In vivo neuronal and astrocytic activation in somatosensory cortex by acupuncture stimuli.

Acupuncture is a medical treatment that has been widely practiced in China for over 3000 years, yet the neural mechanisms of acupuncture are not fully understood. We hypothesized that neurons and astrocytes act independently and synergistically under acupuncture stimulation. To investigate this, we used two-photon in vivo calcium recording to observe the effects of acupuncture stimulation at ST36 (Zusanli) in mice. Acupuncture stimulation in peripheral acupoints potentiated calcium signals of pyramidal neurons and astrocytes in the somatosensory cortex and resulted in late-onset calcium transients in astrocytes. Chemogenetic inhibition of neurons augmented the astrocytic activity. These findings suggest that acupuncture activates neuronal and astrocytic activity in the somatosensory cortex and provide evidence for the involvement of both neurons and astrocytes in acupuncture treatment.

Perioperatively Inhaled Hydrogen Gas Diminishes Neurologic Injury Following Experimental Circulatory Arrest in Swine.

This study used a swine model of mildly hypothermic prolonged circulatory arrest and found that the addition of 2.4% inhaled hydrogen gas to inspiratory gases during and after the ischemic insult significantly decreased neurologic and renal injury compared with controls. With proper precautions, inhalational hydrogen may be administered safely through conventional ventilators and may represent a complementary therapy that can be easily incorporated into current workflows. In the future, inhaled hydrogen may diminish the sequelae of ischemia that occurs in congenital heart surgery, cardiac arrest, extracorporeal life-support events, acute myocardial infarction, stroke, and organ transplantation.

HIV-1 inhibitory properties of eCD4-Igmim2 determined using an Env-mediated membrane fusion assay.

Human Immunodeficiency Virus-1 (HIV-1) entry is dependent on the envelope glycoprotein (Env) that is present on the virion and facilitates fusion between the envelope and the cellular membrane. The protein consists of two subunits, gp120 and gp41, with the former required for binding the CD4 receptor and either the CXCR4 or CCR5 coreceptor, and the latter for mediating fusion. The requirement of fusion for infection has made Env an attractive target for HIV therapy development and led to the FDA approval of enfuvirtide, a fusion inhibitor. Continued development of entry inhibitors is warranted because enfuvirtide resistant HIV-1 strains have emerged. In this study, a novel HIV-1 fusion assay was validated using neutralizing antibodies and then used to investigate the mechanism of action of eCD4-Igmim2, an HIV-1 inhibitor proposed to cooperatively bind the CD4 binding site and the sulfotyrosine-binding pocket of gp120. Greater reduction in fusion levels was observed with eCD4-Igmim2 in the fusion assay than all of the gp120 antibodies evaluated. Lab adapted isolates, HIV-1HXB2 and HIV-1YU2, were sensitive to eCD4-Igmim2 in the fusion assay, while primary isolates, HIV-1BG505 and HIV-1ZM651 were resistant. These results correlated with greater IC50 values for primary isolates compared to the lab adapted isolates observed in a virus neutralization assay. Analysis of gp120 models identified differences in the V1 and V2 domains that are associated with eCD4-Igmim2 sensitivity. This study highlights the use of a fusion assay to identify key areas for improving the potency of eCD4-Igmim2.

Ancient Chinese medicine and mechanistic evidence of acupuncture physiology.

Acupuncture has been widely used in China for three millennia as an art of healing. Yet, its physiology is not yet understood. The current interest in acupuncture started in 1971. Soon afterward, extensive research led to the concept of neural signaling with possible involvement of opioid peptides, glutamate, adenosine and identifying responsive parts in the central nervous system. In the last decade scientists began investigating the subject with anatomical and molecular imaging. It was found that mechanical movements of the needle, ignored in the past, appear to be central to the method and intracellular calcium ions may play a pivotal role. In this review, we trace the technique of clinical treatment from the first written record about 2,200 years ago to the modern time. The ancient texts have been used to introduce the concepts of yin, yang, qi, de qi, and meridians, the traditional foundation of acupuncture. We explore the sequence of the physiological process, from the turning of the needle, the mechanical wave activation of calcium ion channel to beta-endorphin secretion. By using modern terminology to re-interpret the ancient texts, we have found that the 2nd century B.C.: physiologists were meticulous investigators and their explanation fits well with the mechanistic model derived from magnetic resonance imaging (MRI) and confocal microscopy. In conclusion, the ancient model appears to have withstood the test of time surprisingly well confirming the popular axiom that the old wine is better than the new.

