• Genes and Genomics
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• 제40권11호
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• pp.1149-1155
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• 2018

Epileptic encephalopathies are genetically heterogeneous disorders which leads to epilepsy and cause neurological disorders. Seizure threshold 2 (SZT2) gene located on chromosome 1p34.2 encodes protein mainly expressed predominantly in the parietal and frontal cortex and dorsal root ganglia in the brain. Previous studies in mice showed that mutation in this gene can confers low seizure threshold, enhance epileptogenesis and in human may leads to facial dysmorphism, intellectual disability, seizure and macrocephaly. Objective of this study was to find out novel gene or novel mutation related to the gene phenotype. We have identified a large consanguineous Saudi family segregating developmental delay, intellectual disability, epilepsy, high forehead and macrocephaly. Exome sequencing was performed in affected siblings of the family to study the novel mutation. Whole exome sequencing data analysis, confirmed by subsequent Sanger sequencing validation study. Our results showed a novel homozygous mutation (c.9368G>A) in a substitution of a conserved glycine residue into a glutamic acid in the exon 67 of SZT2 gene. The mutation was ruled out in 100 unrelated healthy controls. The missense variant has not yet been reported as pathogenic in literature or variant databases. In conclusion, the here detected homozygous SZT2 variant might be the causative mutation that further explain epilepsy and developmental delay in this Saudi family.

• The Korean Journal of Pain
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• 제34권1호
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• pp.4-18
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• 2021

Except for carbamazepine for trigeminal neuralgia, gabapentinoid anticonvulsants have been the standard for the treatment of neuropathic pain. Pregabalin, which followed gabapentin, was developed with the benefit of rapid peak blood concentration and better bioavailability. Mirogabalin besylate (DS-5565, Tarlige®) shows greater sustained analgesia due to a high affinity to, and slow dissociation from, the α2δ-1 subunits in the dorsal root ganglion (DRG). Additionally, it produces a lower level of central nervous system-specific adverse drug reactions (ADRs), due to a low affinity to, and rapid dissociation from, the α2δ-2 subunits in the cerebellum. Maximum plasma concentration is achieved in less than 1 hour, compared to 1 hour for pregabalin and 3 hours for gabapentin. The plasma protein binding is relatively low, at less than 25%. As with all gabapentinoids, it is also largely excreted via the kidneys in an unchanged form, and so the administration dose should also be adjusted according to renal function. The equianalgesic daily dose for 30 mg of mirogabalin is 600 mg of pregabalin and over 1,200 mg of gabapentin. The initial adult dose starts at 5 mg, given orally twice a day, and is gradually increased by 5 mg at an interval of at least a week, to 15 mg. In conclusion, mirogabalin is anticipated to be a novel, safe gabapentinoid anticonvulsant with a greater therapeutic effect for neuropathic pain in the DRG and lower ADRs in the cerebellum.

• The Korean Journal of Pain
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• 제35권4호
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• pp.391-402
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• 2022

Background: The mechanism of peripheral axon transport in neuropathic pain is still unclear. Chemokine ligand 13 (CXCL13) and its receptor (C-X-C chemokine receptor type 5, CXCR5) as well as GABA transporter 1 (GAT-1) play an important role in the development of pain. The aim of this study was to explore the axonal transport of CXCL13/CXCR5 and GAT-1 with the aid of the analgesic effect of botulinum toxin type A (BTX-A) in rats. Methods: Chronic constriction injury (CCI) rat models were established. BTX-A was administered to rats through subcutaneous injection in the hind paw. The pain behaviors in CCI rats were measured by paw withdrawal threshold and paw withdrawal latencies. The levels of CXCL13/CXCR5 and GAT-1 were measured by western blots. Results: The subcutaneous injection of BTX-A relieved the mechanical allodynia and heat hyperalgesia induced by CCI surgery and reversed the overexpression of CXCL13/CXCR5 and GAT-1 in the spinal cord, dorsal root ganglia (DRG), sciatic nerve, and plantar skin in CCI rats. After 10 mmol/L colchicine blocked the axon transport of sciatic nerve, the inhibitory effect of BTX-A disappeared, and the levels of CXCL13/CXCR5 and GAT-1 in the spinal cord and DRG were reduced in CCI rats. Conclusions: BTX-A regulated the levels of CXCL13/CXCR5 and GAT-1 in the spine and DRG through axonal transport. Chemokines (such as CXCL13) may be transported from the injury site to the spine or DRG through axonal transport. Axon molecular transport may be a target to enhance pain management in neuropathic pain.

