Bae Hwan Lee

Neural substrates, experimental evidences and functional hypothesis of acupuncture mechanisms.

Objectives –  Athough acupuncture therapy has demonstrated itself to be effective in several clinical areas, the underlying mechanisms of acupuncture in general and the analgesic effect in particular are, however, still not clearly delineated. We, therefore, have studied acupuncture analgesic effect through fMRI and proposed a hypothesis, based on the obtained result, which will enlighten the central role of the brain in acupuncture therapy.

Injury in the spinal cord may produce cell death in the brain

Functional deficits after spinal cord injury have originated not only from the direct physical damage itself, but from the secondary biochemical and pathological changes. Apoptotic cell death has been seen around the periphery of an injured site and has been known to ultimately progress to necrosis and infarction. We have initiated the present study focusing on the role of apoptosis in the secondary injury of the brain after acute spinal cord injury (SCI), and conducted a series of experiments, the study examining the morphological changes in the brain following the spinal injury. Under pentobarbital anesthesia, male Sprague-Dawley rats were subjected to SCI model. Rats were laminectomized and SCI was induced using NYU spinal impactor at T9 segment. The behavioral test was performed. Electrophysiologically, motor evoked potentials (MEPs) were recorded. The animals were subjected to morphological study at 12, 24, 48, 72 h, and 1 week, postoperatively. Locomotor deficits were observed after SCI, and changes in the amplitudes and latencies of the MEPs were observed. The morphological changes were evidenced by terminal TUNEL staining and Calbindin-D(28K) immunohistochemistry. The TUNEL-positive cells were located at the brain motor cortex after SCI. TUNEL-positive cells were seldom found 4 h after injury. In addition, Calbindin-D28K immunoreactive neurons were observed in the motor cortex after injury. These results suggest that apoptosis may play an important role in the pathophysiology of the brain motor cortex following acute spinal cord injury and functions that were deteriorated after SCI may be related to these electrophysiological and morphological changes.

Dehydroascorbic acid prevents oxidative cell death through a glutathione pathway in primary astrocytes

Ascorbic acid (AA) is a well‐known antioxidant. It also has pro‐oxidant effects, however, in the presence of free transition metals. Because of the pro‐oxidant effects of AA, dehydroascorbic acid (DHA), an oxidized form of AA, has been used as a substitute for AA. DHA has been shown recently to have a protective effect in an experimental stroke model. This study was carried out to determine if DHA has different effects from AA on hydrogen peroxide (H2O2)‐induced oxidative cell death in primary astrocytes. DHA was found to prevent cell death and reverse mitochondrial dysfunction after exposure to H2O2. DHA significantly increased the glutathione peroxidase (GPx) and glutathione reductase (GR) activities 1 hr after H2O2 exposure. Moreover, DHA not only reversed the decrease in the glutathione (GSH) levels, but also significantly enhanced it by stimulating the pentose phosphate pathway (PPP) 15 hr after H2O2 exposure. DHA also reduced production of reactive oxygen species (ROS) after H2O2 exposure. In contrast, AA accelerated H2O2‐induced cell death. To determine if the pro‐oxidant effect of AA is related to iron, the effect of AA on cell death was examined using an iron chelator, desferrioxamine. Even though co‐pretreatment with AA and desferrioxamine could abrogate the aggravating effects of AA on H2O2‐induced cell death at early stages, it could not prevent H2O2‐induced cell death over a 24‐hr period. These results suggest that DHA has distinct effects from AA and prevent H2O2‐induced cell death by increasing the GSH levels mediated by the GPx and GR activities and PPP.

Microinjection of opiates into the periaqueductal gray matter attenuates neuropathic pain symptoms in rats.

&NA; We have previously demonstrated that electrical stimulation of the ventral periaqueductal gray matter (PAG) produced analgesia in neuropathic pain in rats. Opioids were also shown to be involved in analgesic effects. This study sought to determine whether opiates microinjected into the ventral PAG produce analgesia. Male Sprague–Dawley rats were chronically implanted with a guide cannula in the PAG under pentobarbital anesthesia and both the tibial and sural nerves were completely cut. Pain sensitivity was postoperatively measured with a von Frey filament and acetone applied to the sensitive area for 1 week. Opioids such as [D‐Ala2,N‐MePhe4,Gly(ol)5]‐enkephalin (DAMGO) and [D‐Pen2,D‐Pen5]‐enkephalin (DPDPE) were injected into the PAG. DAMGO, a γ‐opioid agonist, and DPDPE, a δ‐opioid agonist, were highly effective in reducing neuropathic pain. These effects were reversed by naloxone. These results suggest that the neurons in the ventral PAG are activated by opioids to produce analgesia and that specific opioid receptors are involved in the descending pain inhibition system from the PAG.

Changes in Cytokine Expression after Electroacupuncture in Neuropathic Rats

The production of proinflammatory cytokines including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) plays a key role in chronic pain such as neuropathic pain. We investigated changes in cytokine expression in injured peripheral nerves and dorsal root ganglia (DRG) following electroacupuncture (EA) treatment. Neuropathic pain was induced by peripheral nerve injury to the left hind limb of Sprague-Dawley rats under pentobarbital anesthesia. Two weeks later, the nerve-injured rats were treated by EA for 10 minutes. The expression levels of IL-1β, IL-6, and TNF-α in peripheral nerves and DRG of neuropathic rats were significantly increased in nerve-injured rats. However, after EA, the cytokine expression levels were noticeably decreased in peripheral nerves and DRG. These results suggest that EA stimulation can reduce the levels of proinflamtory cytokines elevated after nerve injury.

