Nodakenetin Alleviates Inflammatory Pain Hypersensitivity by Suppressing NF-κB Signal Pathway.

BACKGROUND: Inflammatory pain mediated by nuclear factor kappa-B (NF-κB) signal pathway has become an increasingly important clinical issue in the last decade. As a potent antioxidant, Nodakenetin has been shown to have a prominent inhibitory effect on inflammation. However, the therapeutic effects and underlying pharmacological mechanisms of Nodakenetin for inflammatory pain remain unclear. METHODS: Intraplanar injection of complete Freund's adjuvant (CFA) was used to establish a model of chronic inflammation pain in C57BL/6 mice. The chronic neuropathic pain model was conducted by the sciatic nerve ligation surgery. QRT-PCR was performed to estimate the RNA levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). Western blot was used to demonstrated the protein levels of phospho-IkappaBα (IκBα), p50, and p65 in HEK293T cells. RESULTS: The bioactive components of the traditional Chinese medicine Notopterygium forbesii boiss mainly include Nodakenetin, isoimperatorin, and pregnenolone. Nodakenetin significantly alleviated CFA-induced inflammatory pain but showed no significant therapeutic effect on surgically induced neuralgia in a mouse model. In contrast, isoimperatorin and pregnenolone did not relieve CFA-induced inflammatory pain. Mechanistically, Nodakenetin inhibited IL-1ß-induced activation of the NF-κB pathway and phosphorylation of IκBα in HEK293T cells. Furthermore, Nodakenetin treatment suppressed the expression of IL-6, TNF-α, and IL-1ß in mouse bone marrow-derived macrophages. CONCLUSION: Nodakenetin alleviates inflammatory pain induced by CFA injection in vivo and modulates NF-κB signal pathway in vitro.

Does Pregnenolone Adjunct to Risperidone Ameliorate Irritable Behavior in Adolescents With Autism Spectrum Disorder: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial?

OBJECTIVES: Pregnenolone is a neurosteroid with modulatory effects on γ-aminobutyric acid neurotransmission. Here, we aimed to evaluate the effectiveness and safety of pregnenolone add-on to risperidone in adolescents with autism spectrum disorders (ASD). METHODS: Sixty-four ASD patients were randomly allocated to receive either pregnenolone (n = 32) or matching placebo (n = 32) in addition to risperidone. The Aberrant Behavior Checklist-Community Edition scale was used to evaluate the behavioral status of patients at baseline, week 5, and the trial end point. The change in score of irritability subscale was the primary outcome. Frequency of adverse effects due to trial medications was compared between the treatment groups. RESULTS: Fifty-nine patients completed the trial (30 in pregnenolone and 29 in the placebo arm). Baseline characteristics of both treatment groups were similar (P > 0.05). Repeated measures analysis was suggestive of greater exhibited improvement for the pregnenolone group on irritability, stereotypy, and hyperactivity subscales of the Aberrant Behavior Checklist-Community Edition over the trial period (F = 3.84, df = 1.96, P = 0.025; F = 4.29, df = 1.39, P = 0.029; F = 6.55, df = 1.67, P = 0.004, respectively). Nonetheless, the alterations in lethargy and inappropriate speech domains scores were similar for both arms (F = 0.93, df = 1.49, P = 0.375; F = 1.10, df = 1.60, P = 0.325, respectively). There was no significant difference in frequency as well as severity of adverse effects between the 2 groups. CONCLUSIONS: Pregnenolone adjunct to risperidone could attenuate core features associated with ASD.

Pregnenolone as an adjunct to risperidone for treatment of women with schizophrenia: A randomized double-blind placebo-controlled clinical trial.

