Nerve Growth Factor: A Dual Activator of Noradrenergic and Cholinergic Systems of the Rat Ovary

The functioning of the ovary is influenced by the autonomic system (sympathetic and cholinergic intraovarian system) which contributes to the regulation of steroid secretion, follicular development, and ovulation. There is no information on the primary signal that activates both systems. The nerve growth factor (NGF) was the first neurotrophic factor found to regulate ovarian noradrenergic neurons and the cholinergic neurons in the central nervous system. The aim of this study was to determine whether NGF is one of the participating neurotrophic factors in the activation of the sympathetic and cholinergic system of the ovary in vivo and its role in follicular development during normal or pathological states. The administration of estradiol valerate (a polycystic ovary [PCO] phenotype model) increased norepinephrine (NE) (through an NGF-dependent mechanism) and acetylcholine (ACh) levels. Intraovarian exposure of rats for 28 days to NGF (by means of an osmotic minipump) increased the expression of tyrosine hydroxylase and acetylcholinesterase (AChE, the enzyme that degrades ACh) without affecting enzyme activity but reduced ovarian ACh levels. In vitro exposure of the ovary to NGF (100 ng/ml for 3 h) increased both choline acetyl transferase and vesicular ACh transporter expression in the ovary, with no effect in ACh level. In vivo NGF led to an anovulatory condition with the appearance of follicular cysts and decreased number of corpora lutea (corresponding to noradrenergic activation). To determine whether the predominance of a NE-induced polycystic condition after NGF is responsible for the PCO phenotype, rats were exposed to an intraovarian administration of carbachol (100 μM), a muscarinic cholinergic agonist not degraded by AChE. Decreased the number of follicular cysts and increased the number of corpora lutea, reinforcing that cholinergic activity of the ovary participates in controlling its functions. Although NGF increased the biosynthetic capacity for ACh, it was not available to act in the ovary. Hence, NGF also regulates the ovarian cholinergic system, implying that NGF is the main regulator of the dual autonomic control. These findings highlight the need for research in the treatment of PCO syndrome by modification of locally produced ACh as an in vivo regulator of follicular development.

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In vivo blockade of ovarian sympathetic activity by Neosaxitoxin prevents polycystic ovary in rats

Journal of Endocrinology ◽

10.1530/joe-19-0545 ◽

2020 ◽

Vol 244 (3) ◽

pp. 523-533

Author(s):

Miguel del Campo ◽

Néstor Lagos ◽

Hernán Lara

Keyword(s):

Plasma Levels ◽

Polycystic Ovary ◽

Follicular Development ◽

Sympathetic Nerves ◽

Estradiol Valerate ◽

Plasma Testosterone ◽

Corpora Lutea ◽

Follicular Cyst ◽

Estrous Cycling

A high sympathetic tone is observed in the development and maintenance of the polycystic ovary (PCO) phenotype in rats. Neosaxitoxin (NeoSTX) specifically blocks neuronal voltage-dependent Na+ channels, and we studied the capacity of NeoSTX administered into the ovary to block sympathetic nerves and PCO phenotype that is induced by estradiol valerate (EV). The toxin was administered with a minipump inserted into the bursal cavity using two protocols: (1) the same day as EV administration and (2) 30 days after EV to block the final step of cyst development and maintenance of the condition. We studied the estrous cycling activity, follicular morphology, steroid plasma levels, and norepinephrine concentration. NeoSTX administered together with EV decreased NA intraovarian levels that were induced by EV, increased the number of corpora lutea, decreased the number of follicular cyst found after EV administration, and decreased the previously increased testosterone plasma levels induced by the PCO phenotype. Estrous cycling activity also recovered. NeoSTX applied after 30 days of EV administration showed near recovery of ovary function, suggesting that there is a specific window in which follicular development could be protected from cystic development. In addition, plasma testosterone levels decreased while those of progesterone increased. Our data strongly suggest that chronic inhibition of sympathetic nerves by a locally applied long-lasting toxin is a new tool to manage the polycystic phenotype in the rat and could be applied to other mammals depending on sympathetic nerve activity.

