Korean Red Ginseng Ameliorates Fatigue via Modulation of 5-HT and Corticosterone in a Sleep-Deprived Mouse Model

Central fatigue, which is neuromuscular dysfunction associated with neurochemical alterations, is an important clinical issue related to pathologic fatigue. This study aimed to investigate the anti-central fatigue effect of Korean red ginseng (KRG) and its underlying mechanism. Male BALB/c mice (8 weeks old) were subjected to periodic sleep deprivation (SD) for 6 cycles (forced wakefulness for 2 days + 1 normal day per cycle). Simultaneously, the mice were administered KRG (0, 100, 200, or 400 mg/kg) or ascorbic acid (100 mg/kg). After all cycles, the rotarod and grip strength tests were performed, and then the changes regarding stress- and neurotransmitter-related parameters in serum and brain tissue were evaluated. Six cycles of SD notably deteriorated exercise performance in both the rotarod and grip strength tests, while KRG administration significantly ameliorated these alterations. KRG also significantly attenuated the SD-induced depletion of serum corticosterone. The levels of main neurotransmitters related to the sleep/wake cycle were markedly altered (serotonin was overproduced while dopamine levels were decreased) by SD, and KRG significantly attenuated these alterations through relevant molecules including brain-derived neurotropic factor and serotonin transporter. This study demonstrated the anti-fatigue effects of KRG in an SD mouse model, indicating the clinical relevance of KRG.

Persistent Herpes Simplex Virus Type 1 Infection of Enteric Neurons Triggers CD8+ T Cell Response and Gastrointestinal Neuromuscular Dysfunction

Behind the central nervous system, neurotropic viruses can reach and persist even in the enteric nervous system (ENS), the neuronal network embedded in the gut wall. We recently reported that immediately following orogastric (OG) administration, Herpes simplex virus (HSV)-1 infects murine enteric neurons and recruits mononuclear cells in the myenteric plexus. In the current work, we took those findings a step forward by investigating the persistence of HSV-1 in the ENS and the local adaptive immune responses against HSV-1 that might contribute to neuronal damage in an animal model. Our study demonstrated specific viral RNA transcripts and proteins in the longitudinal muscle layer containing the myenteric plexus (LMMP) up to 10 weeks post HSV-1 infection. CD3+CD8+INFγ+ lymphocytes skewed towards HSV-1 antigens infiltrated the myenteric ganglia starting from the 6th week of infection and persist up to 10 weeks post-OG HSV-1 inoculation. CD3+CD8+ cells isolated from the LMMP of the infected mice recognized HSV-1 antigens expressed by infected enteric neurons. In vivo, infiltrating activated lymphocytes were involved in controlling viral replication and intestinal neuromuscular dysfunction. Indeed, by depleting the CD8+ cells by administering specific monoclonal antibody we observed a partial amelioration of intestinal dysmotility in HSV-1 infected mice but increased expression of viral genes. Our findings demonstrate that HSV-1 persistently infects enteric neurons that in turn express viral antigens, leading them to recruit activated CD3+CD8+ lymphocytes. The T-cell responses toward HSV-1 antigens persistently expressed in enteric neurons can alter the integrity of the ENS predisposing to neuromuscular dysfunction.

TrkB Signaling Contributes to Transdiaphragmatic Pressure Generation in Aged Mice

Ventilatory deficits are common in old age and may result from neuromuscular dysfunction. Signaling via the tropomyosin-related kinase receptor B (TrkB) regulates neuromuscular transmission and in young mice is important for the generation of transdiaphragmatic pressure (Pdi). Loss of TrkB signaling worsened neuromuscular transmission failure and reduced maximal Pdi, and these effects are similar to those observed in old age. Administration of TrkB agonists such as 7,8-dihydroxyflavone (7,8-DHF) improves neuromuscular transmission in young and old mice (18 months; 75% survival). We hypothesized that TrkB signaling contributes to Pdi generation in old mice, particularly during maximal force behaviors. Old male and female TrkBF616A mice, with a mutation that induces 1NMPP1-mediated TrkB kinase inhibition, were randomly assigned to systemic treatment with vehicle, 7,8-DHF, or 1NMPP1 one hour prior to experiments. Pdi was measured during eupneic breathing (room air), hypoxia-hypercapnia (10% O2/5% CO2), tracheal occlusion, spontaneous deep breaths ("sighs"), and bilateral phrenic nerve stimulation (Pdimax). There were no differences in the Pdi amplitude across treatments during ventilatory behaviors (eupnea, hypoxia-hypercapnia, occlusion or sigh). As expected, Pdi increased from eupnea and hypoxia-hypercapnia (~7 cm H2O) to occlusion and sighs (~25 cm H2O), with no differences across treatments. Pdimax was ~50 cm H2O in the vehicle and 7,8-DHF groups and ~40 cm H2O in the 1NMPP1 group (F8,74 = 2; p = 0.02). Our results indicate that TrkB signaling is necessary for generating maximal forces by the diaphragm muscle in old mice, and are consistent with aging effects of TrkB signaling on neuromuscular transmission.

Prognostic significance of prenatal ultrasound in fetal arthrogryposis multiplex congenita

Purpose Fetal arthrogryposis multiplex congenita (AMC) describes a heterogeneous disease entity characterized by multiple contractures affecting at least two different body areas. The aim of our study was to identify additional sonographic abnormalities in fetuses with AMC Type I–III associated with an unfavorable prognosis and to describe when those signs were first detected. Methods This retrospective study included 41 pregnancies of suspected AMC diagnosed 1999–2017 at our tertiary referral center. The affected pregnancies were divided into the 3 AMC subgroups; the time of detection and outcome were analyzed. Prenatal sonograms, pediatric charts, genetic tests, and autopsy reports were studied. Results Pregnancy outcome data were verifiable in 34 out of 41 cases; in 27 cases, AMC was confirmed. Hydrops was present in 50% of postnatally deceased fetuses, 53% of cases resulting in termination of pregnancy vs. 0% of the surviving 8 children. Absent stomach filling was found in 67% of the children with neonatal death. After subcategorization, the limb-involvement-only-group, 8% showed hydrops vs. 100% in system anomaly group vs. 70% in neuromuscular dysfunction cohort (p = 0.001). Scoliosis, nuchal edema, and absent stomach filling were significantly indicating for a neurological etiology. Conclusion In addition to disease-defining sonographic findings, those with prognostic significance were identified. Hydrops, nuchal edema, scoliosis and absent stomach filling were associated with unfavorable outcomes implicating a neuromuscular etiology. This knowledge can help to predict the further course of the disease and support patient counseling.