There have been few studies of pregnenolone therapy in schizophrenia and those that exist have been subject to several critical limitations, thus yielding inconsistent results. We attempted to assess the therapeutic effect of pregnenolone in a patient sample as homogeneous as possible. In this randomized double-blind clinical trial, 82 female inpatients with chronic schizophrenia, who had discontinued their antipsychotic medications for at least one week in case of any oral antipsychotic medication or a month for any depot antipsychotic medication, received risperidone plus either pregnenolone (50 mg/day) or placebo for 8 weeks. Inclusion criteria were acute illness with a baseline Positive and Negative Syndrome Scale (PANSS) negative subscale score of ≥20. Exclusion criteria were the presence of severe depression or other concomitant psychiatric disorders. Primary outcome was defined as the difference in the PANSS total score change from baseline to week 8 in the pregnenolone group compared to the placebo group. No significant difference was found in the PANSS total score changes between the two arms (mean difference (CI 95%) = -9.41 (-20.24 to 1.41); p = 0.087). Significant differences were initially found for PANSS negative change scores (mean difference (CI 95%) = -2.61 (-5.03 to -0.19); p = 0.035) and general psychopathology change scores (mean difference (CI 95%) = -5.93 (-11.37 to -0.48); p = 0.033). However, these findings did not survive Bonferroni correction for multiple testing. While this trial may suggest a potential effect of pregnenolone on schizophrenia symptoms, further studies are warranted.

Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia.

RATIONALE: Preclinical and clinical data suggest that pregnenolone may be a promising therapeutic in schizophrenia. Pregnenolone is neuroprotective and enhances learning and memory, myelination, and microtubule polymerization. Treatment with pregnenolone elevates allopregnanolone (a neurosteroid that enhances GABAA receptor responses) and pregnenolone sulfate (a positive NMDA receptor modulator). Pregnenolone could thus potentially mitigate GABA dysregulation and/or NMDA receptor hypofunction in schizophrenia via metabolism to other neurosteroids. OBJECTIVE: The objective of this study is to conduct a randomized controlled trial of adjunctive pregnenolone in schizophrenia. METHODS: Following a placebo lead-in, 120 participants were randomized to pregnenolone or placebo for 8 weeks (Institute for Mental Health, Singapore). Primary endpoints were changes in MATRICS Consensus Cognitive Battery (MCCB) composite scores (cognitive symptoms), UCSD Performance-based Skills Assessment-Brief (UPSA-B) composite scores (functional capacity), and Scale for Assessment of Negative Symptoms (SANS) total scores (negative symptoms). A modified intent-to-treat analysis approach was utilized. RESULTS: No significant changes compared to placebo were demonstrated in composite MCCB scores. In contrast, participants randomized to pregnenolone (n = 56) demonstrated greater improvements in functional capacity (UPSA-B composite changes) compared to placebo (n = 55), p = 0.03. Pregnenolone was also superior to placebo in the communication subscale of the UPSA-B (p < 0.001). Serum pregnenolone changes post-treatment were correlated with UPSA-B composite score changes in females (r s = 0.497, p < 0.042, n = 17) but not in males. Mean total SANS scores were very low at baseline and did not improve further post-treatment. Pregnenolone was well-tolerated. CONCLUSIONS: Pregnenolone improved functional capacity in participants with schizophrenia, but did not improve cognitive symptoms over an 8-week treatment period. Neurosteroid changes correlated with functional improvements in female participants. Neurosteroid interventions may exhibit promise as new therapeutic leads for schizophrenia.

Pregnenolone treatment reduces severity of negative symptoms in recent-onset schizophrenia: an 8-week, double-blind, randomized add-on two-center trial.