• Korean Journal of Acupuncture
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• 제39권4호
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• pp.132-141
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• 2022

Objectives : Some acupoints are commonly utilized to treat a variety of diseases. The acupoints appear to have a wide range of effects caused by several mechanisms. The purpose of this study is to investigate into the potential role of microRNAs (miRNAs) in the multipotent effects of individual acupoint stimulation. Methods : We examined the miRNA expressions in the dorsal root ganglia (DRG) of neuropathic or inflammatory pain rats following ST36 and GB34 electroacupuncture (EA) stimulation. Neuropathic pain was induced by L5 spinal nerve ligation. Inflammatory pain was induced by knee joint injection of Complete Freund's adjuvant (CFA). EA was given under gaseous anesthesia with the same parameters (1mA, 2Hz, 30 min) in 5 consecutive days. Pain behaviors and miRNA expressions were analyzed. Results : In rats with neuropathic and inflammatory pain, EA treatments significantly enhanced the paw withdrawal threshold and weight-bearing force. After nerve injury, 36 miRNAs were upregulated in the DRG of neuropathic rats, while EA downregulated 10 of them. Furthermore, 14 miRNAs were downregulated following nerve damage, while one was increased by EA. 15 miRNAs were increased in the DRG of inflammatory rats following CFA injection, while 5 were downregulated by EA. Furthermore, 17 miRNAs were downregulated following CFA injection, while 7 were increased by EA. The miRNAs rno-miR-335, rno-miR-381-5p, rno-miR-1306-3p, and rno-miR-1839-3p were regulated by EA in both models. Conclusions : In two pain models, EA applied to ST36 and GB34 regulated miRNA expression differently. There appeared to be both acupoint-specific and non-specific miRNAs, and miRNA regulation of differential protein expression may modulate a variety of EA mechanisms.

• The Korean Journal of Pain
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• 제33권1호
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• pp.23-29
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• 2020

Background: Neuropathic pain (NP) is considered a clinically incurable condition despite various treatment options due to its diverse causes and complicated disease mechanisms. Since the early 2000s, multipotent human mesenchymal stem cells (hMSCs) have been used in the treatment of NP in animal models. However, the effects of hMSC injections have not been studied in chronic post-ischemia pain (CPIP) mice models. Here, we investigated whether intrathecal (IT) and intrapaw (IP) injections of hMSCs can reduce mechanical allodynia in CPIP model mice. Methods: Seventeen CPIP C57/BL6 mice were selected and randomized into four groups: IT sham (n = 4), IT stem (n = 5), IP sham (n = 4), and IP stem (n = 4). Mice in the IT sham and IT stem groups received an injection of 5 μL saline and 2 × 10⁴ hMSCs, respectively, while mice in the IP sham and IP stem groups received an injection of 5 μL saline and 2 × 10⁵ hMSCs, respectively. Mechanical allodynia was assessed using von Frey filaments from pre-injection to 30 days post-injection. Glial fibrillary acidic protein (GFAP) expression in the spinal cord and dorsal root ganglia were also evaluated. Results: IT and IP injections of hMSCs improved mechanical allodynia. GFAP expression was decreased on day 25 post-injection compared with the sham group. Injections of hMSCs improved allodynia and GFAP expression was decreased compared with the sham group. Conclusions: These results suggested that hMSCs may be also another treatment modality in NP model by ischemia-reperfusion.

• The Korean Journal of Pain
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• 제33권2호
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• pp.99-107
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• 2020

Chronic severe pain results in a detrimental effect on the patient's quality of life. Such patients have to take a large number of medications, including opioids, often without satisfactory effect, sometimes leading to medication abuse and the pain worsening. Spinal cord stimulation (SCS) is one of the most effective technologies that, unlike other interventional pain treatment methods, achieves long-term results in patients suffering from chronic neuropathic pain. The first described mode of SCS was a conventional tonic stimulation, but now the novel modalities (high-frequency and burst), techniques (dorsal root ganglia stimulations), and technical development (wireless and implantable pulse generator-free systems) of SCS are becoming more popular. The improvement of SCS systems, their miniaturization, and the appearance of new mechanisms for anchoring electrodes results in a significant reduction in the rate of complications and revision surgeries, and the appearance of new waves of stimulation allows not only to avoid the phenomenon of addiction, but also to improve the long-term results of chronic SCS. The purpose of this review is to describe the current condition of SCS and up-to-date technical advances.

