[show abstract][hide abstract] ABSTRACT: One of biggest recent achievements of neurobiology is the study on neurotrophic factors. The neurotrophins are exciting examples of these factors. They belong to a family of proteins consisting of nerve growth fac-tor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5, NT-6, and NT-7. Today, NGF and BDNF are well recognized to mediate a diz-zying number of trophobiological effects, ranging from neurotrophic through immunotrophic and epitheliotro-phic to metabotrophic effects. These are implicated in the pathogenesis of various diseases. In the same vein, recent studies in adipobiology reveal that this tissue is the body's largest endocrine and paracrine organ producing multiple signaling proteins collectively termed adipokines, with NGF and BDNF being also produced from adipose tissue. Altogether, neurobio-logy and adipobiology contribute to the improvement of our knowledge on diseases beyond obesity such
The World Journal of Pharmacology. 12/2013; 2(4):92.
[show abstract][hide abstract] ABSTRACT: The first cell growth factor, nerve growth factor (NGF), was discovered by Rita Levi-Montalcini (RLM) in the early 1950's. Originally identified as neurite outgrowth-stimulating factor, later studies revealed that non-neuronal cells, including immune cells, endothelial cells, cardiomyocytes, pancreatic beta cells, prostate epithelial and adipose tissue cells, were also targets for and/or sources of NGF. Nerve growth factor is well recognized as mediating multiple biological phenomena, ranging from the neurotrophic through immunotrophic and epitheliotrophic to metabotrophic effects. Consequently, NGF and other members of the neurotrophin family are implicated in the pathogenesis of a large spectrum of neuronal and non-neuronal diseases, ranging from Alzheimer's and other neurodegenerative diseases to atherosclerosis and cardiometabolic disorders. Recent studies have demonstrated the therapeutic potentials of NGF in these conditions, including ocular and cutaneous diseases. NGF TrkA receptor antagonists emerged as novel drugs for pain, prostate and breast cancer, melanoma, and urinary bladder syndromes. Here we briefly describe the "unpredictable" ideogenesis of the discovery of NGF, a eureka in the neuroscience.
Cell Biology International 03/2013; · 1.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: At the end of the nineteenth century, it was envisaged by Santiago Ramon y Cajal but has not been proven that life at the neuronal level requires trophic support. The proof was obtained in the early 1950’s by work initiated by Rita Levi-Montalcini (RLM) discovering the nerve growth factor (NGF). Today, NGF and its relatives collectively designated neurotrophins are well recognized as mediators of multiple biological phenomena in health and disease, ranging from the neurotrophic through immunotrophic and epitheliotrophic to metabotrophic effects. Consequently, NGF and other neurotrophins are implicated in the pathogenesis of a large spectrum of neuronal and non-neuronal diseases, ranging from Alzheimer’s and other neurodegenerative diseases to atherosclerosis and other cardiometabolic diseases. Recent studies demonstrated the therapeutic potentials of NGF in these diseases including ocular and cutaneous diseases. Whereas NGF TrkA receptor antagonists emerged as novel drugs for pain, prostate and breast cancer, melanoma, and urinary bladder syndromes. Altogether, NGF’s multiple potential in health and disease is briefly described here.
[show abstract][hide abstract] ABSTRACT: Diabetic polyneuropathy (DPN), characterized by early hyperalgesia and increased nerve growth factor (NGF), evolves in late irreversible neuropathic symptoms with reduced NGF support to sensory neurons. Electroacupuncture (EA) modulates NGF in the peripheral nervous system, being effective for the treatment of DPN symptoms. We hypothesize that NGF plays an important pathogenic role in DPN development, while EA could be useful in the therapy of DPN by modulating NGF expression/activity. Diabetes was induced in rats by streptozotocin (STZ) injection. One week after STZ, EA was started and continued for three weeks. NGF system and hyperalgesia-related mediators were analyzed in the dorsal root ganglia (DRG) and in their spinal cord and skin innervation territories. Our results show that four weeks long diabetes increased NGF and NGF receptors and deregulated intracellular signaling mediators of DRG neurons hypersensitization; EA in diabetic rats decreased NGF and NGF receptors, normalized c-Jun N-terminal and p38 kinases activation, decreased transient receptor potential vanilloid-1 ion channel, and possibly activated the nuclear factor kappa-light-chain-enhancer of activated B cells (Nf- κ B). In conclusion, NGF signaling deregulation might play an important role in the development of DPN. EA represents a supportive tool to control DPN development by modulating NGF signaling in diabetes-targeted neurons.