Supply chain model for the semiconductor industry in consideration of manufacturing characteristics

The semiconductor industry has a supply chain network that is distributed all over the world, and its manufacturing process has the particular characteristics that should be considered in supply chain modelling. In this paper we suggest an integrated mathematical model for the semiconductor industry supply chain consisting of production and distribution chains, where manufacturing re-entrancy, binning and substitution are considered. To achieve our objective, three policies for the production chain and two policies for the distribution chain with mathematical formulations are suggested. Six combination policies are tested for the evaluation of performances with an example motivated by a major semiconductor manufacturer in Eechon, South Korea. It is shown that the balance policy for the production chain and the pull policy for the distribution outperform other policies.

Behavioral Characteristics of a Mouse Model of Cancer Pain

Pain is a major symptom in cancer patients, and most cancer patients with advanced or terminal cancers suffer from chronic pain related to treatment failure and/or tumor progression. In the present study, we examined the development of cancer pain in mice. Murine hepatocarcinoma cells, HCa-1, were inoculated unilaterally into the thigh or the dorsum of the foot of male C3H/HeJ mice. Four weeks after inoculation, behavioral signs were observed for mechanical allodynia, cold allodynia, and hyperalgesia using a von Frey filament, acetone, and radiant heat, respectively. Bone invasion by the tumor commenced from 7 days after inoculation of tumor cells and was evident from 14 days after inoculation. Cold allodynia but neither mechanical allodynia nor hyperalgesia was observed in mice that received an inoculation into the thigh. On the contrary, mechanical allodynia and cold allodynia, but not hyperalgesia, were developed in mice with an inoculation into the foot. Sometimes, mirror-image pain was developed in these animals. These results suggest that carcinoma cells injected into the foot of mice may develop severe chronic pain related to cancer. This animal model of pain would be useful to elucidate the mechanisms of cancer pain in humans.

Antiallodynic effects produced by stimulation of the periaqueductal gray matter in a rat model of neuropathic pain

It has been well documented that there is opioid resistance in neuropathic pain. This indicates that the endogenous opioid system may not be involved effectively in modulating neuropathic pain. The present study sought to determine if activation of the descending pain inhibition system might produce analgesia in the animal neuropathic model we developed. Under ketamine anesthesia, male Sprague-Dawley rats were chronically implanted with stimulating electrodes in the ventral periaqueductal gray matter (PAG) and both the tibial and sural nerves of the sciatic nerve branches were severed. Pain sensitivity was measured with a von Frey filament and acetone applied to the sensitive area for 1 week postoperatively. Rats with neuropathic pain syndrome after transection of the tibial and sural nerves were tested as to the analgesic effects of ventral PAG stimulation for an additional two weeks. Electrical stimulation of the ventral PAG turned out to be highly effective in alleviating neuropathic pain. Mechanical allodynia and cold allodynia were reduced by PAG stimulation. Naloxone reversed the antiallodynic effects of ventral PAG stimulation. These results suggest that activation of the descending pain inhibition system including the ventral PAG reduces neuropathic pain syndrome and that opiates are involved in this system.

Antiallodynic Effects of Acupuncture in Neuropathic Rats.

Peripheral nerve injury often results in abnormal neuropathic pain such as allodynia or hyperalgesia. Acupuncture, a traditional Oriental medicine, has been used to relieve pain and related symptoms. However, the efficiency of acupuncture in relieving neuropathic pain is not clear. The aim of this study was to investigate the anti-allodynic effects of acupuncture through behavioral and electrophysiological examinations. Male Sprague-Dawley rats were subjected to neuropathic surgery consisting of a tight ligation and transection of the left tibial and sural nerves, under pentobarbital anesthesia. The acupuncture experiment consisted of four different groups, one treated at each of three different acupoints (Zusanli (ST36), Yinlingquan (SP9), and a sham-acupoint) and a control group. Behavioral tests for mechanical allodynia and cold allodynia were performed for up to two weeks postoperatively. Extracellular electrophysiological recordings were made from the dorsal roots using platinum wire electrodes. Mechanical and cold allodynia were significantly reduced after acupuncture treatment at the Zusanli and Yinlingquan acupoints, respectively. Electrophysiological neural responses to von Frey and acetone tests were also reduced after acupuncture at the same two acupoints. These results suggest that acupuncture may be beneficial in relieving neuropathic pain.

Effects of Human Mesenchymal Stem Cell Transplantation Combined with Polymer on Functional Recovery Following Spinal Cord Hemisection in Rats

The spontaneous axon regeneration of damaged neurons is limited after spinal cord injury (SCI). Recently, mesenchymal stem cell (MSC) transplantation was proposed as a potential approach for enhancing nerve regeneration that avoids the ethical issues associated with embryonic stem cell transplantation. As SCI is a complex pathological entity, the treatment of SCI requires a multipronged approach. The purpose of the present study was to investigate the functional recovery and therapeutic potential of human MSCs (hMSCs) and polymer in a spinal cord hemisection injury model. Rats were subjected to hemisection injuries and then divided into three groups. Two groups of rats underwent partial thoracic hemisection injury followed by implantation of either polymer only or polymer with hMSCs. Another hemisection-only group was used as a control. Behavioral, electrophysiological and immunohistochemical studies were performed on all rats. The functional recovery was significantly improved in the polymer with hMSC-transplanted group as compared with control at five weeks after transplantation. The results of electrophysiologic study demonstrated that the latency of somatosensory-evoked potentials (SSEPs) in the polymer with hMSC-transplanted group was significantly shorter than in the hemisection-only control group. In the results of immunohistochemical study, β-gal-positive cells were observed in the injured and adjacent sites after hMSC transplantation. Surviving hMSCs differentiated into various cell types such as neurons, astrocytes and oligodendrocytes. These data suggest that hMSC transplantation with polymer may play an important role in functional recovery and axonal regeneration after SCI, and may be a potential therapeutic strategy for SCI.