Electroacupuncture alleviates traumatic brain injury by inhibiting autophagy via increasing IL-10 production and blocking the AMPK/mTOR signaling pathway in rats.

Autophagy, switched by the AMPK/mTOR signaling, has been revealed to contribute greatly to traumatic brain injury (TBI). Electroacupuncture (EA) is a promising therapeutic method for TBI, however, the underlying mechanism is still unclear. Herein, we hypothesize that the therapeutic effect of EA on TBI is associated with its inhibition on AMPK/mTOR-mediated autophagy. Sprague-Dawley rats were randomly divided into three groups: sham, TBI, and TBI + EA. TBI model was established by using an electronic controlled cortical impactor. Rats were treated with EA at 12 h after modeling, 15 min daily for 14 consecutive days. EA was applied at the acupuncture points Quchi (LI 11), Hegu (LI4), Baihui (GV20), Guanyuan (CV4), Zusanli (ST36) and Yongquan (KI1), using dense-sparse wave, at frequencies of 1 Hz, and an amplitude of 1 mA. After 3, 7 and 14 days of modeling, the modified neurological severity scale (mNSS), rota rod system, and Morris Water Maze (MWM) test showed that EA treatment promoted neurological function recovery in TBI rats. Moreover, EA treatment alleviated brain edema, pathological damage, neuronal apoptosis in TBI rats. EA improved abnormal ultrastructure, including abnormal mitochondrial morphology and increased autophagosomes, in the brain neurons of TBI rats, as measured by transmission electron microscopy, and the concentration of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP). Western blot and immunohistochemistry (IHC) assays were performed to measure the protein levels of interleukin 10 (IL-10), autophagy-related proteins and key proteins in the AMPK/mTOR signaling pathway. EA treatment increased IL-10 production, inhibited the AMPK/mTOR signaling, and inhibited excessive autophagy in TBI rats. Additionally, AMPK inhibitor Compound C treatment had similar effects to EA. Both AMPK agonist AICAR and IL-10 neutralizing antibody treatments reversed the effects of EA on the related protein levels of autophagy and the AMPK/mTOR signaling pathway, and abolished the protective effects of EA on TBI rats. In conclusion, EA treatment promoted neurological function recovery and alleviated pathological damage and neuronal apoptosis in TBI rats through inhibiting excessive autophagy via increasing IL-10 production and blocking the AMPK/mTOR signaling pathway.

Orexin Receptor-1 in the Rostral Ventrolateral Medulla Mediates the Antihypertensive Effects of Electroacupuncture.

Electroacupuncture (EA) has been used to treat numerous diseases, including hypertension. This study aimed to investigate the long-term effect and underlying mechanisms of EA stimulation at the LI11 point on the hypertension and sympathetic nerve activity in two-kidney, one-clip (2K1C) hypertensive rats. EA (0.1-0.4 mA, 2 and 15 Hz) was applied to the acupoints LI11 overlying the deep radial nerve once a day for 6 weeks. The mean arterial pressure (MAP) and heart rate (HR) were determined by radiotelemetry, and the sympathetic nerve activity was evaluated by telemetric analyses of the low-frequency component of blood pressure (BP) and by plasma epinephrine and norepinephrine levels. The results showed 6 weeks of EA significantly lowered the increased BP effectively, inhibited the enhanced sympathetic nerve activities and attenuated cardiac hypertrophy in 2K1C hypertensive rats. The level of orexin receptor-1 (OX1R) in the rostral ventrolateral medulla (RVLM) after EA treatment was markedly reduced in 2K1C rats, while there was no difference in the RVLM expression of orexin receptor-2 (OX2R) in 2K1C and 2K1C+EA rats. Moreover, the increased pressor and depressor responses to microinjection of orexin A or OX1R antagonist SB408124 into the RVLM of 2K1C rats were significantly blunted by the EA treatment. These findings suggest that BP-lowering effect of EA on renovascular hypertension may be through inhibition of central sympathetic activities and modulation of functional orexin receptors in the RVLM.

