Evaluation of the effect of N-acetylcysteine on the prevention and amelioration of paclitaxel-induced peripheral neuropathy in breast cancer patients: a randomized controlled study.

PURPOSE: The aim of the current study was to evaluate the effect of N-acetylcysteine (NAC) on the incidence and severity of paclitaxel-induced peripheral neuropathy (PIPN) in breast cancer patients. METHOD: A prospective randomized controlled open label study was conducted on 75 breast cancer patients receiving adjuvant paclitaxel 80 mg/m2 weekly for 12 weeks. Eligible patients were randomized to either the low dose group; 1200 mg daily NAC, the high dose group; 1200 mg NAC twice daily or the control group; received paclitaxel only. The primary endpoint was the incidence of different grades of PIPN using National Cancer Institute's common toxicity criteria for adverse event (NCI-CTCAE) while secondary endpoints were the severity of PIPN using modified total neuropathy score (mTNS), quality of life (QOL) using Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-NTX) subscale, serum nerve growth factor (NGF), and serum malondialdehyde (MDA). RESULTS: At the end of the 12-week period, the incidence of grade (2, 3) peripheral neuropathy was significantly lower in the high dose group (28.6%) compared to the low dose group (61.9%) and the control group (100%), p value < 0.001. A significant improvement in the mTNS and QOL scores was observed after 6 and 12 weeks in the high dose group and the low dose group compared to the control, p value < 0.001. Significantly higher levels of serum NGF in the high dose group and lower level of serum MDA in the high dose and the low dose group were observed. CONCLUSION: Oral NAC (1200 mg once and twice daily) might reduce the incidence and severity of PIPN and improve the patients' QOL. TRIAL REGISTRY: Clinical Trial.gov registration number: NCT03492047.

Effects of hydrotherapy with massage on serum nerve growth factor concentrations and balance in middle aged diabetic neuropathy patients.

BACKGROUND: and purpose: Nerve growth factor (NGF) concentrations and balance are reduced in diabetic neuropathy (DN) patients. We examined the effects of hydrotherapy and massage on NGF, balance and glycemic markers in middle aged DN patients. MATERIALS AND METHODS: Patients were randomly assigned into four groups, aquatic exercise (AE; n = 10), AE + massage (AM; n = 10), massage (M; n = 10) or control (C; n = 9). Subjects in AE and AM groups exercised three times per week. Subjects in the AM and M groups received massage during the same period. Glycemic markers, NGF and balance were evaluated prior to and following the interventions. RESULTS: NGF, glycemic markers and dynamic balance improved in AE, AM and M groups; however, the increase was greater following the AM trial (p < 0.01) when compared to the other trials. CONCLUSION: A combination of hydrotherapy and massage enhances NGF concentrations, balance and the glycemic profile compared to hydrotherapy or massage alone.

The Effects of Tocotrienol-Rich Vitamin E (Tocovid) on Diabetic Neuropathy: A Phase II Randomized Controlled Trial.

Chronic hyperglycemia increases oxidative stress, activates inflammatory pathways and reduces nerve growth factor (NGF) among diabetic patients, which contribute to development of diabetic peripheral neuropathy (DPN). Tocotrienol-Rich Vitamin E (Tocovid) possesses potent antioxidant and anti-inflammatory properties which are postulated to target these pathogeneses in order to ameliorate DPN. This study aims to evaluate the effects of Tocovid on nerve conduction parameters and serum biomarkers among diabetic patients. This multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial was conducted on 80 eligible participants. The intervention group (n = 39) was randomly allocated to receive 200 mg of Tocovid twice a day, and the control group (n = 41) received placebo twice a day. At the end of eight weeks, the nerve conduction parameters, as assessed by nerve conduction study, as well as serum biomarkers (NGF, malondialdehyde, vascular cell adhesion molecule 1, tumor necrosis factor receptor 1 and thromboxane B2) were compared between the two groups. Compared to placebo, Tocovid significantly improves the nerve conduction velocities of all nerves (+1.25 m/s, interquartile range [IQR] 3.35, p < 0.001, median nerve; +1.60 m/s, IQR 1.80, p < 0.001, sural nerve; +0.75 m/s, IQR 2.25, p < 0.001, tibial nerve). Meanwhile, the levels of serum NGF were significantly higher in the Tocovid group as compared to placebo at eight weeks post-intervention. Participants receiving Tocovid illustrated highly significant improvement in terms of nerve conduction velocities for all nerves tested after eight weeks of supplementation. In addition, Tocovid supplementation elevated the levels of serum NGF, in which its increase is postulated to reflect enhanced neuronal functions. This novel finding suggests that Tocovid could be a disease-modifying agent targeting serum NGF to improve nerve conduction velocities.