AIMS: Management of recent-onset schizophrenia (SZ) and schizoaffective disorder (SA) is challenging owing to frequent insufficient response to antipsychotic agents. This study aimed to test the efficacy and safety of the neurosteroid pregnenolone in patients with recent-onset SZ/SA. METHODS: Sixty out- and inpatients who met DSM-IV criteria for SZ/SA, with suboptimal response to antipsychotics were recruited for an 8-week, double-blind, randomized, placebo-controlled, two-center add-on trial, that was conducted between 2008 and 2011. Participants were randomized to receive either pregnenolone (50 mg/day) or placebo added on to antipsychotic medications. The primary outcome measures were the Positive and Negative Symptoms Scale and the Assessment of Negative Symptoms scores. Secondary outcomes included assessments of functioning, and side-effects. RESULTS: Analysis was by linear mixed model. Fifty-two participants (86.7%) completed the trial. Compared to placebo, adjunctive pregnenolone significantly reduced Positive and Negative Symptoms Scale negative symptom scores with moderate effect sizes (d = 0.79). Significant improvement was observed in weeks 6 and 8 of pregnenolone therapy among patients who were not treated with concomitant mood stabilizers (arms × visit × mood stabilizers; P = 0.010). Likewise, pregnenolone significantly reduced Assessment of Negative Symptoms scores compared to placebo (d = 0.57), especially on blunted affect, avolition and anhedonia domain scores. Other symptoms, functioning, and side-effects were not significantly affected by adjunctive pregnenolone. Antipsychotic agents, benzodiazepines and sex did not associate with pregnenolone augmentation. Pregnenolone was well tolerated. CONCLUSIONS: Thus, add-on pregnenolone reduces the severity of negative symptoms in recent-onset schizophrenia and schizoaffective disorder, especially among patients who are not treated with concomitant mood stabilizers. Further studies are warranted.

TRPM3 is a nociceptor channel involved in the detection of noxious heat.

Transient receptor potential melastatin-3 (TRPM3) is a broadly expressed Ca(2+)-permeable nonselective cation channel. Previous work has demonstrated robust activation of TRPM3 by the neuroactive steroid pregnenolone sulfate (PS), but its in vivo gating mechanisms and functions remained poorly understood. Here, we provide evidence that TRPM3 functions as a chemo- and thermosensor in the somatosensory system. TRPM3 is molecularly and functionally expressed in a large subset of small-diameter sensory neurons from dorsal root and trigeminal ganglia, and mediates the aversive and nocifensive behavioral responses to PS. Moreover, we demonstrate that TRPM3 is steeply activated by heating and underlies heat sensitivity in a subset of sensory neurons. TRPM3-deficient mice exhibited clear deficits in their avoidance responses to noxious heat and in the development of inflammatory heat hyperalgesia. These experiments reveal an unanticipated role for TRPM3 as a thermosensitive nociceptor channel implicated in the detection of noxious heat.

Pregnenolone and dehydroepiandrosterone as an adjunctive treatment in schizophrenia and schizoaffective disorder: an 8-week, double-blind, randomized, controlled, 2-center, parallel-group trial.

OBJECTIVE: Pregnenolone (PREG) and dehydroepiandrosterone (DHEA) are reported to have a modulatory effect on neuronal excitability, synaptic plasticity, and response to stress; they are associated with mood regulation and cognitive performance. We investigated the influence of PREG and DHEA on psychotic symptoms and cognitive functioning as an add-on to ongoing antipsychotic treatment of patients with chronic schizophrenia or schizoaffective disorder. METHOD: This 8-week, double-blind, randomized, placebo-controlled, 2-center study compared 30 mg/d of PREG (PREG-30), 200 mg/d of PREG (PREG-200), 400 mg/d of DHEA, and placebo as an adjunctive treatment of 58 chronic schizophrenia or schizoaffective disorder patients (DSM-IV). The data were collected from February 2005 until June 2007. The outcome measures were symptomatic and neurocognitive changes, functioning, and tolerability as assessed primarily by the Clinical Global Impressions-Severity of Illness scale and the Positive and Negative Syndrome Scale. Analyses are presented for 44 patients who completed 8 weeks of treatment and for 14 noncompleters. RESULTS: Compared with subjects who received placebo, those administered PREG-30 had significant reductions in positive symptom scores and extrapyramidal side effects (EPS) and improvement in attention and working memory performance, whereas subjects treated with PREG-200 did not differ on outcome variable scores for the study period. The general psychopathology severity and general functioning of patients receiving placebo and PREG-30 improved more than that of those subjects treated with DHEA, while EPS improved more in subjects treated with DHEA than in patients receiving placebo. Negative symptoms and akathisia were not significantly benefited by any treatment. The administration of PREG and DHEA was well tolerated. CONCLUSIONS: Low-dose PREG augmentation demonstrated significant amelioration of positive symptoms and EPS and improvement in attention and working memory performance of schizophrenia and schizoaffective disorder patients. Further double-blind controlled studies are needed to investigate the clinical benefit of pregnenolone augmentation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00174889.