Electroacupuncture Improves Baroreflex and γ-Aminobutyric Acid Type B Receptor-Mediated Responses in the Nucleus Tractus Solitarii of Hypertensive Rats.

Electroacupuncture (EA) has been reported to benefit hypertension, but the underlying mechanisms are still unclear. We hypothesized that EA attenuates hypertension, in part, through modulation of γ-aminobutyric acid (GABA) receptor function in the nucleus tractus solitarii (NTS). In the present study, the long-term effect of EA on GABA receptor function and expression was examined in the NTS of two-kidney, one-clip (2K1C) renovascular hypertensive rats. EA (0.1-0.4 mA, 2 and 15 Hz) was applied at Zusanli (ST36) acupoints overlying the deep fibular nerve for 30 min once a day for two weeks. The results showed that long-term EA treatment improved blood pressure (BP) and markedly restored the baroreflex response in 2K1C hypertensive rats. The increased pressor and depressor responses to microinjection of GABAB receptor agonist and antagonist into the NTS in the hypertensive rats were blunted by the EA treatment. Moreover, EA treatment attenuated the increased GABAB receptor expression in the NTS of hypertensive rats. In contrast, EA had no significant effect on the GABAA receptor function and expression in the NTS of 2K1C hypertensive rats. These findings suggest that the beneficial effects of EA on renovascular hypertension may be through modulation of functional GABAB receptors in the NTS.

Complementary and alternative interventions for fatigue management after traumatic brain injury: a systematic review.

BACKGROUND: We systematically reviewed randomized controlled trials (RCTs) of complementary and alternative interventions for fatigue after traumatic brain injury (TBI). METHODS: We searched multiple online sources including ClinicalTrials.gov, the Cochrane Library database, MEDLINE, CINAHL, Embase, the Web of Science, AMED, PsychINFO, Toxline, ProQuest Digital Dissertations, PEDro, PsycBite, and the World Health Organization (WHO) trial registry, in addition to hand searching of grey literature. The methodological quality of each included study was assessed using the Jadad scale, and the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. A descriptive review was performed. RESULTS: Ten RCTs of interventions for post-TBI fatigue (PTBIF) that included 10 types of complementary and alternative interventions were assessed in our study. There were four types of physical interventions including aquatic physical activity, fitness-center-based exercise, Tai Chi, and aerobic training. The three types of cognitive and behavioral interventions (CBIs) were cognitive behavioral therapy (CBT), mindfulness-based stress reduction (MBSR), and computerized working-memory training. The Flexyx Neurotherapy System (FNS) and cranial electrotherapy were the two types of biofeedback therapy, and finally, one type of light therapy was included. Although the four types of intervention included aquatic physical activity, MBSR, computerized working-memory training and blue-light therapy showed unequivocally effective results, the quality of evidence was low/very low according to the GRADE system. CONCLUSIONS: The present systematic review of existing RCTs suggests that aquatic physical activity, MBSR, computerized working-memory training, and blue-light therapy may be beneficial treatments for PTBIF. Due to the many flaws and limitations in these studies, further controlled trials using these interventions for PTBIF are necessary.

[Mechanism of electroacupuncture on "Zusanli (ST 36)" for chemotherapy-induced peripheral neuropathy].