The effect of combined scalp acupuncture and cognitive training in patients with stroke on cognitive and motor functions.

OBJECTIVE: To investigate the effect of combined scalp acupuncture and cognitive training on cognitive and motor functioning in patients with stroke during the recovery stage. METHODS: Seventy patients with post-stroke cognitive impairment were randomly divided into an experimental group and a control group. Patients in the experimental group additionally received scalp acupuncture and cognitive training, while the control group received sham scalp acupuncture and cognitive training. The cognitive and motor functioning of all patients were assessed using MMSE, LOTCA, and FMA, before and 12 weeks after treatment. In addition, the plasma BDNF and NGF levels were measured from peripheral blood samples using ELISA kits. RESULTS: After 12 weeks, the MMSE, LOTCA and FMA scores were significantly higher in the experimental group than in the control group. In the experimental group, there was an improvement in the total MMSE score, orientation, spatial executive function, the total LOTCA score, and the score of command of language orientation post-treatment. Significant improvements of BDNF and NGF were found in the experimental group after treatment, while only significant improvements of NGF was found in the control group after treatment. Both BDNF and NGF in the experiment group were higher than those in the control group at the last day of treatment. CONCLUSIONS: Combined scalp acupuncture and cognitive training can efficiently enhance cognitive and motor functions in patients with stroke during the recovery stage, which may be a more effective rehabilitation treatment after stroke than routine therapy and rehabilitation training alone.

Zinc supplementation does not influence serum levels of VEGF, BDNF, and NGF in diabetic retinopathy patients: a randomized controlled clinical trial.

Objectives: This study was aimed to evaluate the effects of zinc (Zn) supplementation on serum levels of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in patients with diabetic retinopathy (DR). Methods: In this randomized clinical trial, 50 patients with DR were allocated into the Zn (n = 25) and placebo (n = 25) groups to receive 30 mg Zn gluconate or maltose dextrin per day, respectively, for three months. Metabolic parameters and blood pressure were measured. Serum levels of Zn were assessed by atomic absorption spectrophotometry and serum levels of VEGF, BDNF and NGF by ELISA. Results: Forty-five patients completed the intervention. Levels of VEGF, BDNF and NGF were not affected by the Zn supplementation. Levels of VEGF correlated negatively with levels of Zn and positively with BDNF and NGF. There was also a positive correlation between BDNF and NGF. Serum levels of VEGF, BDNF and NGF were negatively correlated with serum levels of the diabetic parameters measured. Conclusions: Strong positive relationship between the growth factors and their inverse association with metabolic factors is possibly suggesting the contribution of these factors in the pathogenesis of DR through acting in a same biological pathway.

Targeted ablation of cardiac sympathetic neurons improves ventricular electrical remodelling in a canine model of chronic myocardial infarction.

