology and the behaviour of these tumours.
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Neurotrophic Factor expression in childhood low-grade astrocytomas and ependymomas.
Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, 2004Co-Authors: Antonio Chiaretti, Alessia Antonelli, Marco Piastra, Luigi Aloe, Antonio Ruggiero, Riccardo Riccardi, Giampiero Tamburrini, Concezio Di RoccoAbstract:Background Neurotrophic Factors (nerve growth Factor [NGF], brain-derived Neurotrophic Factor [BDNF] and glial-derived Neurotrophic Factor [GDNF]) are growth Factors implicated in the growth and differentiation of brain nerve cells. An involvement of these Factors in the biology and progression of some specific tumours has been suggested. In accordance with the role of Neurotrophic Factors in tumour behaviour the aim of the present study was to investigate their expression in two childhood brain neoplasms, namely low-grade astrocytomas and ependymomas.
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Correlation between Neurotrophic Factor expression and outcome of children with severe traumatic brain injury.
Intensive care medicine, 2003Co-Authors: Antonio Chiaretti, Alessia Antonelli, Concezio Di Rocco, Marco Piastra, Giancarlo Polidori, Elena Caresta, Tiziana Amendola, Luigi AloeAbstract:Objectives We evaluated the Neurotrophic Factors [nerve growth Factor (NGF), brain-derived Neurotrophic Factor (BDNF), glia-derived Neurotrophic Factor (GDNF)] expression and their association with the severity and outcome of children with traumatic brain injury.
Nancy Lee - One of the best experts on this subject based on the ideXlab platform.
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In vivo localization and characterization of functional ciliary Neurotrophic Factor receptors which utilize JAK-STAT signaling.
Neuroscience, 2000Co-Authors: Aj Maclennan, B.k. Devlin, K.l. Neitzel, Jesús T. García, G.a Hauptman, Isabelle Gloaguen, A Di Marco, Ralph Laufer, Nancy LeeAbstract:Abstract The ciliary Neurotrophic Factor receptor is critically involved in embryonic motor neuron development. Postnatally, it may contribute to neuronal maintenance and regeneration. In addition, pharmacological stimulation of the receptor may slow the progression of several neurodegenerative disorders. The widespread nervous system expression of ciliary Neurotrophic Factor receptor components and the effects of low ciliary Neurotrophic Factor concentrations on a wide variety of cells in culture combine to suggest that functional ciliary Neurotrophic Factor receptors are expressed by many classes of neurons in vivo . However, the in vivo signaling properties and distribution of functional ciliary Neurotrophic Factor receptors have not been directly determined. We developed a novel in vivo assay of functional ciliary Neurotrophic Factor receptors which revealed that, in the adult nervous system, cranial and spinal motor neurons are very sensitive to ciliary Neurotrophic Factor and display a rapid, robust increase in phospho-STAT3 in their dendrites, cell bodies and nuclei, which is specifically blocked by the ciliary Neurotrophic Factor receptor antagonist, AADH-CNTF. In distinct contrast, several other classes of ciliary Neurotrophic Factor receptor expressing neurons fail to increase phospho-STAT3 levels following ciliary Neurotrophic Factor treatment, even when ciliary Neurotrophic Factor is applied at high concentrations. Leukemia inhibitory Factor and epidermal growth Factor elicit the same cell-type-dependent pattern of phospho-STAT3 increases. Responsive and non-responsive neurons express comparable levels of STAT3. Therefore, in vivo ciliary Neurotrophic Factor receptor-initiated STAT3 signal transduction is regulated in a very cell-type-dependent manner. The present data suggest that at least some of this regulation occurs at the STAT3 tyrosine phosphorylation step. These unexpected results also suggest that other forms of receptor-initiated STAT3 signal transduction may be similarly regulated.
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Regulation of ciliary Neurotrophic Factor receptor α in sciatic motor neurons following axotomy
Neuroscience, 1999Co-Authors: A. John Maclennan, B.k. Devlin, K.l. Neitzel, D.l. Mclaurin, Kevin J. Anderson, Nancy LeeAbstract:Spinal motor neurons are one of the few classes of neurons capable of regenerating axons following axotomy. Injury-induced expression of Neurotrophic Factors and corresponding receptors may play an important role in this rare ability. A wide variety of indirect data suggests that ciliary Neurotrophic Factor receptor alpha may critically contribute to the regeneration of injured spinal motor neurons. We used immunohistochemistry, in situ hybridization and retrograde tracing techniques to study the regulation of ciliary Neurotrophic Factor receptor alpha in axotomized sciatic motor neurons. Ciliary Neurotrophic Factor receptor alpha immunoreactivity, detected with two independent antisera, is increased in a subpopulation of caudal sciatic motor neuron soma one, two and six weeks after sciatic nerve transection and reattachment, while no changes are detected at one day and 15 weeks post-lesion. Ciliary Neurotrophic Factor receptor alpha messenger RNA levels are augmented in the same classes of neurons following an identical lesion, suggesting that increased synthesis contributes, at least in part, to the additional ciliary Neurotrophic Factor receptor alpha protein. Separating the proximal and distal nerve stumps with a plastic barrier does not noticeably affect the injury-induced change in ciliary Neurotrophic Factor receptor alpha regulation, thereby indicating that this injury response is not dependent on signals distal to the lesion traveling retrogradely through the nerve or signals generated by axonal growth through the distal nerve. The prolonged increases in ciliary Neurotrophic Factor receptor alpha protein and messenger RNA found in regenerating sciatic motor neurons contrast with the responses of non-regenerating central neurons, which are reported to display, at most, a short-lived increase in ciliary Neurotrophic Factor receptor alpha messenger RNA expression following injury. The present data are the first to demonstrate, in vivo, neuronal regulation of ciliary Neurotrophic Factor receptor alpha protein in response to injury. Moreover, they suggest that the ability of a subpopulation of spinal motor neurons to regulate ciliary Neurotrophic Factor receptor alpha levels in response to injury may play a role in their survival and axonal regeneration. Consistent with such a role, we also find relatively high, and probably elevated, levels of ciliary Neurotrophic Factor receptor alpha immunoreactivity in regenerating axons.