Physiology and cell biology of acupuncture observed in calcium signaling activated by acoustic shear wave.

This article presents a novel model of acupuncture physiology based on cellular calcium activation by an acoustic shear wave (ASW) generated by the mechanical movement of the needle. An acupuncture needle was driven by a piezoelectric transducer at 100 Hz or below, and the ASW in human calf was imaged by magnetic resonance elastography. At the cell level, the ASW activated intracellular Ca(2+) transients and oscillations in fibroblasts and endothelial, ventricular myocytes and neuronal PC-12 cells along with frequency-amplitude tuning and memory capabilities. Monitoring in vivo mammalian experiments with ASW, enhancement of endorphin in blood plasma and blocking by Gd(3+) were observed; and increased Ca(2+) fluorescence in mouse hind leg muscle was imaged by two-photon microscopy. In contrast with traditional acupuncture models, the signal source is derived from the total acoustic energy. ASW signaling makes use of the anisotropy of elasticity of tissues as its waveguides for transmission and that cell activation is not based on the nervous system.

An fMRI study of acupuncture-induced brain activation of aphasia stroke patients.

This investigation aims to test the effect of acupuncture on word generation activation (WGA) in post-stroke aphasia patients. Seven vascular aphasia patients and 14 control subjects were studied using functional magnetic resonance imaging (fMRI). Each performed: (1) a word generation (WG) task alone, followed by (2) repeating WG after insertion of acupuncture needles (WGN) into SJ 8 (a language-implicated acupoint), followed by (3) repeating WGN reinforced by electrical stimulation (WGA) of SJ 8, and finally (4) electrical stimulation (ES) of SJ 8 alone. Significant activation was found in the opercular, triangular, or insula during the ES stimulation in patients when comparing each patient to 14 normal controls. For the WG task, significant activation was found in the inferior frontal gyrus when comparing each patient to 14 normal controls. The signal induced by acupuncture was larger than that of the WG task in the left middle frontal gyrus with the comparison of WGA vs. WGN in seven patients. Further, main significant effects in the right insula in patients were observed when comparing seven patients to 14 normal controls. The activation induced by ES stimulation was only found on the left side in controls. This activation was observed on the lesion side of superior and middle frontal gyrus (SMFG) in patients. This study demonstrates for the first time that language-deficit-implicated acupoint stimulation can selectively activate the brain on the lesion side in post-stroke aphasia patients. These results suggest that acupuncture may have therapeutic benefits in post-stroke aphasia patients.

Diet supplement CoQ10 delays brain atrophy in aged transgenic mice with mutations in the amyloid precursor protein: an in vivo volume MRI study.

We tested the hypotheses that supplemental intake of the diet supplement Coenzyme Q10 (CoQ10) could delay brain atrophy in double transgenic amyloid precursor protein (APP) / presenilin 1 (PS1), single transgenic APP and PS1 as well as wild type mice by volume MR image in vivo. One hundred and twelve mice (28 APP/PS1, 28 APP, 28 PS1 and 28 wild types) were studied. Half of each genotype group (n = 14 per group) was treated with CoQ10 2400 mg/kg/day, and the other half with placebo for 60 days. Magnetic resonance (MR) images were used to obtain the volumes of the hemispheres and hippocampi. APP / PS1, APP, PS1 and wild type mice treated with CoQ10 exhibited significantly less atrophy in hemisphere and hippocampus than those receiving placebo. The neuro-protective effect of the CoQ10 on hemispheric volume, and hippocampal volume was related to genotype; greater in APP/PS1 than APP and PS1 mice and less in wild type mice. Our result indicated that CoQ10 may have therapeutic potential in the prevention and treatment of MCI and AD.