Aims: The purpose of this study was to evaluate the cardiac electrophysiologic effects of targeted ablation of cardiac sympathetic neurons (TACSN) in a canine model of chronic myocardial infarction (MI). Methods and results: Thirty-eight anaesthetized dogs were randomly assigned into the sham-operated, MI, and MI-TACSN groups, respectively. Myocardial infarction-targeted ablation of cardiac sympathetic neuron was induced by injecting cholera toxin B subunit-saporin compound in the left stellate ganglion (LSG). Five weeks after surgery, the cardiac function, heart rate variability (HRV), ventricular electrophysiological parameters, LSG function and neural activity, serum norepinephrine (NE), nerve growth factor (NGF), and brain natriuretic peptide (BNP) levels were measured. Cardiac sympathetic innervation was determined with immunofluorescence staining of growth associated protein-43 (GAP43) and tyrosine hydroxylase (TH). Compared with MI group, TACSN significantly improved HRV, attenuated LSG function and activity, prolonged corrected QT interval, decreased Tpeak-Tend interval, prolonged ventricular effective refractory period (ERP), and action potential duration (APD), decreased the slopes of APD restitution curves, suppressed the APD alternans, increased ventricular fibrillation threshold, and reduced serum NE, NGF, and BNP levels. Moreover, the densities of GAP43 and TH-positive nerve fibres in the infarcted border zone in the MI-TACSN group were lower than those in the MI group. Conclusion: Targeted ablation of cardiac sympathetic neuron attenuates sympathetic remodelling and improves ventricular electrical remodelling in the chronic phase of MI. These data suggest that TACSN may be a novel approach to treating ventricular arrhythmias.

Neutralizing IL-6 reduces heart injury by decreasing nerve growth factor precursor in the heart and hypothalamus during rat cardiopulmonary bypass.

AIMS: To investigate whether the expression of nerve growth factor precursor (proNGF) changes during cardiopulmonary bypass (CPB) and whether neutralizing interleukin-6 (IL-6) during CPB has cardiac benefits. MAIN METHODS: Thirty patients undergoing CPB were recruited and their serum proNGF and troponin-I (TNI) were detected. In addition, rats were divided into three groups: CPB group, CPB with cardiac ischemia-reperfusion (IR) group, and a control group. The pre-CPB standard deviation of N-N intervals (SDNN) and post-CPB SDNN were compared. At the end of CPB, nerve peptide Y (NPY), acetylcholinesterase, cell apoptosis, and proNGF protein expression were measured in the heart and hypothalamus. Another rat cohort undergoing CPB was divided into two groups: an anti-IL-6 group with IL-6 antibody and a control group with phosphate buffer solution. At the end of CPB, serum hs-troponin-T and cardiac caspases 3 and 9 were detected. NPY and proNGF in the heart and hypothalamus were detected. KEY FINDINGS: In patients, serum proNGF increased during CPB, and the concentration was positively correlated with TNI. In rats, cardiac autonomic nervous function was disturbed during CPB. More apoptotic cells and higher levels of proNGF were found in the heart and hypothalamus in the CPB groups than in the control groups. Neutralizing IL-6 was beneficial to lower cardiac injury by decreasing proNGF and apoptosis. SIGNIFICANCE: CPB induced changes in proNGF in the heart and hypothalamus. Suppressing inflammation attenuated myocardial apoptosis and autonomic nerve function disturbance in CPB rats, likely due in part to regulation of proNGF in the heart and hypothalamus.

Cranial electrotherapy stimulation affects mood state but not levels of peripheral neurotrophic factors or hypothalamic- pituitary-adrenal axis regulation.

Cranial electrotherapy stimulation (CES) is reported to aid in relieving symptoms of depression and anxiety, though the mechanism underlying this effect remains unclear. Therefore, the present study aimed to evaluate changes in the hypothalamic-pituitary-adrenal (HPA) axis response and levels of neurotrophic factors, as well as changes in mood state, in patients undergoing CES therapy. Fifty healthy postmenopausal women were randomly assigned to either a Sham CES group (n = 25) or an Active CES group (n = 25). CES treatment was conducted in 20-minute sessions, three times per week for 8 weeks, using a micro current cranial electrotherapy stimulator. Blood samples were collected prior to and following the 8-week treatment period for measurement of cortisol, adrenocorticotropic hormone (ACTH), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) levels. Changes in mood state were also examined at the time of blood collection using the Profile of Mood States (POMS). No significant differences in cortisol, ACTH, BDNF, or NGF were observed between the two participant groups (p > 0.05) following the treatment period. However, those in the Active CES group exhibited significantly decreased Tension-Anxiety and Depression-Dejection scores on the POMS relative to pre-treatment scores (p < 0.05). Furthermore, Depression-Dejection scores following treatment were significantly lower in the Active CES group than in the Sham CES group (p < 0.05). No significant differences were observed in any other POMS scores such as Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment (p > 0.05). These results suggest that 8 weeks of CES treatment does not induce changes in blood levels of neurotrophic factors or HPA-axis-related hormones, though such treatment may be effective in treating symptoms of anxiety and depression.