OBJECTIVE: To observe the effects and duration of electroacupuncture on the mechanical pain threshold induced by paclitaxel and explore its analgesic mechanism. METHODS: Sixty-four C57BL/6J male mice were randomly divided into 4 groups, a normal+sham EA group, a normal+EA group, a medicine+sham EA(Med+ sham EA) group, a medicine + EA (Med + EA) group, 16 cases in each group. The model of chemotherapy-induced peripheral neuropathy was established with paclitaxel intraperitoneal injection on the 1st, 3rd, 5th, 7th day in the Med + sham EA group and the Med + EA group. EA of 30 min was used on bilateral "Zusanli (ST 36)" on the 9th, 11th, 13th, 16th, 18th, 20th, 23rd, 25th, 27th, 30th day in the EA groups, 2 Hz/100 Hz and 1~ 1.5 mA. Acupuncture was applied on the same acupoint at the same times in the sham EA groups. Mechanical pain thresholds were tested by VonFrey before and after model establishment, namely on the 8th, 14th; 21st and, 28th day. The heart blood of 8 mice was drawn quickly to collect serum in every group on the 31st day, and the contents of tumor necrosis factor α (TNF-α), interleukin-1α (IL-1α), interleukin-1ß (IL-1ß) in proinflammatory cytokine were examined by ELISA. Mechanical pain thresholds were tested by VonFrey for the rest 8 mice of each group until there was no apparent difference in the two paclitaxel groups once a week,namely on the 35th, 42nd, 49th day. RESULTS: The pain thresholds of each group were not statistically different before model establishment (P > 0.05). After model establishment (on the 8th day), thresholds of the paclitaxel groups were lower than those of the normal groups (all P < 0.05). After EA, the mechanical pain thresholds of the Med + EA group were higher than those of the Med + sham EA group at all the time points, and there was statistical difference on the 14th, 21st and 28th day (all P < 0.05). The analgesic effect was lasting to the 49th day. The contents of TNF-α, IL-1α, IL-1ß of the Med + EA group were decreased than those of the Med+sham EA group in different degree, with statistical significance of IL-1α (P < 0.05). CONCLUSION: EA can effectively treat paclitaxel-induced peripheral neuropathy,and the analgesic mechanism is probably related to decreasing the proinflammatory cytokine.

Electrical signal propagated across acupoints along Foot Taiyang Bladder Meridian in rats.

OBJECTIVE: To investigate the electrical signals propagated along Foot Taiyang Bladder Meridian (BL) in a rat model. METHODS: The experiments were performed on Dark-Agouti (DA), DA.1U and Sprague Dawley (SD) rats. The antidromic electrical stimulation was applied on the nerve innervating "Pishu" (BL 20) to mimic the acupoint electro-acupuncture (EA). The activities recording from adjacent nerve innervating acupoint "Danshu" (BL 19) or "Weishu" (BL 21) were recorded as indics for acupoint, including the mechanical threshold and discharge rate. RESULTS: After mimic EA on BL 20, C and Aδ units from adjacent BL 19 or BL 21 were sensitized including the decrease in mechanical threshold and increase in discharge rates in DA, DA.1U and SD rats, especially in DA rats. The average discharge rate increased from 2.40±0.26 to 6.06±0.55 and from 1.92±0.42 to 6.17±1.10 impulse/min (P<0.01), and the mechanical threshold decreased from 0.52±0.12 to 0.24±0.05 and from 0.27±0.02 to 0.16±0.01 mmol/L (P<0.01) in C (n=15) and Aδ (n=18) units in DA rats. The net change in discharge rates from C units were 152.5%, 144.7% and 42.4% in DA, DA.1U and SD rats, respectively, among which DA rat's was the highest (P<0.05). In Aδ units, the net change in DA rats were also the highest (221.5%, 139.2% and 49.2% in DA, DA.1U and SD rats). CONCLUSIONS: These results showed that mimic acupoint EA activated adjacent acupoints along BL in three rat strains, which might be related to propagated sensation along meridians (PSM). In addition, DA rats were more sensitive and might be a good model animal for PSM research.

Effects of thrust amplitude and duration of high-velocity, low-amplitude spinal manipulation on lumbar muscle spindle responses to vertebral position and movement.