Evidence-based Complementary and Alternative Medicine 01/2013; 2013:652735. · 1.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: the 1986 Nobel Prize win-ner in Physiology or Medicine for the discovery of nerve growth factor (NGF), died Sunday, 30 December 2012, at her home in Rome, Italy. She was 103 years old. Her amazing journey in Eureka-land started from her "pri-vate laboratory" in Turin which she named Robinson Crusoe, later on through Viktor Hamburger's Department of Zool-ogy of Washington University in St Louis, MO and in Herta Mayer's Tissue Culture Laboratory in Rio de Janeiro to Rome, Italy where in 1962, Levi-Montalcini became Director of the Institute of Cell Biology, splitting her time between St Louis and Rome until 1977. Levi-Montalcini's NGF provided a conceptual framework for the formulation of the neurotrophic hypothesis: particu-lar neuronal types require trophic ("nutritional") factor(s) for neurite growth and neurotransmitter production for proper function and survival. Her data on the prototype neurotrophic factor, NGF, triggered an unprecedented search for a family of related proteins now commonly called neurotrophins. More importantly, Levi-Montalcini's NGF determined a new concept of biology, that cells require specific protein signals for differentiation and survival, that is, the general theory of cell growth factors. All this resulted in the discovery of hundreds of growth factors that affect almost all facets of cell biology. In analogy with Mendelevium (Md), Einsteinium (Es) and Fermium (Fm) in Dimitri Mendeleev's Periodic Table of chemical elements, we may now introduce NGF as Mon-talcinium (Mt) in the Periodic Table of biomolecules. Her centennial life created the scientific bridge between two millenia, a path followed by many generations. This is the guarantee of her "presence in the absence".
[show abstract][hide abstract] ABSTRACT: The physiological role of the neurotrophin nerve growth factor (NGF) has been characterized, since its discovery in the 1950s, first in the sensory and autonomic nervous system, then in central nervous, endocrine and immune systems. NGF plays its trophic role both during development and in adulthood, ensuring the maintenance of phenotypic and functional characteristic of several populations of neurons as well as immune cells. From a translational standpoint, the action of NGF on cholinergic neurons of the basal forebrain and on sensory neurons in dorsal root ganglia first gained researcher's attention, in view of possible clinical use in Alzheimer's disease patients and in peripheral neuropathies respectively. The translational and clinical research on NGF have, since then, enlarged the spectrum of diseases that could benefit from NGF treatment, at the same time highlighting possible limitations in the use of the neurotrophin as a drug. In this review we give a comprehensive account for almost all of the clinical trials attempted until now by using NGF. A perspective on future development for translational research on NGF is also discussed, in view of recent proposals for innovative delivery strategies and/or for additional pathologies to be treated, such as ocular and skin diseases, gliomas, traumatic brain injuries, vascular and immune diseases.
