scholarly journals Evaluation of the Toxicity and Neurological Effects of Fulranumab in Adult Cynomolgus Monkeys

2019 ◽  
Vol 38 (3) ◽  
pp. 173-182 ◽  
Author(s):  
Meredith Rocca ◽  
Chao Han ◽  
Mark Butt ◽  
Timothy P. Coogan
Keyword(s):  
Nervous System ◽  
Sympathetic Neurons ◽  
Repeat Dose ◽  
Cynomolgus Monkeys ◽  
Standard Design ◽  
Cervical Ganglion ◽  
Apparent Decrease ◽  
Effect Level ◽  
Neurological Effects ◽  
Human Nerve

Fulranumab, an anti-human nerve growth factor antibody, was evaluated in a series of nonclinical toxicology studies. No treatment effects were observed in adolescent cynomolgus monkeys in standard design, repeat-dose toxicology studies of up to 6 months. Adverse effects on the developing nervous system were observed in offspring of pregnant cynomolgus monkeys treated with fulranumab. Subsequent studies including detailed morphologic investigations of the nervous system did reveal fulranumab-related changes in adult cynomolgus monkeys; this article is focused on those findings. A single dose of ≥1 mg/kg fulranumab administered subcutaneously (SC) caused a decrease in neuron and sympathetic ganglion size (superior cervical ganglion), observed morphologically and stereologically, with a resulting appearance of increased glial cell density. Similar results were observed in repeat-dose (15 to 52 weeks) toxicity studies at ≤50 mg/kg/wk fulranumab SC. These effects recovered after a 3-month treatment-free period. Fulranumab did not cause any neuronal death, necrosis, apoptosis, or any apparent decrease in function of sympathetic neurons/ganglia at any time point examined. A no observed effect level (NOEL) was established at 0.25 mg/kg fulranumab SC every 4 weeks for 28 weeks.

scholarly journals p75-deficient embryonic dorsal root sensory and neonatal sympathetic neurons display a decreased sensitivity to NGF

Development ◽  
1994 ◽  
Vol 120 (4) ◽  
pp. 1027-1033 ◽  
Author(s):  
K.F. Lee ◽  
A.M. Davies ◽  
R. Jaenisch
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Neural Development ◽  
Dorsal Root ◽  
Sympathetic Neurons ◽  
Mutant Mice ◽  
Neurotrophin Receptor ◽  
Cervical Ganglion ◽  
Response Specificity

To understand the role of low-affinity neurotrophin receptor p75 in neural development, we previously generated mice carrying a null mutation in the p75 locus (Lee, K. F., Li, E., Huber, L. J., Landis, S. C., Sharpe, A. H., Chao, M. V. and Jaenisch, R. (1992) Cell 69, 737–749). To elucidate the mechanisms leading to deficits in the peripheral nervous system in p75 mutant mice, we have employed dissociated cultures to examine the responses of p75-deficient dorsal root ganglion (DRG) and superior cervical ganglion (SCG) neurons to different neurotrophins. We found that p75-deficient DRG and SCG neurons displayed a 2- to 3-fold decreased sensitivity to NGF at embryonic day 15 (E15) and postnatal day 3 (P3), respectively, ages that coincide with the peak of naturally occurring cell death. Furthermore, while p75-deficient E15 DRG neurons did not change their response specificity to BDNF, NT-3, and NT-4/5, P3 SCG neurons became more responsive to NT-3 at higher concentrations (nanomolar ranges). These results may help explain the deficits in the peripheral nervous system in p75 mutant mice and provide evidence that p75 can modulate neurotrophin sensitivity in some neurons.