[Effect of Tanshinone IIA in Preventing and Treating Oxaliplatin Induced Peripheral Neuropathy].

OBJECTIVE: To observe preventive and therapeutic effects of Tanshinone IIA (T II A) on oxaliplatin induced peripheral neuropathy (OlPN) and to explore its effects on the expression of calcitonin gene related peptide (CGRP) and never growth factor (NGF). METHODS: Totally 36 phase II - III patients with malignant tumor of digestive tract undergoing chemotherapy program with oxaliplatin, were equally assigned to the T II A group (using THA at 80 mg/day 1 day before oxaliplatin chemotherapy for 3 successive days) and the control group (using chemotherapy program with oxaliplatin alone) by segmented randomization. After 4 cycles of chemotherapy, the incidence degree and incidence of OlPN were evaluated. Sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity ( MNCV) were tested by EMG evoked potential device. Serum levels of CGRP and NGF were also detected in the two groups before and after chemotherapy. The correlation of serum levels of CGRP and NGF to OIPN was assessed using linear correlation analysis. RESULTS: After chemotherapy the OlPN incidence was 27.8% (5/18 cases) in the T II A group, obviously lower than that in the control group (55.6%, 10/18 cases; P < 0.05). Compared with before treatment in the same group, SNCV and MNCV of common peroneal nerve were slowed down, serum NGF levels decreased, and serum CGRP levels obviously increased in the two groups (all P < 0.05). Compared with the control group after treatment, SNCV and MNCV of common peroneal nerve were obviously accelerated, serum NGF levels increased, and serum CGRP levels obviously decreased in the THA group (all P < 0.05). Results of linear correlation analysis indicated serum NGF level was negatively correlated with peripheral neuropathy (PN), serum CGRP expression was positively correlated with neurotoxicity (P < 0.05). CONCLUSION: T II A could reduce the incidence of OlPN, which might be associated with inhibiting the expression of CGRP and up-regulating NGF activities.

[Effect of Electroacupuncture stimulation of acupoints of the Pericardium Meridian on serum NGF and Nogo-A contents and cerebral NGF and Nogo-A expression in cerebral ischemia rats].

OBJECTIVE: To observe the effect of Electroacupuncture (EA) stimulation of "Tianquan"(PC 2), "Quze" (PC 3), "Neiguan" (PC 6), "Daling" (PC 7) of the Pericardium Meridian on cerebral angiogenesis in cerebral ischemia (CI) rats, so as to reveal its mechanisms underlying improvement of stroke. METHODS: A total of 50 SD rats were equally randomized into normal control, sham, model, EA-Pericardium-Meridian acupoints (EA-PCM) and EA-Lung-Meridian acupoint (EA-LUM) groups. The CI model was established by occlusion of the middle cerebral artery. EA (2-4 V, 20 Hz) was applied to PC 2, PC 3, PC 6, PC 7 and "Tianfu"(LU 3), "Chize" (LU 5), "Lieque" (LU 7), "Taiyuan" (LU 9) of the Lung Meridian for 30 min, once at time-points of 0 h, 6 h, 24 h, 48 h and 72 h, respectively after modeling. Serum nerve growth factor (NGF) and Nogo protein-A (Nogo-A) contents were assayed by enzyme linked immunosorbent assay (ELISA), and cerebral NGF and Nogo-A immunoactivity levels in the ischemic cerebral tissue were detected by immunohistochemistry. RESULTS: (1) Compared to the normal control group, serum NGF and Nogo-A contents, and cerebral NGF immunoactivity level in the model group were significantly increased (P < 0.01). Following EA interventions, serum and cerebral NGF levels were further significantly up-regulated in the EA-PCM and EA-LUM groups (P < 0.01), while serum Nogo-A contents were down-regulated in the two EA groups (P < 0.01). The effect of EA-PCM was markedly superior to that of EA-LUM in up-regulating serum and cerebral NGF levels and down-regulating serum No- go-A level (P < 0.01). No significant differences were found between the normal control and sham groups in serum and cerebral NGF and Nogo-A levels (P > 0.05) , and among the 5 groups in cerebral Nogo-A levels (P > 0.05). CONCLUSION: EA stimulation of acupoints of both Pericardium Meridian and Lung Meridian can up-regulate serum NGF, cerebral NGF expression and down-regulate serum Nogo-A in CI rats, and the effect of Pericardium Meridian is markedly superior to that of Lung Meridian, suggesting a possible better nerve repair effect of EA-PCM acupoints on ischemic brain.

