Decrease In Nerve Growth Factor Research Articles

MAFB in macrophages regulates cold-induced neuronal density in brown adipose tissue

Transcription factor MAFB regulates various homeostatic functions of macrophages. This study explores the role of MAFB in brown adipose tissue (BAT) thermogenesis using macrophage-specific Mafb-deficient (Mafbf/f::LysM-Cre) mice. We find that Mafb deficiency in macrophages reduces thermogenesis, energy expenditure, and sympathetic neuron (SN) density in BAT under cold conditions. This phenotype features a proinflammatory environment that is characterized by macrophage/granulocyte accumulation, increases in interleukin-6 (IL-6) production, and IL-6 trans-signaling, which lead to decreases in nerve growth factor (NGF) expression and reduction in SN density in BAT. We confirm MAFB regulation of IL-6 expression using luciferase readout driven by IL-6 promoter in RAW-264.7 macrophage cell lines. Immunohistochemistry shows clustered organization of NGF-producing cells in BAT, which are primarily TRPV1+ vascular smooth muscle cells, as additionally shown using single-cell RNA sequencing and RT-qPCR of the stromal vascular fraction. Treating Mafbf/f::LysM-Cre mice with anti-IL-6 receptor antibody rescues SN density, body temperature, and energy expenditure.

Genicular Artery Embolization for Treatment of Knee Osteoarthritis: Interim Analysis of a Prospective Pilot Trial Including Effect on Serum Osteoarthritis-Associated Biomarkers

PurposeTo characterize the safety, efficacy, and potential role of genicular artery embolization (GAE) as a disease-modifying treatment for symptomatic knee osteoarthritis (OA). Materials and MethodsThis is an interim analysis of a prospective, single-arm clinical trial of patients with symptomatic knee OA who failed conservative therapy for greater than 3 months. Sixteen patients who underwent GAE using 250-μm microspheres and had at least 1 month of follow-up were included. Six patients completed the 12-month follow-up, and 10 patients remain enrolled. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was evaluated at baseline and at 1, 3, and 12 months. Serum and plasma samples were collected for biomarker analysis. The primary end point was the percentage of patients who achieved the minimal clinically important difference (MCID) for WOMAC pain score at 12 months. Baseline and follow-up outcomes were analyzed using the Wilcoxon matched-pairs signed-rank test. ResultsTechnical success of the procedure was 100%, with no major adverse events. The MCID was achieved in 5 of the 6 (83%) patients at 12 months. The mean WOMAC pain score decreased from 8.6 ± 2.7 at baseline to 4.9 ± 2.7 (P = .001), 4.4 ± 2.8 (P < .001), and 4.7 ± 2.7 (P = .094) at 1, 3, and 12 months, respectively. There was a statistically significant decrease in nerve growth factor (NGF) levels at 12 months. The remaining 8 biomarkers showed no significant change at 12 months. ConclusionsGAE is a safe and efficacious treatment for symptomatic knee OA. Decreased NGF levels after GAE may contribute to pain reduction and slowing of cartilage degeneration.

Autophagy and anti-inflammation ameliorate diabetic neuropathy with Rilmenidine.

To evaluate the neuroprotective effects of Rilmenidine on diabetic peripheral neuropathy (DPN) in a rat model of diabetes induced by streptozotocin (STZ). STZ (60 mg/kg) was administered to adult Sprague-Dawley rats to induce diabetes. On the 30th day after STZ administration, electromyography (EMG) and motor function tests confirmed the presence of DPN. Group 1: Control (n = 10), Group 2: DM + 0.1 mg/kg Rilmenidine (n = 10), and Group 3: DM + 0.2 mg/kg Rilmenidine (n = 10) were administered via oral lavage for four weeks. EMG, motor function test, biochemical analysis, and histological and immunohistochemical analysis of sciatic nerves were then performed. The administration of Rilmenidine to diabetic rats substantially reduced sciatic nerve inflammation and fibrosis and prevented electrophysiological alterations. Immunohistochemistry of sciatic nerves from saline-treated rats revealed increased perineural thickness, HMGB-1, tumor necrosis factor-α, and a decrease in nerve growth factor (NGF), LC-3. In contrast, Rilmendine significantly inhibited inflammation markers and prevented the reduction in NGF expression. In addition, Rilmenidine significantly decreased malondialdehyde and increased diabetic rats' total antioxidative capacity. The findings of this study suggest that Rilmenidine may have therapeutic effects on DNP by modulating antioxidant and autophagic pathways.