TRPC1, TRPC3, and TRPC4 in Rat Orofacial Structures

2017 ◽  
Vol 204 (5-6) ◽  
pp. 293-303 ◽  
Author(s):  
Masatoshi Fujita ◽  
Tadasu Sato ◽  
Takehiro Yajima ◽  
Eiji Masaki ◽  
Hiroyuki Ichikawa
Keyword(s):  
Transient Receptor Potential ◽  
Sympathetic Neurons ◽  
Receptor Potential ◽  
Monovalent Cation ◽  
Calcitonin Gene ◽  
Cervical Ganglion ◽  
Parasympathetic Neurons ◽  
Transient Receptor ◽  
And Function ◽  
And Control

TRPC (transient receptor potential cation channel subfamily C) members are nonselective monovalent cation channels and control Ca2+ inflow. In this study, immunohistochemistry for TRPC1, TRPC3, and TRPC4 was performed on rat oral and craniofacial structures to elucidate their distribution and function in the peripheries. In the trigeminal ganglion (TG), 56.1, 84.1, and 68.3% of sensory neurons were immunoreactive (IR) for TRPC1, TRPC3, and TRPC4, respectively. A double immunofluorescence method revealed that small to medium-sized TG neurons co-expressed TRPCs and calcitonin gene-related peptide. In the superior cervical ganglion, all sympathetic neurons showed TRPC1 and TRPC3 immunoreactivity. Parasympathetic neurons in the submandibular ganglion, tongue, and parotid gland were TRPC1, TRPC3, and TRPC4 IR. Gustatory and olfactory cells were also IR for TRPC1, TRPC3, and/or TRPC4. In the musculature, motor endplates expressed TRPC1 and TRPC4 immunoreactivity. It is likely that TRPCs are associated with sensory, autonomic, and motor functions in oral and craniofacial structures.

Plasticity of postganglionic sympathetic neurons in the rat superior cervical ganglion after axotomy

1994 ◽  
Vol 29 (2) ◽  
pp. 120-130 ◽  
Author(s):  
Lars Klimaschewski ◽  
Thang D. Tran ◽  
Rainer Nobiling ◽  
Christine Heym
Keyword(s):  
Superior Cervical Ganglion ◽  
Sympathetic Neurons ◽  
Cervical Ganglion

Analysis of the development of the nervous system of the zebrafish, Brachydanio rerio

Development ◽  
1968 ◽  
Vol 19 (2) ◽  
pp. 109-119
Author(s):  
Judith Shulman Weis
Keyword(s):  
Spinal Cord ◽  
Nervous System ◽  
Neural Crest ◽  
Neural Tube ◽  
Sympathetic Neurons ◽  
Dorsal Surface ◽  
Teleost Fishes ◽  
Brachydanio Rerio ◽  
Solid Structure ◽  
Derivatives Of

In teleost fishes, unlike many other vertebrates, the spinal cord originates as a solid structure, the neural keel, which subsequently hollows out. Unlike vertebrates in which the neural tube is formed from neural folds, and where the neural crest arises from wedge-shaped masses of tissue connecting the neural tube to the general ectoderm, teleosts do not possess a clear morphological neural crest. Initially, the dorsal surface of the keel is broadly attached to the ectoderm as described by Shepard (1961). As the neural primordia become larger and more discrete, the region of attachment narrows, and cells become loose (the ‘loose crest stage’). These cells represent the neural crest. Subsequently they begin to migrate and to differentiate into the various derivatives of neural crest. Both sensory and sympathetic neurons arise from neural crest. At the time of their migration the cells are not morphologically distinguishable.

Postganglionic sympathetic neurons express endothelin

1998 ◽  
Vol 274 (3) ◽  
pp. R873-R878 ◽  
Author(s):  
Deborah H. Damon
Keyword(s):  
Spinal Cord ◽  
Superior Cervical Ganglion ◽  
Sympathetic Neurons ◽  
Northern Analysis ◽  
Rat Pups ◽  
Cervical Ganglion ◽  
Brain And Spinal Cord ◽  
The Brain

Endothelin (ET) is a peptide originally identified as an endothelial-derived vasoconstrictor. It is now recognized that ET is produced by and acts on many other tissues including the brain and spinal cord, where it is believed to modulate neurotransmission. The present studies demonstrate that ET is synthesized by and secreted from postganglionic sympathetic neurons. With the use of Northern analysis, ET-1 mRNA was detected in cultures of sympathetic superior cervical ganglion (SCG) neurons isolated from 3- to 5-day old rat pups. ET-1 and ET-3 peptides were also detected in cultured SCG neurons using immunohistochemistry. ET-1 (50 pg/106 cells) and ET-3 (173 pg/106 cells) were detected by radioimmunoassay of media conditioned by cultured SCG. ET-1 (77 pg/mg protein) and ET-3 (30 pg/mg protein) were also detected by radioimmunoassay of extracts of adult SCG.

scholarly journals Immunohistochemical analysis of nerve growth factor receptor expression in normal and malignant human tissues.