Effect of Bushenwenyanghuayu decoction on nerve growth factor and bradykinin/bradykinin B1 receptor in a endometriosis dysmenorrhea mouse model.

OBJECTIVE: To observe the effects of Bushenwenyanghuayu decoction (BD), a Traditional Chinese Medicine (TCM), on the serum concentration of nerve growth factor (NGF) and bradykinin (BK), and protein and mRNA levels of NGF and bradykinin B1 receptor (BKB1R) in a mouse model of endometriosis dysmenorrhea. METHODS: Seventy-five experimental female BALB/c mice were randomly divided into five groups, 15 mice each: sham, model, BD high dose (61.67 g/kg), BD low dose (15.42 g/kg), and gestrinone (0.4 mg/kg) groups. All the mice except for those in the sham group underwent auto-transplantation surgery and were gavaged estradiol valerate (0.5 mg/kg, daily for 12 days) after surgery. On the 12th day, 1 h after administration, writhing response was induced by intraperitoneal injection of oxytocin at 2 U/mouse. The writhing frequency and latency were recorded and the volume of the ectopic foci was measured. The concentration of serum NGF and BK was detected by enzyme-linked immunosorbent assay, the protein expression of NGF and BKB1R was tested by immunohistochemistry and western blotting, and NGF and BKB1R mRNAs were detected by real-time PCR. RESULTS: Compared with the model group, the volume of the ectopic foci in the treatment groups was significantly lower (P < 0.01), the writhing frequency was decreased (P < 0.05), and the writhing latency was prolonged (P < 0.01). Compared with the sham group, serum NGF and BK levels in the model group were significantly increased (P < 0.01). There were positive correlations for writhing frequency among the NGF and BK groups (P < 0.01). The serum NGF and BK levels were significantly lower in the treatment groups than the model group (P < 0.05). The protein expression of NGF, BKB1R was significantly decreased in the treatment groups compared with the model group (P < 0.01). NGF and BKB1R mRNA expression was significantly decreased in the treatment groups compared with the model group (P < 0.01). CONCLUSION: NGF and BK/BKB1R may play an important role in the development of endometriosis-associated dysmenorrhea, and BD was found to inhibit the development of endometriosis and relieve dysmenorrhea by influencing NGF and BK/ BKB1R mRNA and protein levels.

Association of obesity-mediated insulin resistance and hypothalamic volumes: possible sex differences.

The hypothalamus is important in hunger and metabolism. Although a lot is known about the basic role of the human hypothalamus, less is known about how the in vivo volume is affected in obesity, particularly among adolescents. Based on pediatric body mass index percentiles, 95 participants were assigned to lean or obese groups. All subjects had medical evaluations, including fasting blood tests, to assess insulin sensitivity and circulating CRP and neurotrophins (NGF and BDNF) and an MRI of the brain. Hypothalamic volumes were measured by a segmentation method combining manual and automated steps. Overall, obese participants had descriptively smaller hypothalamic volumes, although this difference did not reach statistical significance; however, among obese participants, females had significantly smaller hypothalamic volumes than their male counterparts. There was a significant interaction between insulin resistance and sex on hypothalamus volume; obese females with significant insulin resistance have smaller hypothalamic volumes than obese males. Obese adolescents had higher circulating CRP and neurotrophin levels. Furthermore, among obese females, BDNF concentrations were inversely associated with hypothalamus volumes (r = −0.48). Given this negative association between BDNF and hypothalamus volumes among obese insulin-resistant females, elevated neurotrophin levels may suggest an attempt at protective compensation.

Prenatal omega 3 fatty acid supplementation to a micronutrient imbalanced diet protects brain neurotrophins in both the cortex and hippocampus in the adult rat offspring.