Journal of Translational Medicine 11/2012; 10(1):239. · 3.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: VEGF and NGF are known to modulate corneal healing, neovascularisation and tear secretion. While a VEGF-NGF cross talk has been recently shown to modulate corneal healing in rats, it is not known whether it also plays a role in the regulation of lacrimal function. In this study we aim to investigate the effects of anti-VEGF eye drop treatment on lacrimal gland function and on the local expression of VEGF and NGF in rats. Tear function was measured in 3 months old rats by modified Schirmer test at baseline and after 3 weeks of topical anti-VEGF eye drop treatment. Whole lacrimal glands from rats were removed after treatment and analysed by ELISA for VEGF and NGF levels. To investigate if the effects of anti-VEGF were mediated by changes in the NGF-pathway, we repeated the experiments in RCS rats, a strain with NGF-pathway impairment associated with decreased tear flow. After topical treatment with anti-VEGF eye drops, an increase in tear secretion was observed in both wild-type and RCS rats. A significant decrease of VEGF levels was also observed in lacrimal glands of both RCS and SD rats, accompanied by a significant increase in NGF levels. Inhibition of VEGF at the ocular surface in rats results in changes of tear function and lacrimal gland levels of VEGF and NGF. Further studies on the VEGF/NGF cross-talk at the ocular surface may expand our knowledge on the pathogenesis of several diseases characterized by tear dysfunction.
Archives italiennes de biologie 03/2012; 150(1):15-21. · 1.43 Impact Factor
[show abstract][hide abstract] ABSTRACT: Effects of 3-month exposure to microgravity environment on the expression of genes and proteins in mouse brain were studied. Moreover, responses of neurobiological parameters, nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), were also evaluated in the cerebellum, hippocampus, cortex, and adrenal glands. Spaceflight-related changes in gene and protein expression were observed. Biological processes of the up-regulated genes were related to the immune response, metabolic process, and/or inflammatory response. Changes of cellular components involving in microsome and vesicular fraction were also noted. Molecular function categories were related to various enzyme activities. The biological processes in the down-regulated genes were related to various metabolic and catabolic processes. Cellular components were related to cytoplasm and mitochondrion. The down-regulated molecular functions were related to catalytic and oxidoreductase activities. Up-regulation of 28 proteins was seen following spaceflight vs. those in ground control. These proteins were related to mitochondrial metabolism, synthesis and hydrolysis of ATP, calcium/calmodulin metabolism, nervous system, and transport of proteins and/or amino acids. Down-regulated proteins were related to mitochondrial metabolism. Expression of NGF in hippocampus, cortex, and adrenal gland of wild type animal tended to decrease following spaceflight. As for pleiotrophin transgenic mice, spaceflight-related reduction of NGF occurred only in adrenal gland. Consistent trends between various portions of brain and adrenal gland were not observed in the responses of BDNF to spaceflight. Although exposure to real microgravity influenced the expression of a number of genes and proteins in the brain that have been shown to be involved in a wide spectrum of biological function, it is still unclear how the functional properties of brain were influenced by 3-month exposure to microgravity.
PLoS ONE 01/2012; 7(7):e40112. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recently, the secretory -endocrine, paracrine and autocrine -phenotype of adipose tissue, consisting of adipo-cytes, stromovascular cells and immune cells, has increasingly been recognized. In humans, adipose tissue is partitioned into two large depots (subcutaneous and visceral) and many small depots associated with heart, blood vessels, major lymph nodes, pancreas, prostate gland, ovaries. Accordingly, two major subfields of adipobiology have emerged, adi-poendocrinology (studying the endocrine activity of adipose tissue) and adipoparacrinology (studying the paracrine activ-ity of adipose tissue). Traditional concept of the pathogenesis of atherosclerosis focuses on intimal surface, where endo-thelial dysfunction expressed by an "inside-out" inflammatory process triggers the formation of atherosclerotic plaque. The present short review highlights evidence for the possible role of dysfunctional paracrine activity of epicardial adipose tissue and of periadventitial adipose tissue in an "outside-in" pathway in the development of coronary and peripheral athe-rosclerosis, respectively. Such a paradigm may have various therapeutic applications including in coronary artery bypass surgery.