1988 ◽  
Vol 36 (4) ◽  
pp. 383-389 ◽  
Author(s):  
P G Chesa ◽  
W J Rettig ◽  
T M Thomson ◽  
L J Old ◽  
M R Melamed
Keyword(s):  
Nervous System ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Normal Development ◽  
Malignant Tumors ◽  
Sympathetic Neurons ◽  
Growth Factor Receptor ◽  
Nerve Growth Factor Receptor ◽  
Receptor Expression ◽  
Nerve Growth

Nerve growth factor (NGF) is a polypeptide important for normal development of the nervous system and promotion of survival and differentiation of sensory and sympathetic neurons in culture. The cellular effects of NGF are mediated by a specific cell surface molecule, nerve growth factor receptor (NGF-R). In the present study we have used a monoclonal antibody against human NGF-R to examine, by the avidin-biotin-immunoperoxidase method, the receptor distribution in a wide range of normal tissues and in more than 200 malignant tumors. Our results show that (a) human NGF-R is expressed in the peripheral nervous system but not in any of the central nervous system areas tested; (b) NGF-R expression is not restricted to neural tissues but is also found in a number of normal epithelial, mesenchymal, and lymphoid tissues; (c) NGF-R expression changes during normal development; and (d) NGF-R expression in malignant tumors generally parallels its normal tissue distribution. Thus, NGF-R is detected in a proportion of neuroectoderm-derived tumors, carcinomas, and lymphomas, and also in a characteristic group of small round-cell tumors (Ewing's sarcomas and embryonal rhabdomyosarcomas). These findings suggest a normal regulatory role for NGF in both neuronal and non-neuronal cells and identify a range of human tumors in which the NGF/NGF-R system may contribute to the malignant phenotype.

Neurotrophins affect the pattern of DRG neurite growth in a bioassay that presents a choice of CNS and PNS substrates

Development ◽  
1995 ◽  
Vol 121 (5) ◽  
pp. 1301-1309 ◽  
Author(s):  
R. Tuttle ◽  
W.D. Matthew
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Sciatic Nerve ◽  
Sympathetic Neurons ◽  
Neurite Growth ◽  
Drg Neurons ◽  
Substrate Preferences

Neurons can be categorized in terms of where their axons project: within the central nervous system, within the peripheral nervous system, or through both central and peripheral environments. Examples of these categories are cerebellar neurons, sympathetic neurons, and dorsal root ganglion (DRG) neurons, respectively. When explants containing one type of neuron were placed between cryosections of neonatal or adult sciatic nerve and neonatal spinal cord, the neurites exhibited a strong preference for the substrates that they would normally encounter in vivo: cerebellar neurites generally extended only on spinal cord, sympathetic neurites on sciatic nerve, and DRG neurites on both. Neurite growth from DRG neurons has been shown to be stimulated by neurotrophins. To determine whether neurotrophins might also affect the substrate preferences of neurites, DRG were placed between cryosections of neonatal spinal cord and adult sciatic nerve and cultured for 36 to 48 hours in the presence of various neurotrophins. While DRG cultured in NGF-containing media exhibited neurite growth over both spinal cord and sciatic nerve substrates, in the absence of neurotrophins DRG neurites were found almost exclusively on the CNS cryosection. To determine whether these neurotrophin-dependent neurite patterns resulted from the selective survival of subpopulations of DRG neurons with distinct neurite growth characteristics, a type of rescue experiment was performed: DRG cultured in neurotrophin-free medium were fed with NGF-containing medium after 36 hours in vitro and neurite growth examined 24 hours later; most DRG exhibited extensive neurite growth on both peripheral and central nervous system substrates.(ABSTRACT TRUNCATED AT 250 WORDS)

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