Attenuation of opioid tolerance by ETB receptor agonist, IRL-1620, is independent of an accompanied decrease in nerve growth factor in mice.

AimETA receptor antagonists reverse opioid tolerance but the involvement of ETB receptors is unknown. In morphine or oxycodone tolerant mice we investigated (1) the effect of ETB receptor agonist, IRL-1620, on analgesic tolerance; (2) changes in expression of the brain ETA and ETB receptors; and (3) alterations in the brain VEGF, NGF, PI3K and notch-1 expression.Main methodsBody weight, body temperature, and tail-flick latency were assessed before and after a challenge dose of morphine or oxycodone in vehicle or IRL-1620 treated mice. Expression studies were carried out using Western blots.Key findingsTail flick latency to a challenge dose of opioid was significantly increased by IRL-1620 from 39% to 100% in morphine tolerant and from 8% to 83% in oxycodone tolerant mice. Morphine or oxycodone did not alter ETA or ETB receptor expression. IRL-1620 had no effect on ETA however it increased (61%) expression of ETB receptors. IRL-1620-induced increase in ETB receptor expression was attenuated by morphine (39.8%) and oxycodone (51.8%). VEGF expression was not affected by morphine or oxycodone and was unaltered by IRL-1620. However, NGF and PI3K expression was decreased (P < 0.001) by morphine and oxycodone and was unaffected by IRL-1620. Notch-1 expression was not altered by morphine, oxycodone or IRL-1620.SignificanceETB receptor agonist, IRL-1620, restored analgesic tolerance to morphine and oxycodone, but it did not affect morphine and oxycodone induced decrease in NGF/PI3K expression. It is concluded that IRL-1620 attenuates opioid tolerance without the involvement of NGF/PI3K pathway.

Dioscorea Extract (DA-9801) Modulates Markers of Peripheral Neuropathy in Type 2 Diabetic db/db Mice.

The purpose of this study was to investigate the therapeutic effects of DA-9801, an optimized extract of Dioscorea species, on diabetic peripheral neuropathy in a type 2 diabetic animal model. In this study, db/db mice were treated with DA-9801 (30 and 100 mg/kg, daily, p.o.) for 12 weeks. DA-9801 reduced the blood glucose levels and increased the withdrawal latencies in hot plate tests. Moreover, it prevented nerve damage based on increased nerve conduction velocity and ultrastructural changes. Decrease of nerve growth factor (NGF) may have a detrimental effect on diabetic neuropathy. We previously reported NGF regulatory properties of the Dioscorea genus. In this study, DA-9801 induced NGF production in rat primary astrocytes. In addition, it increased NGF levels in the sciatic nerve and the plasma of type 2 diabetic animals. DA-9801 also increased neurite outgrowth and mRNA expression of Tieg1/Klf10, an NGF target gene, in PC12 cells. These results demonstrated the attenuation of diabetic peripheral neuropathy by oral treatment with DA-9801 via NGF regulation. DA-9801 is currently being evaluated in a phase II clinical study.

Maternal sympathetic stress impairs follicular development and puberty of the offspring.

Chronic cold stress applied to adult rats activates ovarian sympathetic innervation and develops polycystic ovary (PCO) phenotype. The PCO syndrome in humans originates during early development and is expressed before or during puberty, which suggests that the condition derived from in utero exposure to neural- or metabolic-derived insults. We studied the effects of maternal sympathetic stress on the ovarian follicular development and on the onset of puberty of female offspring. Timed pregnant rats were exposed to chronic cold stress (4 °C, 3 h/daily from 1000 to 1300 h) during the entire pregnancy. Neonatal rats exposed to sympathetic stress during gestation had a lower number of primary, primordial, and secondary follicles in the ovary and a lower recruitment of primary and secondary follicles derived from the primordial follicular pool. The expression of the FSH receptor and response of the neonatal ovary to FSH were reduced. A decrease in nerve growth factor (NGF) mRNA was found without change in the low-affinity NGF receptor. The FSH-induced development of secondary follicles was decreased. At puberty, estradiol plasma levels decreased without changes in LH plasma levels. Puberty onset (as shown by the vaginal opening) was delayed. Ovarian norepinephrine (NE) was reduced; there was no change in its metabolite, 3-methoxy-4-hydroxyphenylglycol, in stressed rats and no change in NE turnover. The changes in ovarian NE in prepubertal rats stressed during gestation could represent a lower development of sympathetic nerves as a compensatory response to the chronically increased NE levels during gestation and hence participate in delaying reproductive performance in the rat.