[show abstract][hide abstract] ABSTRACT: White adipose tissue (WAT) is a dynamic multicellular assembly composed of adipocytes and stromovascular cells, including fibroblasts, endothelial and immune cells, nerve fibers, and stem cells. In humans, WAT is a responsive and secretory (endocrine and paracrine) tissue partitioned into two large
depots (subcutaneous and visceral) and many small depots associated with the heart, blood vessels, major lymph nodes, prostate gland, ovaries and mammary glands. This short review conceptualizes evidence for the paracrine activity of adipose tissue in founding a new research field, designated adipoparacrinology. Here we focus on (i) epicardial and periadventitial adipose tissue in atherogenesis, (ii) mammary gland-associated adipose tissue in breast cancer, and (iii) periprostatic adipose tissue in prostate cancer. Other examples include: (i) mesenteric adipose tissue in Crohn’s disease, (ii) lymph node-associated (perinodal) adipose tissue in Crohn’s disease and HIV-associated adipose redistribution syndrome, (iii) infrapatellar fat pad (Hoffa’s fat pad) in knee osteoarthritis, (iv) orbital adipose tissue in thyroid-associated (Graves’) ophthalmopathy, and (v) parasellar region-associated adipose tissue in brain disorders. The therapy aspect of adipoparacrinology is also discussed.
Key Words: Adipokines, atherosclerosis, breast cancer, epicardial adipose tissue, NGF, periadventitial adipose tissue, periprostatic adipose tissue, prostate cancer
[show abstract][hide abstract] ABSTRACT: Human adipose tissue is partitioned into two large depots (subcutaneous and visceral), and many small depots associated with internal organs, e.g. heart, blood vessels, major lymph nodes, pancreas, prostate gland and ovaries. Since the adipose 'Big Bang' led to the discovery of leptin (Zhang, Proenca, Maffei, Barone, Leopold and Friedman, Nature 1994;372:425-32), adipose tissue has been seen not merely as a lipid store, but as a secretory - endocrine and paracrine - organ, particularly in the pathogenesis of a number of diseases. Accordingly, two major sub-fields of adipobiology have emerged, viz. adipoendocrinology and adipoparacrinology, the latter herein being illustrated by PAAT (periadventitial adipose tissue) in vascular walls. A long-standing paradigm holds that the vascular wall consists of three coats, tunica intima, tunica media and tunica adventitia. It is now imperative that 'to further elucidate vascular function, we should no longer, as hitherto, separate adventitia and PAAT from the vascular wall, but keep them attached and in place, and subject to thorough examination' (Chaldakov, Fiore, Ghenev, Stankulov and Aloe, Int Med J 2000;7:43-9; Chaldakov, Stankulov and Aloe, Atherosclerosis 2001;154:237-8; Chaldakov GN, Stankulov IS, Fiore M, Ghenev PI and Aloe L, Atherosclerosis 2001;159:57-66). From the available data, we propose that it is time to rethink about vascular wall composition, and suggest that the PAAT may be considered the fourth and outermost vascular coat, hence, tunica adiposa (regarding the proximal segment of coronary artery, it is the innermost part of the EAT (epicardial adipose tissue) situated around the coronary adventitia). Its significance in the pathogenesis and therapy of CMDs (cardiometabolic diseases), particularly atherosclerosis and hypertension, requires further basic, translational and clinical studies.
Cell Biology International 12/2011; 36(3):327-30. · 1.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: Diabetes is considered the leading cause of neuropathies in developed countries. Dysfunction of nerve growth factor (NGF) production and/or utilisation may lead to the establishment of diabetic neuropathies. Electroacupuncture has been proved effective in the treatment of human neuropathic pain as well as in modulating NGF production/activity. We aimed at using electroacupuncture to correct the development of thermal hyperalgesia and the tissue alteration of NGF and sensory neuromodulators in a rat model of type 1 diabetes.
Adult rats were injected with streptozotocin to induce diabetes and subsequently treated with low-frequency electroacupuncture for 3 weeks. Variation in thermal sensitivity was studied during the experimental course. Hindpaw skin and spinal cord protein content of NGF, NGF receptor tyrosine kinase A (TrkA), substance P (SP), transient receptor potential vanilloid 1 (TRPV1) receptor and glutamic acid decarboxylase-67 (GAD-67) were measured after electroacupuncture treatments. The skin and spinal cord cellular distribution of TrkA was analysed to explore NGF signalling.