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Gangliosides potentiate in vivo and in vitro effects of nerve growth factor on central cholinergic neurons.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.86.6.2056 ◽

1989 ◽

Vol 86 (6) ◽

pp. 2056-2060 ◽

Cited By ~ 102

Author(s):

A. C. Cuello ◽

L. Garofalo ◽

R. L. Kenigsberg ◽

D. Maysinger

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Cholinergic Neurons ◽

Nerve Growth ◽

In Vitro Effects

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The effect of nerve growth factor and its antibody on mast cells in vivo

Journal of Neuroimmunology ◽

10.1016/0165-5728(88)90129-4 ◽

1988 ◽

Vol 18 (1) ◽

pp. 1-12 ◽

Cited By ~ 57

Author(s):

L ALOE

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Mast Cells ◽

Nerve Growth

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Cartilage injury regulates nerve growth factor (NGF) in vitro and in vivo and drives painful behaviour in murine OA

Osteoarthritis and Cartilage ◽

10.1016/j.joca.2014.02.084 ◽

2014 ◽

Vol 22 ◽

pp. S35

Author(s):

C. Driscoll ◽

A. Chanalaris ◽

C. Knight ◽

C. Gentry ◽

S. Bevan ◽

...

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Cartilage Injury ◽

Nerve Growth

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The Biology of Nerve Growth Factor in Vivo

Neurobiology of Amino Acids, Peptides and Trophic Factors ◽

10.1007/978-1-4613-1721-0_7 ◽

1988 ◽

pp. 101-114 ◽

Cited By ~ 4

Author(s):

Eugene M. Johnson ◽

Pamela T. Manning ◽

Christine Wilcox

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Nerve Growth

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The in vitro effect of the nerve growth factor on chick embryo spinal ganglia—a light-microscopic evaluation

Development ◽

10.1242/dev.24.2.381 ◽

1970 ◽

Vol 24 (2) ◽

pp. 381-392

Author(s):

Peddrick Weis

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Chick Embryo ◽

Culture Period ◽

Spinal Ganglia ◽

Nerve Growth ◽

Microscopic Evaluation ◽

Vitro Effect

The effect of the nerve growth factor (NGF) on chick embryo spinal ganglia was studied in the hanging-drop bioassay system by comparison with parallel development in vivo. The well-differentiated ventrolateral neuroblasts, which in vivo increase 1·33 times in size during the culture period, did not increase in size at all in vitro. Only 65–72% survived to the end of the culture period regardless of the NGF concentration. The less-differentiated mediodorsal (M-D) neuroblasts, which in vivo increase 1·31 times in size during the culture period, were found to increase equally in vitro if sufficient NGF was present. Such a quantity was greater than that which evoked maximum outgrowth of neurites. Survival of M-D neuroblasts was also related to NGF concentration but did not equal the in vivo condition even at the highest concentration. The hyperchromatic type of degeneration prevented by high NGF concentrations is that which results in vivo from insufficient peripheral field. From this and other reports it would appear that the response to NGF seen in vitro is due only to the M-D neuroblasts, and that all biochemical and cytological observations which have been reported would therefore represent conditions within those cells only.

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Multiple myeloma increases nerve growth factor and other pain-related markers through interactions with the bone microenvironment

Scientific Reports ◽

10.1038/s41598-019-50591-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Sam W. Z. Olechnowicz ◽

Megan M. Weivoda ◽

Seint T. Lwin ◽

Szi K. Leung ◽

Sarah Gooding ◽

...

Keyword(s):

Multiple Myeloma ◽

Nerve Growth Factor ◽

Growth Factor ◽

Cell Activation ◽

Cellular Interactions ◽

Bone Microenvironment ◽

Related Factors ◽

Nerve Growth ◽

Tnf Α

Abstract Interactions between multiple myeloma (MM) and bone marrow (BM) are well documented to support tumour growth, yet the cellular mechanisms underlying pain in MM are poorly understood. We have used in vivo murine models of MM to show significant induction of nerve growth factor (NGF) by the tumour-bearing bone microenvironment, alongside other known pain-related characteristics such as spinal glial cell activation and reduced locomotion. NGF was not expressed by MM cells, yet bone stromal cells such as osteoblasts expressed and upregulated NGF when cultured with MM cells, or MM-related factors such as TNF-α. Adiponectin is a known MM-suppressive BM-derived factor, and we show that TNF-α-mediated NGF induction is suppressed by adiponectin-directed therapeutics such as AdipoRON and L-4F, as well as NF-κB signalling inhibitor BMS-345541. Our study reveals a further mechanism by which cellular interactions within the tumour-bone microenvironment contribute to disease, by promoting pain-related properties, and suggests a novel direction for analgesic development.

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