OBJECTIVE: Our earlier studies show that maternal diets imbalanced in micronutrients like folic acid and vitamin B12 reduced brain docosahexaenoic acid (DHA) and brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the offspring at birth and postnatal d21. This study followed the offspring till 3 months to examine the hypothesis that impaired brain neurotrophins at birth and d21 due to altered maternal micronutrients can be reversed by prenatal omega 3 fatty acid but not a postnatal control diet leading to altered cognition in adult life. MATERIALS AND METHODS: Pregnant rats were divided into control and five treatment groups at two levels of folic acid (normal and excess folate) in the presence and absence of vitamin B12 (NFBD, EFB and EFBD). Omega 3 fatty acid supplementation was given to the vitamin B12 deficient groups (NFBDO and EFBDO). Following delivery, 8 dams from each group were shifted to control and remaining continued on same diet. RESULTS: Imbalance in maternal micronutrients up to 3months decreased DHA, BDNF and NGF in cortex and only BDNF in the hippocampus and impaired cognitive performance. Postnatal control diet normalized BDNF in the cortex but not the hippocampus and also altered cognitive performance. Prenatal omega 3 fatty acid supplementation normalized DHA, BDNF and NGF while long term supplementation was not beneficial only when micronutrients were imbalanced. CONCLUSION: Patterns established at birth are not totally reversible by postnatal diets and give clues for planning intervention studies for improving brain functioning and cognitive abilities.

Progressive muscle relaxation therapy for atopic dermatitis: objective assessment of efficacy.

The aims of this study were to validate the efficacy of progressive muscle relaxation (PMR) in patients with atopic dermatitis and to evaluate the serological parameters that may serve as objective measures of the efficacy of PMR. A total of 25 patients with atopic dermatitis were randomly assigned to either a PMR group (n = 15) or a control group (n = 10). Serum levels of nerve growth, neuropeptide Y, and Th2 cytokines (IL-4, IL-5, and IL-13) were measured at baseline and after one month. At baseline, only anxiety was positively correlated with pruritus score (state anxiety: R = 0.496, p = 0.014; trait anxiety: R = 0.423, p = 0.04). Serum levels of neuropeptide Y were inversely related to the State-Trait Anxiety Inventory (STAI) (state anxiety: R = -0.475, p = 0.019; trait anxiety: R = -0.418, p = 0.042) and pruritus scores (R = -0.451, p = 0.035). After one month of PMR therapy, the degree of pruritus and loss of sleep was significantly decreased in the PMR group (p < 0.001), but not among controls. State anxiety scores showed significant improvement after treatment only in the PMR group (p = 0.005). There were no significant changes in the serological parameters in either group. Reductions in Eczema Area and Severity Index (EASI) scores were significant, but similar, in both groups. PMR may be a useful adjunctive modality for the management of atopic dermatitis through the reduction of anxiety. No change was found in biological parameters, but it was observed that neuropeptide Y may be related to high levels of anxiety in atopic dermatitis at baseline.

Mobilization of CD133(+)CD34(-) cells in healthy individuals following whole-body acupuncture for spinal cord injuries.

Acupuncture can alleviate symptoms of spinal cord injuries (SCI). The underlying mechanism, however, is unknown. We hypothesized that stem cells could be mobilized by acupuncture. Therefore, we enrolled 14 healthy study participants using acupuncture points for the treatment of SCI. The frequency of CD133 and CD34 cells in peripheral blood and the serum concentrations of matrix metalloproteinase (MMP)-9, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and interleukin-6 were determined before and after acupuncture (<1 hr, 24 hr, and 48 hr). CD133(+)34(-) cells were doubled 48 hr after acupuncture, with concomitant decreases in BDNF and MMP-9 levels. Interleukin-6 remained below detectable levels, eliminating a stress-induced cell release. Individuals acupunctured on control counterpoints showed no changes in CD133(+) cells. Our results indicate that acupuncture for SCI can mobilize human CD133(+)34(-) cells. (c) 2009 Wiley-Liss, Inc.

Oral administration of Yokukansan inhibits the development of atopic dermatitis-like lesions in isolated NC/Nga mice.

