NTF-3, a gene involved in the enteric nervous system development, as a candidate gene for Hirschsprung disease

Hirschsprung disease (HSCR) is a congenital disorder caused by a failure of neural crest cells to migrate, proliferate, and/or differentiate during the enteric nervous system (ENS) development. The requirement of the NTF-3/TrkC signaling for the proper development of the ENS, together with the evidences presented by animal models, led us to investigate the involvement of NTF-3 gene in HSCR. We performed both a mutational screening of NTF-3 and a complete evaluation of 3 polymorphisms as genetic susceptibility factors for HSCR. We identified a novel sequence variant, G76R, present in 2 different patients and absent in controls. We postulate that this variation could generate a lack of mature functional NTF-3 proteins in neural crest cell precursors; thus, altering the NTF-3/TrkC signaling pathway and influencing in the adequate ENS development. Although these results do not provide complete assurance of the involvement of this gene in HSCR, given the polygenic nature of the disease and its etiology, investigation of the genes encoding protein members of the signaling pathways governing the ENS development could provide new key findings in the elucidation of this complex disease.     

NGF plasma levels increase due to alcohol intoxication and decrease during withdrawal

Recent studies show that alcohol dependence is associated with alterations in plasma levels of nerve growth factor (NGF). The aim of this study was to further elucidate reported alterations in NGF plasma levels during alcohol intoxication and withdrawal. Therefore, we assessed NGF plasma levels by enzyme-linked immunosorbent assay (ELISA) on admission (day 0) and day 7 of alcohol withdrawal in male alcohol dependent patients (n=75) in comparison to healthy controls (n=44). We found significant higher (U=1005.0, p<0.001) NGF plasma levels in the alcohol-dependent patients. Subgroup analysis showed significant higher (U=-2.934, p=0.003) NGF plasma levels in patients suffering from acute alcohol intoxication (group A) than in early abstinent patients (group B). From day 0 to day 7 of alcohol withdrawal NGF plasma levels decreased significantly in both groups (group A: Z=-3.118, p=0.002, group B: Z=-2.103, p=0.035). Our results suggest that acute alcohol intoxication is associated with an increase in NGF plasma levels, which decrease during alcohol withdrawal. These results suggest that NGF plasma levels increase as part of a regulation mechanism that counteracts alcohol intoxication.     

Exercising Our Brains: How Physical Activity Impacts Synaptic Plasticity in the Dentate Gyrus

Exercise that engages the cardiovascular system has a myriad of effects on the body; however, we usually do not give much consideration to the benefits it may have for our minds. An increasing body of evidence suggests that exercise can have some remarkable effects on the brain. In this article, we will introduce how exercise can impact the capacity for neurons in the brain to communicate with one another. To properly convey this information, we will first briefly introduce the field of synaptic plasticity and then examine how the introduction of exercise to the experimental setting can actually alter the basic properties of synaptic plasticity in the brain. Next, we will examine some of the candidate physiological processes that might underlay these alterations. Finally, we will close by noting that, taken together, this data points toward our brains being dynamic systems that are in a continual state of flux and that physical exercise may help us to maximize the performance of both our body and our minds.     

TrkC: a new predictive marker in breast cancer?

Available data involve neurotrophins and their receptors in carcinomas. Quantitative evaluation of these molecules in these tumors might be useful as prognostic marker and eventual treatments. Our study on 40 mammary tumors tries to correlate expression of these molecules and prognosis. Immunohistochemistry for NGF, BDNF, NT3, TrkA, TrkB, TrkC, and p75 was used. Patient's age, histopathology, Bloom-Richardson grading, estrogen and progesterone receptors, Ki-67 index, HER-2, p53 were evaluated. Statistics found inverse relationship between grading and TrkC expression. We found significantly higher TrkC expression in Grade I than in Grade III tumors. Rise in TrkC expression could indicate good prognosis.     

Tyrosine receptor kinase B (TrkB) protein expression in the human endometrium

Tyrosine kinase receptor B (TrkB) gene expression, a neurotrophic factor receptor expressed in the brain and ovary, has recently been identified in deep infiltrating endometriosis by gene array. TrkB is thought to be important in resistance to anchorage independent apoptosis (ANOIKIS) and thus could be important in the pathogenesis of endometriosis. However, TrkB protein expression in the eutopic endometrium of women with and without endometriosis is unknown. Therefore, we examined TrKB protein expression in the endometrium by Western blot (n = 50) and immunohistochemistry (n = 17). Immunoblots of endometrial biopsies were prepared from women with endometriosis (n = 21) vs. healthy controls (n = 29) undergoing benign gynecological surgery at McMaster University Medical Centre. TrkB protein expression was significantly higher in immunoblots from women with endometriosis compared to women without endometriosis. In samples of archived paraffin-embedded endometrial tissue TrkB was localized to the cytoplasm of epithelial cells of the eutopic endometrium from women with endometriosis (n = 7) and without endometriosis (n = 10). We conclude that TrkB protein is expressed in human endometrium. Our results also suggest that TrkB expression may be greater in women with endometriosis compared to women without endometriosis.     