• 대한한방내과학회지
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• 제33권2호
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• pp.126-144
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• 2012

Background : Peripheral nerves more rapidly recover than central nerves. However, it has been known that the degree of reaction of axons of peripheral nerves is affected by distinctive characteristics of axons and environmental factors near the axons. Taxol is a widely used medicine as for ovarian, breast, lung and gastric cancer. However it causes patients difficulties under treatment due to its toxic and side effects, which include persistent pain. Objectives : This study reviewed how SJT extract in vitro and in vivo affects nerve tissues of a sciatic nerve damaged by Taxol. It also studied how SJT extract in vivo affects axons of the sciatic nerve after the sciatic nerve was damaged by pressing. Methods : After vehicle, Taxol, and Taxol plus SJT were treated respectively for tissue of the sciatic nerve in vitro and then tissues were observed using Neurofilament 200, Hoechst, ${\beta}$-tubulin, $S100{\beta}$, caspase-3 and anti-cdc2. SJT was also oral medicated by injecting Taxol into the sciatic nerve of in vivo rats. Tissues of the sciatic nerve and axons of DRG sensory nerves were then observed using Neurofilament 200, Hoechst, ${\beta}$-tubulin, $S100{\beta}$, caspase-3 and p-Erk1/2. After inflicting pressing damage to the sciatic nerve of in vivo rats, tissues of the sciatic nerve and DRG sensory nerve were observed using Neurofilament 200, Hoechst, $S100{\beta}$, caspase-3, anti-cdc2, phospho-vimentin, ${\beta}1$-integrin, Dil reverse tracking and p-Erk1/2. Results : The group of in vitro Taxol plus SJT treatment had meaningful effects after sciatic nerve tissue was damaged by Taxol. The group of in vivo SJT treatment had effects of regenerating Schwann cells and axons which were damaged by Taxol treatment. The group of in vivo SJT had effects of regenerating axons in damaged areas after the sciatic nerve was damaged by pressing, and also had variations of distribution in Schwann cells at DRG sensory nerves and axons. Conclusions : This study confirmed that SJT treatment is effective for growth of axons in the sciatic nerve tissues and improvement of Schwann cells after axons of the sciatic nerve tissues was damaged. After tissues of sciatic nerve was damaged by pressing in vivo, SJT treatment had effects on promoting regeneration of axon in the damaged area and reactional capabilities in axons of DRG sensory nerves.

• 대한수의학회지
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• 제25권2호
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• pp.103-112
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• 1985

국내에서 분리된 enterovirus의 병원성을 관찰하기 위하여 1~2일령의 자돈 10두와 35일 령의 유돈 6두에 enterovirus 조직배양부유액을 뇌내 또는 근육내 주사한 후 임상 및 병리학적으로 관찰하였던 바 다음과 같은 결과를 얻었다. 임상적으로는 체온의 상승, 보양창랑, 보행실조, 유약성 마비 및 고도의 삭수가 관찰되었다. 병리조직학적으로는 중추신경계 전반에 걸쳐 수막하 세포침윤, 혈관주위 원형세포침윤, 신경세포의 변성, 미만성과 한국성 gliosis, glial nodule의 형성 등이 관찰되었으며 백질부보다 회백질부에서 다소 심한 경향이었고 배측 신경절염이 전 실험예에서 인정되었다. 한편 hog cholera백신과 enterovirus의 공동주사예에서는 중추신경계의 병변이 enterovirus 단독주사예에 비해 급격히 진행되는 경향이었다. 이상의 소견들을 종합해 볼때 국내에서 분리된 enterovirus는 뇌내 또는 근육내에 접종하였을 때 자돈에서 polioencephalomyelitis를 일으킬 수 있는 병원성이 강한 형으로 추측되며 hog cholera백신과 enterovirus를 공동주사한 예에서 병변의 진행이 급격한 점으로 보아 enterovirus의 자연감염에 hog cholera 백신 등의 stress요인이 작용될 것으로 추측된다.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제31권3호
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• pp.199-218
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• 2005