BACKGROUND: Increasing evidence suggests that stress can trigger and exacerbate atopic dermatitis (AD). Psychotherapy is becoming more important in the treatment of AD patients. Yokukansan (YKS, Yi-Gan San in Chinese), a traditional Japanese medicine, has been widely utilized in the treatment of neurosis, insomnia and anxiety especially in Asian countries. Furthermore, it was reported that YKS inhibited skin lesions in socially isolated mice but not in group-housed mice. Therefore, in the present study it was investigated whether or not YKS was effective in the treatment of AD using socially isolated NC/Nga mice. OBJECTIVE: The present study was designed to assess the effect of YKS on the development of AD-like lesions in socially isolated NC/Nga mice to obtain information about its usefulness in the treatment of AD. METHODS: Ten-week-old male NC/Nga mice were socially isolated under conventional conditions. YKS was administered orally to mice at the dose of 0.5% or 1.0% together with diet. The efficacy of YKS was evaluated by assessing skin lesion severity, scratching behaviors, skin hydration, and infiltration of inflammatory cells in the skin. Grooming behaviors evoked by social isolation stress and serum corticosterone levels were also measured. RESULTS: Oral administration of YKS to socially isolated NC/Nga mice resulted in the inhibition of exacerbation of AD-like skin lesions. It seemed that the inhibition of exacerbation of AD-like skin lesions observed in NC/Nga mice might be due to suppression of the scratching and grooming behaviors, inhibition of the infiltration of mast cells and eosinophils, and retention of humidity in the skin. Serum corticosterone levels were also significantly inhibited in the 1%-YKS-treated mice as compared with those of the control mice. There were no significant differences in the levels of serum total IgE and nerve growth factor (NGF) between the YKS-treated mice and the non-treated control mice. CONCLUSION: YKS inhibited the development of AD-like skin lesions in socially isolated NC/Nga mice by suppressing scratching and infiltration of inflammatory cells in the skin. These results indicate that YKS possesses an anti-itching property, and its anti-itching may be partly through attenuation on social isolation stress. It is expected that YKS might provide an effective alternative therapy for AD in human patients.

Low-frequency electro-acupuncture reduces the nociceptive response and the pain mediator enhancement induced by nerve growth factor.

A number of studies have shown that the potential clinical benefits of nerve growth factor (NGF) administration are limited by its hyperalgesic side effects. The ancient therapeutic technique of acupuncture and its modern derivate electro-acupuncture (EA) have been proven effective in reducing hyperalgesia as well as nociceptive and neuropathic pain in several pathological conditions. The present study addresses the question of whether EA can influence the hyperalgesia induced by NGF administration. We treated adult healthy rats with repeated injections of murine NGF and/or low-frequency electro-acupuncture. We found that EA was able to counteract the NGF-induced hyperalgesic response when assessed by a hot plate test. Moreover, EA counteracted the NGF-driven variation of substance P (SP) and transient receptor potential vanilloid type 1 (TRPV1) response in both hind-paw skin as well as the corresponding dorsal root ganglia (DRG). Our findings indicate that low-frequency EA could be useful as a supportive therapy to reduce NGF-induced side effects, such as hypersensitivity and hyperalgesia, when clinical treatment with NGF is necessary.

All-trans retinoic acid induces nerve regeneration and increases serum and nerve contents of neural growth factor in experimental diabetic neuropathy.

Local diminution of the neural growth factor (NGF) contributes to the apparition of diabetic neuropathy. All-trans retinoic acid (RA) increases the expression of neural growth factor and its receptor participating in translation pathways. This study evaluates RA as a treatment of diabetic neuropathy: 120 mice were assigned randomly to 4 groups. Group A (n = 30) was taken as control; group B (n = 30) received 50 mg/kg intraperitoneal streptozotocin (STZ); group C (n = 30) received STZ, and after diabetic neuropathy developed, they were treated with subcutaneous RA 20 mg/kg daily during 60 days; and group D (n = 30) only received RA. Plasma glucose, thermosensitive tests, serum, and the nerve contents of NGF were measured in all animals. Evaluation by electron microscopy was performed in search of morphologic changes secondary to neuropathy and nerve regeneration. Diabetic mice had an increased threshold to pain. Treatment with RA in diabetic mice reverted changes in sensitivity as compared with diabetic mice that received placebo (P < 0.001). No differences in pain threshold among controls, RA, and diabetes mellitus (DM) + RA groups were found. Glucose levels were not affected by the treatment with RA. NGF diminished significantly in the sciatic nerve in diabetic mice as compared with controls and with the RA group. Animals with DM + RA had a significant increase of NGF in nerves as compared with the other groups. RA also regressed the ultrastructural changes induced by diabetes that showed increased neural regeneration. RA can revert functional and ultrastructural changes and induce neural regeneration after the establishment of diabetic neuropathy, possibly because of the increased of NGF concentrations in nerve terminals.