Early after streptozotocin treatment, thermal hyperalgesia developed that was corrected by electroacupuncture. The parallel increases in NGF and TrkA in the spinal cord were counteracted by electroacupuncture. Streptozotocin also induced variation in skin/spinal TrkA phosphorylation, increases in skin SP and spinal TRPV1 and a decrease in spinal GAD-67. These changes were counteracted by electroacupuncture.
Our results point to the potential of electroacupuncture as a supportive therapy for the treatment of diabetic neuropathies. The efficacy of electroacupuncture might depend on its actions on spinal/peripheral NGF synthesis/utilisation and normalisation of the levels of several sensory neuromodulators.
[show abstract][hide abstract] ABSTRACT: Type 1 diabetes (DB) is a multifactorial metabolic disorder characterized by loss of insulin-producing pancreatic ß-cells, and metabolic and functional deficits in a number of cells, including kidney cells. Nerve growth factor (NGF) is a signaling molecule that is up-regulated in cells affected by diabetes-linked disorders. However, whether DB alters the expression of NGF in the kidney is not known.
DB was induced in adult male rats with a single injection of streptozotocin (STZ), and NGF protein levels were analyzed in a time-course study in serum and kidney. The expression of NGF receptors in the kidneys of healthy and DB rats was evaluated by immunohistochemistry. NGF levels as well as apoptotic features in the kidneys of healthy rats injected with purified NGF were also assessed.
This study revealed that DB elevates NGF levels in serum and NGF expression in the kidney and that subcutaneous administration of NGF causes a marked uptake of NGF in kidney cells. The elevated presence of NGF in kidney cells is not associated with proapoptotic factor expression.
The present data suggest that NGF presence in the kidney might play a survival, and most probably protective, role in kidney cells.
Journal of nephrology 03/2011; 24(6):798-805. · 2.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Acupuncture has been used as treatment for infertility for hundreds of years, and recently it has been studied in male and female infertility and in assisted reproductive technologies, although its role in reproductive medicine is still debated.
To review studies on acupuncture in reproductive medicine, in experimental and clinical settings.
Papers were retrieved on PubMed and Google Scholar and were included in the review if at least the abstract was in English.
There is evidence of benefit mainly when acupuncture is performed on the day of embryo transfer (ET) in the live birth rate. Benefit is also evident when acupuncture is performed for female infertility due to polycystic ovary syndrome (PCOS). There is some evidence of sperm quality improvement when acupuncture is performed on males affected by idiopathic infertility. Experimental studies suggest that acupuncture effects are mediated by changes in activity of the autonomic nervous system and stimulation of neuropeptides/neurotransmitters which may be involved in the pathogenesis of infertility.
Acupuncture seems to have beneficial effects on live birth rate when performed on the day of ET, and to be useful also in PCOS as well as in male idiopathic infertility, with very low incidence of side effects. However, further studies are necessary to confirm the clinical results and to expand our knowledge of the mechanisms involved.
Journal of endocrinological investigation 02/2011; 34(4):307-11. · 1.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Increasing attention has been focused on the role(s) of nerve growth factor (NGF) in neurobehavioural regulations of adult vertebrates. This interest springs from the emerging evidence that NGF is a "regulator" of physiological processes belonging to the three main homeostatic systems: the nervous, immune and endocrine systems. In fact, the spectrum of action of the NGF molecule is not restricted to neuronal cell types (central basal forebrain; peripheral sensory and sympathetic neurons) but extends also to nonneuronal cells. In mice intermale aggressive behaviour enhances serum NGF levels and promotes its synthesis in some hypothalamic areas. Other types of social events are able to cause NGF release, particularly under stress conditions. The achievement of a social role (dominant vs subordinate) is due to a functional loop involving salivary NGF release-->enhanced production of adrenal hormones-->submissive behaviour-->NGF release. In humans, plasma platelet-derived growth factor (PDGF) increases following mental stress. The aim of this review is to give an updated survey on NGF roles in neurobehavioural regulations of adult animals.