Methamphetamine reversed maternal separation-induced decrease in nerve growth factor in the ventral hippocampus

Stress has been suggested to predispose individuals to drug abuse. The early life stress of maternal separation (MS) is known to alter the response to drugs of abuse later in life. Exposure to either stress or methamphetamine has been shown to alter neurotrophic factors in the brain. Changes in neurotrophin levels may contribute to the underlying molecular mechanisms responsible for drug use- and stress-induced behaviours. The purpose of the present study was to investigate the individual effects of MS and methamphetamine administration during adolescence and the combined effects of both stressors on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the dorsal and ventral hippocampus (HC) in adulthood. Methamphetamine administration (1mg/kg, daily from postnatal day (PND) 33 to 36 and from PND 39 to 42), MS and the combination of the two stressors resulted in decreased BDNF levels in both the dorsal and ventral HC. MS decreased NGF levels in the ventral HC which was restored by methamphetamine administration in adolescence. In the dorsal HC, NGF remained unaltered by either stressor alone or in combination. We propose that the restoration of NGF levels in the ventral HC may reflect a possible compensatory mechanism in response to methamphetamine exposure in adolescence following the early life stress of MS.

Hypoxia‐induced deactivation of NGF‐mediated ERK1/2 signaling in hippocampal cells: Neuroprotection by acetyl‐L‐carnitine

Cellular and molecular pathways underlying hypoxic neurotoxicity and cell death are multifaceted and complex. Although many potentially neuroprotective agents have been investigated, the protection conferred is often inadequate, resulting in their insufficient clinical utility. In light of the above, we investigated the therapeutic potential and mechanism of action of acetyl-L-carnitine (ALCAR) in protecting hippocampal neurons from hypoxia-induced neurotoxicity and cellular death. Results showed decreased viability of hippocampal cells when exposed to hypoxia (3% O(2)) for 48 hr along with concomitant membrane depolarization, adenosine triphosphate depletion, DNA fragmentation, accentuated free radical production, and lactate dehydrogenase activity. Pretreatment with ALCAR significantly attenuated hypoxia-induced cytotoxicity in a dose-dependent manner and improved cellular glutathione levels and cytochrome c oxidase activity compared with normoxic controls. Supplementation of ALCAR also prevented apoptosis by down-regulating caspase-3 levels, cytochrome c release, and p-Bcl-2 expression. A decrease in nerve growth factor (NGF) was observed in hypoxic stress despite increased phosphorylation of ERK1/2 (extracellular signal-related kinase) and its downstream effector, Elk-1. Supplementation of ALCAR, on the other hand, up-regulated NGF and tyrosine kinase A expression along with concomitant increase in ERK1/2 phosphorylation, thus enhancing cell survival. ALCAR therefore provides neuroprotection by stabilizing mitochondrial membrane, restoring the cholinergic transmission, and more importantly, it stimulates NGF receptors, thus triggering cell survival pathway via ERK phosphorylation. Therefore, ALCAR may be useful as an effective therapeutic agent for hypoxic stress and associated neurodegenerative diseases.

Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy

BackgroundTransient receptor potential (TRP) receptors expressed by primary sensory neurons mediate thermosensitivity, and may play a role in sensory pathophysiology. We previously reported that human dorsal root ganglion (DRG) sensory neurons co-expressed TRPV1 and TRPV3, and that these were increased in injured human DRG. Related receptors TRPV4, activated by warmth and eicosanoids, and TRPM8, activated by cool and menthol, have been characterised in pre-clinical models. However, the role of TRPs in common clinical sensory neuropathies needs to be established.MethodsWe have studied TRPV1, TRPV3, TRPV4, and TRPM8 in nerves (n = 14) and skin from patients with nerve injury, avulsed dorsal root ganglia (DRG) (n = 11), injured spinal nerve roots (n = 9), diabetic neuropathy skin (n = 8), non-diabetic neuropathic nerve biopsies (n = 6), their respective control tissues, and human post mortem spinal cord, using immunohistological methods.ResultsTRPV1 and TRPV3 were significantly increased in injured brachial plexus nerves, and TRPV1 in hypersensitive skin after nerve repair, whilst TRPV4 was unchanged. TRPM8 was detected in a few medium diameter DRG neurons, and was unchanged in DRG after avulsion injury, but was reduced in axons and myelin in injured nerves. In diabetic neuropathy skin, TRPV1 expressing sub- and intra-epidermal fibres were decreased, as was expression in surviving fibres. TRPV1 was also decreased in non-diabetic neuropathic nerves. Immunoreactivity for TRPV3 was detected in basal keratinocytes, with a significant decrease of TRPV3 in diabetic skin. TRPV1-immunoreactive nerves were present in injured dorsal spinal roots and dorsal horn of control spinal cord, but not in ventral roots, while TRPV3 and TRPV4 were detected in spinal cord motor neurons.ConclusionThe accumulation of TRPV1 and TRPV3 in peripheral nerves after injury, in spared axons, matches our previously reported changes in avulsed DRG. Reduction of TRPV1 levels in nerve fibres in diabetic neuropathy skin may result from the known decrease of nerve growth factor (NGF) levels. The role of TRPs in keratinocytes is unknown, but a relationship to changes in NGF levels, which is produced by keratinocytes, deserves investigation. TRPV1 represents a more selective therapeutic target than other TRPs for pain and hypersensitivity, particularly in post-traumatic neuropathy.

The effects of adulthood nicotine treatment on D2-mediated behavior and neurotrophins of rats neonatally treated with quinpirole

This study was designed to analyze the effects of nicotine on yawning behavior and neurotrophin content in the hippocampus and frontal cortex of D2-receptor primed female adult Sprague-Dawley rats. Animals were neonatally treated with quinpirole, a dopamine (DA) D2/D3 agonist, from postnatal day 1-21 (P1-21) and raised to P60 and administered nicotine tartarate (0.3 mg/kg free base) or saline twice daily for 14 days. One day after nicotine treatment had ceased, the number of yawns was recorded for 1 h in response to an acute injection of quinpirole (i.p., 100 microg/kg). Yawning is a D2-receptor mediated event. D2-primed rats demonstrated a significant increase in yawning in response to acute quinpirole compared with that of controls, but nicotine did not alleviate this effect. Neonatal quinpirole treatment produced a significant decrease of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the hippocampus that was alleviated by adulthood nicotine treatment. Interestingly, nicotine treatment to controls produced a significant increase of NGF in the frontal cortex, but a significant decrease of both NGF and BDNF in the hippocampus and BDNF in the frontal cortex. The decreases shown in NGF and BDNF is contrary to past findings that have shown nicotine to produce significant increases of hippocampal NGF and BDNF, but these past studies utilized male rats or mice or were performed in vitro. This study shows that nicotine has complex interactions with NGF and BDNF in D2-primed and control animals, and emphasizes the importance of gender differences when analyzing nicotine's effects on neurotrophins.

Differential effects of laughter on allergen-specific immunoglobulin and neurotrophin levels in tears.

Laughter after viewing a humorous video "Modern Times" decreased Japanese cedar pollen-specific immunoglobulin E (IgE) and IgG4 levels, while it enhanced Japanese cedar pollen-specific IgA levels in tears of patients with atopic keratoconjunctivitis, while viewing a nonhumorous weather information video did not do so. Laughter after viewing "Modern Times" also decreased nerve growth factor levels without affecting neurotrophin-3 levels in tears of those patients, while viewing a weather information video did not. These results indicate that laughter decreased allergen-specific IgE and IgG4 production and increased allergen-specific IgA production with concomitant decrease in nerve growth factor. These results indicate that laughter may have some implications for study and treatment of allergic diseases.