OBJECTIVE: Mechanical characteristics of high-velocity, low-amplitude spinal manipulations (HVLA-SMs) can vary. Sustained changes in peripheral neuronal signaling due to altered load transmission to a sensory receptor's local mechanical environment are often considered a mechanism contributing to the therapeutic effects of spinal manipulation. The purpose of this study was to determine whether variation in an HVLA-SM's thrust amplitude and duration alters the neural responsiveness of lumbar muscle spindles to either vertebral movement or position. METHODS: Anesthetized cats (n = 112) received L6 HVLA-SMs delivered to the spinous process. Cats were divided into 6 cohorts depending upon the peak thrust force (25%, 55%, 85% body weight) or thrust displacement (1, 2, 3 mm) they received. Cats in each cohort received 8 thrust durations (0-250 milliseconds). Afferent discharge from 112 spindles was recorded in response to ramp and hold vertebral movement before and after the manipulation. Changes in mean instantaneous frequency (∆MIF) during the baseline period preceding the ramps (∆MIFresting), during ramp movement (∆MIFmovement), and with the vertebra held in the new position (∆MIFposition) were compared. RESULTS: Thrust duration had a small but statistically significant effect on ∆MIFresting at all 6 thrust amplitudes compared with control (0-millisecond thrust duration). The lowest amplitude thrust displacement (1 mm) increased ∆MIFresting at all thrust durations. For all the other thrust displacements and forces, the direction of change in ∆MIFresting was not consistent, and the pattern of change was not systematically related to thrust duration. Regardless of thrust force, displacement, or duration, ∆MIFmovement and ∆MIFposition were not significantly different from control. CONCLUSION: Relatively low-amplitude thrust displacements applied during an HVLA-SM produced sustained increases in the resting discharge of paraspinal muscle spindles regardless of the duration over which the thrust was applied. However, regardless of the HVLA-SM's thrust amplitude or duration, the responsiveness of paraspinal muscle spindles to vertebral movement and to a new vertebral position was not affected.

Relationship between Biomechanical Characteristics of Spinal Manipulation and Neural Responses in an Animal Model: Effect of Linear Control of Thrust Displacement versus Force, Thrust Amplitude, Thrust Duration, and Thrust Rate.

High velocity low amplitude spinal manipulation (HVLA-SM) is used frequently to treat musculoskeletal complaints. Little is known about the intervention's biomechanical characteristics that determine its clinical benefit. Using an animal preparation, we determined how neural activity from lumbar muscle spindles during a lumbar HVLA-SM is affected by the type of thrust control and by the thrust's amplitude, duration, and rate. A mechanical device was used to apply a linear increase in thrust displacement or force and to control thrust duration. Under displacement control, neural responses during the HVLA-SM increased in a fashion graded with thrust amplitude. Under force control neural responses were similar regardless of the thrust amplitude. Decreasing thrust durations at all thrust amplitudes except the smallest thrust displacement had an overall significant effect on increasing muscle spindle activity during the HVLA-SMs. Under force control, spindle responses specifically and significantly increased between thrust durations of 75 and 150 ms suggesting the presence of a threshold value. Thrust velocities greater than 20-30 mm/s and thrust rates greater than 300 N/s tended to maximize the spindle responses. This study provides a basis for considering biomechanical characteristics of an HVLA-SM that should be measured and reported in clinical efficacy studies to help define effective clinical dosages.

Sex differences in spinal processing of transient and inflammatory colorectal stimuli in the rat.

Sex differences in the spinal processing of somatic and visceral stimuli contribute to greater female sensitivity in many pain disorders. The present study examined spinal mechanisms that contribute to sex differences in visceral sensitivity. The visceromotor response to colorectal distention (CRD) was more robust in normal female rats and after intracolonic mustard oil compared with that in male rats. No sex difference was observed in the CRD-evoked response of lumbosacral (LS) and thoracolumbar (TL) colonic afferents in normal and mustard oil-treated rats, but there was a sex difference in spontaneous activity that was exacerbated by intracolonic mustard oil. The response of visceroceptive dorsal horn neurons to CRD was greater in normal female rats in the LS and TL spinal segments. The effect of intracolonic mustard oil on the CRD-evoked response of different phenotypes of visceroceptive dorsal horn neurons was dependent on sex and segment. The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (APV) dose-dependently attenuated the visceromotor response in normal rats with greater effect in male rats. Correspondingly, there was greater cell membrane expression of the GluN1 subunit in dorsal horn extracts in female rats. After intracolonic mustard oil, there was no longer a sex difference in the effect of APV nor GluN1 expression in LS segments, but greater female expression in TL segments. These data document a sex difference in spinal processing of nociceptive visceral stimuli from the normal and inflamed colon. Differences in dorsal horn neuronal activity and NMDA receptor expression contribute to the sex differences in the visceral sensitivity observed in awake rats.