Reviews in the neurosciences 01/2011; 4(1):41-62. · 3.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: The aim of this study was to investigate the effect of nerve growth factor (NGF) administration on retinal ganglion cells (RGCs) in experimentally induced glaucoma (GL) and diabetic retinopathy (DR). GL was induced in adult rats by injection of hypertonic saline into the episcleral vein of the eye and diabetes (DT) was induced by administration of streptozoticin. Control and experimental rats were treated daily with either ocular application of NGF or vehicle solution. We found that both animal models present a progressive degeneration of RGCs and changing NGF and VEGF levels in the retina and optic nerve. We then proved that NGF eye drop administration exerts a protective effect on these models of retinal degeneration. In brief, our findings indicate that NGF can play a protective role against RGC degeneration occurring in GL and DR and suggest that ocular NGF administration might be an effective pharmacological approach.
[show abstract][hide abstract] ABSTRACT: Early stressful events can increase vulnerability for psychopathology, although knowledge on the effectors is still limited. In this report we describe the characterization of a single nucleotide polymorphism (SNP) in rhesus macaques, which results in a Val to Met transition in the pro-BDNF domain, similar to a well described variant in the human gene. Further, we tested the hypothesis that peripheral levels of BDNF, which is involved in the response to stress and in the pathophysiology of anxiety and depression, might be differentially affected in a non-human primate model of early adverse rearing in a genotype-dependent manner. Males and females rhesus macaques reared either with their mothers (MR), in peer-only groups (PR), or in a "surrogate/peer-reared" (SPR) condition with limited peer interactions, were used as experimental subjects. BDNF levels were determined at baseline on postnatal days (PND) 14, 30 and 60 by means of specific ELISA procedure. Data indicate that BDNF levels were increased as a result of peer-rearing and that this increase was moderated by the presence of the SNP. Overall these data indicate that a SNP, which results in a Val to Met transition in the pro-BDNF domain, is present in rhesus macaques and is able to affect BDNF peripheral levels, thus making this primate model a fundamental tool to study gene by environment interactions involving the BDNF gene.
[show abstract][hide abstract] ABSTRACT: Adipose tissue is a dynamic endocrine and paracrine organ producing a large number of signalling proteins collectively termed adipokines. Some of them are mediators in the cross-talk between adipose tissue and the brain in regulating food intake and energy homoeostasis. However, the hypothalamus is not the only brain target for adipokines, and food intake is not the only biological effect of these signals. Rather, some adipokines support various cognitive functions and exert neurotrophic activity. Current data on adipose-derived neuropeptides, neurotrophic factors, pituitary hormones and hypothalamic releasing factors is highlighted in this review. We propose that adipose tissue is a member of the diffuse neuroendocrine system. Cumulatively, this is conceptualized as neuroadipology, a new example of a link between neurobiology and other topics, such as neuroimmunology and neuroendocrinology. Because adipose tissue is a bona fide endocrine organ, neuroadipology may be considered a new discipline in neuroendocrinology. It may have a wide-ranging potential within a variety of neuronal and metabolic functions in health and disease.
Cell Biology International 10/2010; 34(10):1051-3. · 1.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: In the present study, we investigated lacrimal function and presence of the neurotrophin nerve growth factor (NGF) and its receptors in the lacrimal gland (LG) of normal rats and rats with inherited retinitis pigmentosa (IRP).
After anesthesia, modified Schirmer tests were performed on IRP rats and Sprague Dawley (SD) rats to measure tear function. LGs of developing and adult IRP and SD rats were removed and used for histological, immunohistochemical, and biochemical analyses.
The results showed that basal tear secretion is reduced in IRP rats as compared with SD rats. NGF and NGF receptors are expressed in the LG of both rat strains. In SD rats, these NGF markers are low during early life and more elevated in adult life. Conversely in rats with IRP, NGF and its receptors decreased in adult life.
The role of NGF in maintaining ocular surface integrity is well known. The observations of this study further support the hypothesis that neurotrophins play a role in modulating tear secretion and probably in preventing the deleterious effects of dry eye. This hypothesis is presented and discussed.