Purpose of Study: Peripheral nerve regeneration depends on neurotrophism of distal nerve stump, recovery potential of neuron, supporting cell like Schwann cell and neurotrophic factors such as BDNF. Peripheral nerve regeneration can be enhanced by the conduit which connects the both sides of transected nerve. The conduit maintains the effects of neurotrophism and BDNF produced by Schwann cells which can be made by gene therapy. In this study, we tried to enhance the peripheral nerve regeneration by using calcium phosphate coated porous conduit and BDNF-Adenovirus infected Schwann cells in sciatic nerve of rats. Materials and Methods: Microporous filter which permits the tissue fluid essential for nerve regeneration and does not permit infiltration of fibroblasts, was made into 2mm diameter and 17mm length conduit. Then it was coated with calcium phosphate to improve the Schwann cell adhesion and survival. The coated filter was evaluated by SEM examination and MTT assay. For effective allogenic Schwann cell culture, dorsal root ganglia of 1-day old rat were extracted and treated with enzyme and antimitotic Ara-C. Human BDNF cDNA was obtained from cDNA library and amplified using PCR. BDNF gene was inserted into adenovirus shuttle vector pAACCMVpARS in which E1 was deleted. We infected the BDNF-Ad into 293 human mammary kidney cell-line and obtained the virus plaque 2 days later. RT-PCR was performed to evaluate the secretion of BDNF in infected Schwann cells. To determine the most optimal m.o.i of BDNF-Ad, we infected the Schwann cells with LacZ adenovirus in 1, 20, 50, 75, 100, 250 m.o.i for 2 hours and stained with ${\beta}$-galactosidase. Rats(n=24) weighing around 300g were used. Total 14mm sciatic nerve defect was made and connected with calcium phosphate coated conduits. Schwann cells$(1{\times}10^6)$ or BDNF-Ad infected Schwann cells$(1{\times}10^6)$ were injected in conduit and only media(MEM) was injected in control group. Twelve weeks after surgery, degree of nerve regeneration was evaluated with gait analysis, electrophysiologic measurements and histomorphometric analysis. Results: 1. Microporous Millipore filter was effective conduit which permitted the adhesion of Schwann cells and inhibited the adhesion of fibroblast. We could enhance the Schwann cell adhesion and survival by coating Millipore filter with calcium phosphate. 2. Schwann cell culture technique using repeated treatment of Ara-C and GDNF was established. The mean number of Schwann cells obtained 1 and 2 weeks after the culture were $1.54{\pm}4.0{\times}10^6$ and $9.66{\pm}9.6{\times}10^6$. 3. The mRNA of BDNF in BDNF-Ad infected Schwann cells was detected using RT-PCR. In Schwann cell $0.69\;{\mu}g/{\mu}l$ of DNA was detected and in BDNF-Adenovirus transfected Schwann cell $0.795\;{\mu}g/{\mu}l$ of DNA was detected. The most effective infection concentration was determined by LacZ Adenovirus and 75 m.o.i was found the most optimal. Conclusion: BDNF-Ad transfected Schwann cells successfully regenerated the 14mm nerve gap which was connected with calcium phosphate coated Millipore filter. The BDNF-Ad group showed better results compared with Schwann cells only group and control group in aspect to sciatic function index, electrophysiologic measurements and histomorphometric analysis.

• 고려인삼학회:학술대회논문집
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• 고려인삼학회 1988년도 학술대회지
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• pp.92-98
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• 1988

본 연구는 중앙대서전에 인삼의 주 효과중 건망증 방지작용이라고 수록되어 있는 것을 확인하기 위하여 행하여졌다. Step through 시험에서 $GRb_1$과 $GRg_1$은 기억력 획득을 용이하게 하였으며 전기충격 쇼크에 의해 야기되는 기억상실 효과를 억제하였다. 게대가 $Rg_1$은 에타놀 야기 기억재생 저해작용을 방지하였다. Stepdown test에 있어서 $Rb_1,\;Rb_2,\;Rg_1$은 전기충격쇼크에 의해 야기되는 기억보지 저해효과를 방지하였다. 또한 $Rg_1$은 에타놀에 의해 야기되는 기억재생 저해효과를 방지하였으며 단기적 기억력 획득을 용이케 하였다. Shuttle box와 lever press 시험에서도 $Rb_1$을 제외하고 나머지는 기억획득과 재생에 효과를 미치지 못했다. $Rb_1$은 shuttle box 시험에서 조건회피반응의 재생 (retrieval)을 억제하였다. 이와 같은 4가지 시험이 끝난후에 인삼의 구강투여가 진정, 진통, 해열, 진경효과와 자발 및 탐색활동에 미치는 영향을 500 mg/kg 투여 범위내에서 조사하였으나 아무런 반응도 관찰되지 않았다. 현재까지 연구결과는 $Rg_1$이 기억의 재생 및 학습반응의 획득과정에 대하여 효과가 있다는 것을 의미한다. 최근의 신경성장인자(NGF)가 성숙동물에 있어 뇌신경세포의 생존, 재생 및 조절에 미치는 작용에 관한 연구결과는 지능장해와 건망증에 대한 신경성장인자의 중요성을 시사했다. NGF에 의해 야기된 신경세포돌기 성장의 특이성에 관한 연구결과를 병아리 배배근 신경절에 있어서 NGF의 영향은 $Rh_1$에 의해 증가되었다. 다음으로 $Rb_1$은 병아리 배의 감각 및 교감신경단위에 있어서 NGF-관련 신경섬유 증가를 강화시켰다. NGF와 $Rb_1$을 함께 했을 때도 역시 쥐 대뇌피질의 신경세포 생존수를 증가시키는 경향을 보였다. NGF는 쥐의 배격부 부근의 신경세포를 배양했을 때 cholineacetyl transferase 활성을 증가시키지 않았다. 이러한 결과로 $Rb_1$은 뇌에 있어서 신경세포의 생존이나 재생에 중요한 역활을 한다는 것은 알 수 있었다.