Modulation of neurotrophin and neurotrophin receptor expression in nasal mucosa after nasal allergen provocation in allergic rhinitis.

BACKGROUND: Patients with allergic rhinitis (AR) feature both allergic airway inflammation and a hyperresponsiveness to nonspecific stimuli which is partly neuronally controlled. Still, it is unclear whether or not neurotrophins are involved in airway pathophysiology of AR and in nasobronchial interaction. METHODS: Nine AR patients with mono-allergy to grass pollen and nine healthy controls underwent nasal allergen provocation (NP). Serum samples, nasal and bronchial biopsies were taken before (T(0)) and 24 h after (T(24)) NP. Pan-neurotrophin receptor p75(NTR), tyrosine kinase A (trkA), trkB, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) were assessed with immunohistochemistry, and NGF and BDNF levels with ELISA. RESULTS: At T(24), BDNF and NGF were upregulated in nasal mucosa (P < 0.05) and increased in the peripheral blood of AR compared with T(0). The increase in nasal BDNF expression correlated positively with the maximum increase in total nasal symptom score in AR (P = 0.02). p75(NTR) was expressed on peripheral nerves and epithelial layer, trkA on endothelial cells, and trkB on mast cells. trkB + mast cells significantly decreased after NP in AR (P < 0.01). NP did not modulate p75(NTR) and trkA expression in nasal mucosa and had no effect on the expression of neurotrophins and receptors in bronchial mucosa. CONCLUSION: This study shows that neurotrophins and their receptors are expressed in human airways. Allergic rhinitis was characterized by a modulation of BDNF, NGF, and trkB in nasal mucosa after NP and a correlation of nasal BDNF with the maximal increase of total nasal symptom score. Therefore, our data suggest that neurotrophins participate in upper-airway pathophysiology in AR, whereas their role in nasobronchial interaction remains unclear.

Adequate antipsychotic treatment normalizes serum nerve growth factor concentrations in schizophrenia with and without cannabis or additional substance abuse.

Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the development and maintenance of neuron function. Neurodevelopment is thought to be impaired in schizophrenia, and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin (and other substances) may be more harmful to schizophrenic brains than to non-schizophrenic brains, when used chronically. In a previous study we demonstrated an earlier disease onset and significantly higher serum NGF concentrations in drug-naïve schizophrenic patients with previous long-term cannabis abuse than in schizophrenics without cannabis abuse or cannabis abusers without schizophrenia. We therefore investigated whether this difference is still observed after treatment. Serum NGF measured in 114 treated schizophrenic patients (schizophrenia alone, n=66; schizophrenia plus cannabis abuse, n=42; schizophrenia plus multiple substance abuse, n=6) no longer differed significantly among those groups and from the control groups (healthy controls, n=51; cannabis controls, n=24; multiple substance controls, n=6). These results were confirmed by an additional prospective study in 28 patients suffering from schizophrenia (S) or schizophrenia with cannabis abuse (SC). Previously elevated serum NGF levels in the drug-naïve state, also differing between the groups (S: 83.44+/-265.25 pg/ml; SC: 246.89+/-310.24 pg/ml, S versus SC: p=0.03) dropped to 10.72+/-14.13 pg/ml (S) and 34.19+/-38.96 pg/ml (SC) (S versus SC, p>0.05), respectively, after adequate antipsychotic treatment. We thus conclude that antipsychotic treatment leads to recovery of neural integrity, as indicated by renormalized NGF values.