Coenzyme Q10 attenuates beta-amyloid pathology in the aged transgenic mice with Alzheimer presenilin 1 mutation.

One of the neuropathological features of Alzheimer's disease (AD) is the deposition of senile plaques containing beta-amyloid (A beta). There is limited evidence for the treatment to arrest A beta pathology of AD. In our present study, we tested the effect of coenzyme Q10 (CoQ10), an endogenous antioxidant and a powerful free radical scavenger, on A beta in the aged transgenic mice overexpressing Alzheimer presenilin 1-L235P (leucine-to-proline mutation at codon 235, 16-17 months old). The treatment by feeding the transgenic mice with CoQ10 for 60 days (1,200 mg kg(-1) day(-1)) partially attenuated A beta overproduction and intracellular A beta deposit in the cortex of the transgenic mice compared with the age-matched untreated transgenic mice. Meanwhile, an increased oxidative stress reaction was detected as evidenced by elevated level of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) in the transgenic mice relative to the wild-type mice, and supplementation of CoQ10 partially decreased MDA level and upregulated the activity of SOD. The results indicate that oxidative stress is enhanced in the brain of the transgenic mice, that this enhancement may further promote A beta 42 overproduction in a vicious formation, and that CoQ10 would be beneficial for the therapy of AD.

Neuroprotective effect of Coenzyme Q10 on ischemic hemisphere in aged mice with mutations in the amyloid precursor protein.

This study was designed to test whether Coenzyme Q10 (CoQ10) supplementation has neuroprotective effect in aged, double-transgenic amyloid precursor protein (APP)/presenilin 1 (PS1), single transgenic APP and PS1 mice exposed to ischemic injury of the brain. Forty-eight mice (12 each of APP/PS1, APP, PS1 and wild-type) were studied. Half of each genotype groups (n=6 per group) was treated with CoQ10 (1200 mg/kg/day) after ischemic injury and the other half with placebo. Magnetic resonance (MR) images were used to measure the volume of induced infarction (IFV), as well as the volume of the hemispheres and hippocampi. Significantly greater volumes of infarction and lesser volumes of hemisphere/hippocampus on the ischemic side were observed in APP/PS1 and APP mice than in PS1 and wild-type mice. This is consistent with amplification of the effect of ischemia in APP carriers. After 28 days of CoQ10 treatment, APP/PS1 or APP mutations have smaller infarct volumes, while the volumes of hemisphere and hippocampus on the infarcted side were larger than those treated with placebo. No differences between CoQ10- and placebo-treated groups in volumes of infarct, hemisphere and hippocampus were observed in PS1 and wild-type mice. We conclude that CoQ10 has a protective effect on the brain from infarction and atrophy induced by ischemic injury in aged and susceptible transgenic mice.

An fMRI study of somatosensory-implicated acupuncture points in stable somatosensory stroke patients.

PURPOSE: To assess differences in brain responses between stroke patients and controls to tactile and electrical acupuncture stimulation using functional MRI (fMRI). MATERIALS AND METHODS: A total of 12 male, clinically stable stroke patients with left side somatosensory deficits, and 12 age-matched male control subjects were studied. fMRI was performed with two different paradigms; namely, tactile stimuli and electrical stimulation at acupuncture points LI4 and LI11 on the affected side of the body. fMRI data were analyzed using SPM99. RESULTS: Tactile stimulation in both patients and controls produced significant activation in primary and secondary sensory and motor cortical areas and cerebellum. Greater activation was present in patients than controls in the somatosensory cortex with both the tactile task and the acupuncture point (acupoint) stimulation. Activation was greater during the tactile task than the acupuncture stimulation in patients and normal controls. CONCLUSION: Differences observed between patients and controls on both tasks may indicate compensatory over recruitment of neocortical areas involved in somatosensory perception in the stroke patients. The observed differences between patients and controls on the acupoint stimulation task may also indicate that stimulation of acupoints used therapeutically to enhance recovery from stroke, selectively activates areas thought to be involved in mediating recovery from stroke via functional plasticity. fMRI of acupoint stimulation may illustrate the functional substrate of the therapeutically beneficial effect of acupuncture in stroke rehabilitation.