Formulation and evaluation of carnosic acid nanoparticulate system for upregulation of neurotrophins in the brain upon intranasal administration

To develop formulations of carnosic acid nanoparticles and to assess their in vivo efficacy to enhance the expression of neurotrophins in rat model. Carnosic acid loaded chitosan nanoparticles were prepared by ionotropic gelation technique using central composite design. Response surface methodology was used to assess the effect of three factors namely chitosan concentration (0.1–1% w/v), tri-poly phosphate concentration (0.1–1% w/v) and sonication time (2–10?min) on the response variables such as particle size, zeta potential, drug encapsulation efficiency and drug release. The neurotrophins level in the rat brain upon intranasal administration of optimized batch of carnosic acid nanoparticles was determined. The experimental values for the formulation were in good agreement with those predicted by the mathematical models. A single intranasal administration of the optimized formulation of carnosic acid nanoparticles was sufficient to result in comparable levels of endogenous neurotrophins level in the brain that was almost on par with four, once a day intranasal administration of solution in rats. The results clearly demonstrated the fact that nanoparticulate drug delivery system for intranasal administration of carnosic acid would require less number of administrations to elicit the required pharmacological activity owing to its ability to localize on the olfactory mucosal region and provide controlled delivery of carnosic acid for prolonged time periods.     

Effects of estrogen replacement on choline acetyltransferase and trkA mRNA expression in the basal forebrain of aged rats

The effects of one week of estrogen replacement on choline acetyltransferase (ChAT) and trkA mRNA expression are examined in young and aged rodents to determine whether estrogen continues to affect cholinergic neurons in aging brain. Significant increases in ChAT and trkA are observed in the nucleus basalis of Meynert (nBM) of both age groups. ChAT expression is also increased in the HDB without changes in trkA expression. Results indicate modulation of ChAT expression by estrogen is retained in the aged rodent brain and suggests the possibility that changes in ChAT expression may be dissociated from concurrent alterations in trkA.     

Nerve growth factor in the adult brain of a teleostean model for aging research: Nothobranchius furzeri

Nerve growth factor (NGF) acts on central nervous system neurons, regulating naturally occurring cell death, synaptic connectivity, fiber guidance and dendritic morphology. The dynamically regulated production of NGF beginning in development, extends throughout adult life and aging, exerting numerous roles through a surprising variety of neurons and glial cells.This study analyzes the localization of NGF in the brain of the teleost fish Nothobranchius furzeri, an emerging model for aging research due to its short lifespan. Immunochemical and immunohistochemical experiments were performed by employing an antibody mapping at the N-terminus of the mature chain human origin NGF. Western blot analysis revealed an intense and well defined band of 20 kDa, which corresponds to proNGF of N. furzeri. Immunohistochemistry revealed NGF immunoreactivity (IR) diffused throughout all regions of telencephalon, diencephalon, mesencephalon and rhomboencephalon. It was detected in neurons and in glial cells, the latter mostly lining the mesencephalic and rhomboencephalic ventricles. Particularly in neurons, NGF IR was localized in perikarya and, to a less extent, in fibers.The widespread distribution of proNGF suggests that it might modulate numerous physiological functions in the adult brain of N. furzeri. The present survey constitutes a baseline study to enhance the understanding of the mechanisms underlying the role of NGF during aging processes.     

Thymocyte‐derived BDNF influences T‐cell maturation at the DN3/DN4 transition stage

Brain‐derived neurotrophic factor (BDNF) promotes neuronal survival, regeneration, and plasticity. Emerging evidence also indicates an essential role for BDNF outside the nervous system, for instance in immune cells. We therefore investigated the impact of BDNF on T cells using BDNF knockout (KO) mice and conditional KO mice lacking BDNF specifically in this lymphoid subset. In both settings, we observed diminished T‐cell cellularity in peripheral lymphoid organs and an increase in CD4⁺CD44⁺ memory T cells. Analysis of thymocyte development revealed diminished total thymocyte numbers, accompanied by a significant increase in CD4/CD8 double‐negative (DN) thymocytes due to a partial block in the transition from the DN3 to the DN4 stage. This was neither due to increased thymocyte apoptosis nor defects in the expression of the TCR‐β chain or the pre‐TCR. In contrast, pERK but not pAKT levels were diminished in DN3 BDNF‐deficient thymocytes. BDNF deficiency in T cells did not result in gross deficits in peripheral acute immune responses nor in changes of the homeostatic proliferation of peripheral T cells. Taken together, our data reveal a critical autocrine and/or paracrine role of T‐cell‐derived BDNF in thymocyte maturation involving ERK‐mediated TCR signaling pathways.     

Increased plasma levels of BDNF and inflammatory markers in Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Neurotrophic factors and inflammatory markers may play considerable roles in AD. In this study we measured, through Enzyme-Linked Immunosorbent Assay, the plasma levels of brain derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF) and neuronal growth factor (NGF), as well as tumor necrosis factor-alpha soluble receptors, sTNFR1 and sTNFR2, and soluble intercellular adhesion molecule 1 (sICAM-1), in 50 AD patients, 37 patients with mild cognitive impairment (MCI) and 56 healthy elderly controls. BDNF levels, expressed as median and interquartile range, were higher for AD patients (2545.3, 1497.4–4153.4 pg/ml) compared to controls (1503.8, 802.3–2378.4 pg/ml), P < 0.001. sICAM-1 was also higher in AD patients. sTNFR1 levels were increased in AD when compared to controls and also to MCI. GDNF, NGF and sTNFR2 levels showed no significant differences among the studied groups. The increase in BDNF might reflect a compensatory mechanism against early neurodegeneration and seems to be related to inflammation. sTNFR1 appears to mark not only the inflammatory state but also differentiates between MCI and AD, which may be an additional tool for differentiating degrees of cognitive impairment.