Effect of isopregnanolone on rapid tolerance to the anxiolytic effect of ethanol.

OBJECTIVE: It has been shown that neurosteroids can either block or stimulate the development of chronic and rapid tolerance to the incoordination and hypothermia caused by ethanol consumption. The aim of the present study was to investigate the influence of isopregnanolone on the development of rapid tolerance to the anxiolytic effect of ethanol in mice. METHOD: Male Swiss mice were pretreated with isopregnanolone (0.05, 0.10 or 0.20 mg/kg) 30 min before administration of ethanol (1.5 g/kg). Twenty-four hours later, all animals we tested using the plus-maze apparatus. The first experiment defined the doses of ethanol that did or did not induce rapid tolerance to the anxiolytic effect of ethanol. In the second, the influence of pretreatment of mice with isopregnanolone (0.05, 0.10 or 0.20 mg/kg) on rapid tolerance to ethanol (1.5 g/kg) was studied. CONCLUSIONS: The results show that pretreatment with isopregnanolone interfered with the development of rapid tolerance to the anxiolytic effect of ethanol.

Effect of isopregnanolone on rapid tolerance to the anxiolytic effect of ethanol / Influência da isopregnenolona na tolerância rápida ao efeito ansiolítico do etanol

OBJETIVE: It has been shown that neurosteroids can either block or stimulate the development of chronic and rapid tolerance to the incoordination and hypothermia caused by ethanol consumption. The aim of the present study was to investigate the influence of isopregnanolone on the development of rapid tolerance to the anxiolytic effect of ethanol in mice. METHOD: Male Swiss mice were pretreated with isopregnanolone (0.05, 0.10 or 0.20 mg/kg) 30 min before administration of ethanol (1.5 g/kg). Twenty-four hours later, all animals we tested using the plus-maze apparatus. The first experiment defined the doses of ethanol that did or did not induce rapid tolerance to the anxiolytic effect of ethanol. In the second, the influence of pretreatment of mice with isopregnanolone (0.05, 0.10 or 0.20 mg/kg) on rapid tolerance to ethanol (1.5 g/kg) was studied. CONCLUSIONS: The results show that pretreatment with isopregnanolone interfered with the development of rapid tolerance to the anxiolytic effect of ethanol.

OBJETIVO: Estudos prévios têm mostrado que os neuroesteróides podem bloquear ou estimular o desenvolvimento da tolerância rápida e crônica aos efeitos de incoordenação e hipotermia produzidos pelo etanol. O objetivo do presente estudo foi investigar a influência da isopregnenolona sobre o desenvolvimento da tolerância rápida ao efeito ansiolítico do etanol em camundongos. MÉTODO: Camundongos suíços, machos, foram pré-tratados com isopregnenolona (0,05, 0,10 ou 0,20 mg/kg) 30 minutos antes da administração de etanol (1,5 g/kg). Após 24 horas, todos os animais foram testados no labirinto em cruz elevado. O primeiro experimento foi realizado com o intuito de selecionar uma dose de etanol que produzisse tolerância rápida ao efeito ansiolítico do etanol. No segundo experimento, o objetivo foi investigar o efeito da isopregnenolona (ISO; 0,05, 0,10 ou 0,20 mg/kg) sobre a tolerância rápida ao etanol (1,5 g/kg). CONCLUSÕES: Os resultados mostram que o tratamento prévio com isopregnenolona interferiu no desenvolvimento da tolerância rápida ao efeito ansiolítico etanol.

Successful treatment of non-segmental vitiligo: systemic therapy with sex hormone-thyroid powder mixture.

We previously reported a patient with generalized vitiligo improved by oral administration of the drug for menopausal syndrome (sex hormone-thyroid powder mixture). In this study, we reevaluated the efficiency of this drug for vitiligo, and examined its pharmacological action in melanogenesis.