Spinal effects of acupuncture stimulation assessed by proton density-weighted functional magnetic resonance imaging at 0.2 T.

Signal changes can be detected by proton density-weighted functional imaging in both the brain and the spinal cord. These are attributed to changes in extravascular water proton (signal enhancement by extravascular protons) density during neuronal activation. In this study, we used this technique to detect correlations between acupoint stimulation and neural activity in the spinal cord. Stimulation of acupoints associated with treatment of sensorimotor deficits (LI4 and LI11) was performed on 11 volunteers. During stimulation, 8 of the 11 subjects had consistent functional activations in C6/C7. A bilateral activation pattern was common. Our findings show that acupoint stimulation modulates activity in the spinal cord.

Cortical activations upon stimulation of the sensorimotor-implicated acupoints.

Sixty-seven healthy right-handed subjects were studied using a 1.5-T MRI. Activations, which were absent during stimulation of the adjacent nonacupoints over the right arm or leg, were consistently seen over the right premotor area during stimulation of the sensorimotor-implicated acupoints over the left arm or leg. The left premotor area was also activated during stimulation of the arm or leg acupoints. The right precentral and postcentral gyri showed activations during stimulation of the arm acupoints. The volume and location of activations vary when different combinations of the arm acupoints were stimulated. Our results indicate the existence of sensorimotor-implicated acupoints as sensitive sites to obtain somatotopic activations over the sensory cortices with co-activation of the motor cortices.

Visual cortical activations on fMRI upon stimulation of the vision-implicated acupoints.

We used fMRI to reveal the visual cortical activations during conventional or electro-acupuncture over four vision-implicated acupoints in 18 healthy volunteers and compared the results with those obtained during direct visual stimulation. Positive activations were seen over the visual cortex during visual stimulation in all subjects, and similar activations were observed in 10 subjects during conventional acupuncture as well as in eight and seven subjects during electro-acupuncture at 2 and 20 Hz, respectively. Negative activations were also seen over the occipital lobes, temporal gyri and frontal gyri bilaterally in 13 subjects during conventional acupuncture. Thus, acupuncture may modulate the activity of relevant brain sites. Our results also suggest that electro-acupuncture is useful in future studies.

An fMRI study comparing brain activation between word generation and electrical stimulation of language-implicated acupoints.

We compared the brain activation on functional magnetic resonance imaging (MRI) during word generation with the activation during electrical stimulation of two language-implicated acupoints in 17 healthy, Mandarin-speaking, Chinese male volunteers (age 19-26 years). All subjects were strongly right handed according to a handedness inventory. Using a standard functional MRI procedure and a word-generation paradigm, significant activation was seen in the left and right inferior frontal gyri (BA 44, 45) as well as the left superior temporal gyrus (BA 22, 42). Stronger activation with a larger volume was seen in the left hemisphere. Electrical stimulation of either one of the two language-implicated acupoints, SJ 8 (11 subjects) and Du 15 (6 subjects), without the word-generation paradigm in the same cohort, produced significant activation in the right inferior frontal gyrus (BA 44, 46) and in the left and right superior temporal gyri (BA 22, 42), respectively. Nevertheless, no activation was seen in the left inferior frontal gyrus. In addition, electrical stimulation of the adjacent non-acupoints did not produce any significant brain activation. Although our results support the notion of acupoint-brain activation, applying acupuncture at SJ 8 or Du 15 does not activate the typical language areas in the left inferior frontal cortex.