A kinase insert isoform of rat TrkA supports nerve growth factor-dependent cell survival but not neurite outgrowth.

To investigate potential differences between the family of Trk receptors that might have differential consequences on cell signaling, we generated a rat TrkA homologue of the 14-amino acid kinase insert isoform of TrkC termed TrkAKi. Signal transduction by the TrkAKi receptor has been investigated and compared with the homologous signaling defective TrkC(Ki14) receptor. Herein, we demonstrate that TrkAKi receptors show a decrease in the absolute amount of kinase activity relative to wild-type TrkA, yet retain normal patterns of receptor tyrosine phosphorylation, as determined by phosphopeptide mapping studies, unlike TrkC(Ki14). nnr5 cell clones expressing TrkAKi receptors show a decrease in nerve growth factor (NGF)-mediated SHC tyrosine phosphorylation and a loss of high-affinity TrkA-SHC interaction comparable to those expressing TrkC(Ki14). Moreover, nnr5 cells expressing TrkAKi receptors fail to demonstrate NGF-dependent tyrosine phosphorylation of the signaling molecules phospholipase Cgamma-1, MAP kinase/ERK-1, and SNT. TrkAKi receptors internalize NGF comparable to wild-type TrkA, but do not stimulate neurite outgrowth. It is interesting that, unlike TrkC(Ki14), TrkAKi receptors retain phosphatidylinositol 3-kinase activity and nnr5 cells stably expressing TrkAKi receptors retain NGF-dependent cell survival under serum-free conditions. Lastly, TrkAKi receptors fail to stimulate three immediate-early genes (NGF1A, NGF1B, and c-fos), suggesting that these gene products are not required for NGF-dependent cell survival responses.

Cell-specific modulation of basal and seizure-induced neurotrophin expression by adrenalectomy.

Reports of glucocorticoid effects on neurotrophin expression suggest that adrenal hormones may contribute to the pattern of changes in the expression of these factors induced by neuronal activity and seizures. To examine this possibility, the present study evaluated the influence of adrenalectomy on basal expression and seizure-induced alterations in levels of nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 messenger RNAs in hippocampus, entorhinal cortex, and superficial neocortex. For determination of hormone effects on basal expression, adult male rats were adrenalectomized and killed 10-14 days later with paired adrenal-intact controls. For studies of adrenal steroid involvement in expression following seizure, adrenalectomized and adrenal-intact rats received a seizure-producing lesion of the dentate gyrus hilus. Changes in neurotrophin messenger RNA content were assessed by quantitative in situ hybridization. Adrenalectomy alone had no significant effect on brain-derived neurotrophic factor messenger RNA content but did result in cell-specific decreases in nerve growth factor and neurotrophin-3 messenger RNAs. Nerve growth factor messenger RNA levels were reduced in hippocampal stratum granulosum, entorhinal cortex, and neocortex but not in cells of the hippocampal molecular layers or hilus. With adrenalectomy, neurotrophin-3 messenger RNA was virtually eliminated from CA2 stratum pyramidale, partially reduced in stratum granulosum, but unaffected in neurons of the hippocampal molecular layers or entorhinal cortex. These effects were partially reversed by corticosterone (2 mg/l) supplement to the drinking saline. In experimental-seizure rats, adrenalectomy did not alter the direction or basic pattern of seizure-induced changes in neurotrophin expression but did change the time courses and magnitudes of these effects. In all areas measured, brain-derived neurotrophic factor messenger RNA content was more greatly and persistently elevated by seizure in adrenalectomized as compared with adrenal-intact rats. In contrast, with adrenalectomy seizures induced smaller increases in nerve growth factor messenger RNA content. Adrenalectomy augmented the decrease in neurotrophin-3 messenger RNA induced by seizure in hippocampus but not in entorhinal cortex. These results demonstrate that adrenal hormones play a major role in the regulation of basal nerve growth factor and neurotrophin-3 messenger RNA expression by specific populations of forebrain neurons. Moreover, the adrenal steroids have opposite effects on activity-dependent changes in brain-derived neurotrophic factor and nerve growth factor messenger RNA levels but are not required for the basic pattern of changes in neurotrophin messenger RNA expression elicited by recurrent seizures.