궁둥신경 결찰로 유발된 통증에 미치는 minocycline의 작용

구은영(Eun Young Gu),한형수(Hyung Soo Han),박재식(Jae-Sik Park) 대한해부학회 2004 Anatomy & Cell Biology Vol.37 No.4

신경이 손상을 받으면 신경병증 통증이 지속적으로 나타나게 된다고 알려져 있다. 최근의 연구에 의하면 이러한 통증 발생이 미세아교세포(microglia)의 증식과 관련이 있다고 알려져 있다. 한편, 항생제로 사용되고 있는 minocycline은 중추신경손상시 활성화되는 미세아교세포의 증식을 억제하는 물질로 알려져 있고 여러 질병에 실험적으로 사용되어왔다. 하지만 말초신경의 손상에 의한 신경병증 통증에 대한 작용은 잘 알려져 있지 않다. 본 실험에서는 궁둥신경(sciatic nerve)에 손상을 일으킨 후 통각 및 미세아교세포의 증식이 시간이 경과함에 따라 어떻게 변하는지 관찰하여 보았다. 또 minocycline을 투여하여 통각 및 미세아교세포 증식에 미치는 영향을 연구하였다. 실험동물은 수컷 Sprague-Dawley (150~180 g)를 ketamine (60 mg/kg)과 xylazine (7 mg/kg)을 주사하여 마취한 뒤 왼쪽다리 넓적다리의 궁둥신경을 chromic실로 느슨하게 묶어 신경손상을 주었다. 통각을 검사하기 위해 실험동물의 뒷발바닥에 온각, 냉각 그리고 기계적 감각을 가하여 그 반응을 측정하였다. 행동실험은 수술 전, 수술 후 1, 4, 7, 10일에 시행되었으며 행동실험이 끝난 동물에서 L4~6 척수를 분리하여 미세아교세포 활성화 표지인 ED1 항체로 면역조직화학염색법에 이용하였다. Minocycline (50 mg/kg)은 마지막 행동실험이 끝날 때까지 매일 경구 투여하였는데 수술 전에 투여를 시작한 군과 수술 후 1, 3, 그리고 5일이 지나서 투약을 시작하는 군으로 나누어 투여시기에 따른 차이를 비교하였다. 신경성 통각에 대한 실험에서 궁둥신경 수술 후 4일부터 온각, 냉각, 기계적 자극에 대한 역치가 상승하였으며 10일째에 가장 강한 통각을 나타냈다. Minocycline을 수술 전부터 투여한 경우 통각 역치의 변화가 없거나 진통작용이 일어났는데 이런 효과는 약물 투여를 수술 후 1일 또는 3일에 시작하였을 때에는 볼 수 있었으나 5일에 시작한 경우에는 볼 수 없었다. 활성화된 미세아교세포 수의 변화는 통각의 변화와 경시적으로 일치하였다. 또 minocycline 처치는 미세아교세포 활성화를 효과적으로 억제하였다. Nerve injury leads to chronic neuropathic pain syndromes. Activation of microglia has been studied to investigate the role in pain development. Minocycline is known as a potent inhibitor of microglial activation in many types of the brain injury models. But it is not known whether minocycline interferes with pain and microglial activation after the peripheral nerve injury. In this study, we investigated the time course of pain and microglial activation after sciatic nerve injury and also tested the effect of minocycline using sciatic nerve ligation model. All experiments were performed using 150~180 g male Sprague-Dawley rats. The chronic constriction injury (CCI) of the sciatic nerve with four 4.0 chromic gut suture was used to induce neuropathic pain in the left sciatic nerve. The behavioral response of rats to the stimuli (heat, cold & pressure) was assessed by measuring the lifting of the foot and the avoidance of touching the floor at pre-surgical day 1, post-surgical day 1, 4, 7, and 10. The L4~6 spine was fixed and used to detect microglia. Oral minocycline (50 mg/kg) was administered daily to the last day of the experiment. Minocycline was administered to one group of rats from pre-surgical day 1 and minocycline treatment was initiated from post-surgical day 1, 3, and 5 in other groups. Neuropathic pain was evident from day 4 and the peak response was observed at 10 days after CCI. Minocycline significantly attenuated neuropathic pain even when treatment was delayed by 3 days. But, it had no effet when treatment initiated 5 days after injury. Minocycline also attenuated microglial activation. In summary, a correlation was evident between the neuropathic pain and microglial activation in our model and minocycline reduced both development of pain and microglial activation. Thus, minocycline can be a good candidate for the treatment of neuropathic pain. However, the administration should be initiated prior to microglial activation.

P027 Pulsed dye laser treatment combined with oral minocycline for more than 4 weeks reduces recurrence rate of rosacea

( Hye Soo Ko ),( Hee Seong Yoon ),( Si Hyub Lee ),( Seung Dohn Yeom ),( Young Ju Suh ),( Ji Won Byun ),( Gwang Seong Choi ),( Jeonghyun Shin ) 대한피부과학회 2016 대한피부과학회 학술발표대회집 Vol.68 No.2

<div style="display:none">fiogf49gjkf0d</div><div style="display:none">fiogf49gjkf0d</div><div style="display:none">fiogf49gjkf0d</div><div style="display:none">fiogf49gjkf0d</div><div style="display:none">fiogf49gjkf0d</div><div style="display:none">fiogf49gjkf0d</div><div style="display:none">fiogf49gjkf0d</div> Background: Minocycline is one of the most commonly used agents for treatment of rosacea. Pulsed dye laser (PDL) has been suggested to be used adjunctively with oral and topical rosacea regimens for more effective symptom resolution. However, it is not known which treatment method can reduce the recurrence of rosacea effectively. Objectives: The primary objective was to identify whether 595nm-PDL treatment reduced recurrent rate among rosacea patients who were treated with oral minocycline. The secondary objective was to evaluate that the factors such as sex, age, rosacea type, topical agents, and the treatment duration with oral minocycline were associated with the hazard of recurrence of rosacea. Methods: 107 Korean patients with rosacea who started treatment with oral minocycline (100mg per day) with or without 595nm-PDL (total 2-4 sessions) between January 2013 and May 2015 were evaluated retrospectively. The follow-up period was 1 year from the end of the treatment. Results: The recurrence-free survival analysis revealed that the group with oral minocycline plus PDL was significantly different compared with the group with oral minocycline alone. Treatment of oral minocycline for 4 or less weeks without PDL remained a statistically significant risk factor compared with treatment of oral minocycline for more than 4 weeks with PDL. Conclusion: Pulsed dye laser can be used in combination with oral minocycline for more than 4 weeks to reduce relapses of rosacea.

실험 : 신생 흰쥐의 산소유발성 망막증에서 항세포사멸사를 통한 Minocycline의 망막 보호효과

장윤영 ( Yoon Young Jang ),서억수 ( Eok Soo Suh ),김우택 ( Woo Taek Kim ) 대한주산의학회 2010 大韓周産醫學會雜誌 Vol.21 No.1

목적: 미숙아망막병증은 고농도 산소 투여를 받은 미숙아에서 망막에 비정상적인 신생혈관이 생기는 경우로 근래는 적절한 산소 농도 조절로 많이 감소했다가 최근 다시 신생아학 발달로 미숙아 생존이 높아짐으로 증가하고 있다. 신생혈관은 육아 조직을 동반하여 유리체 내로 들어가 섬유조직으로 변하면서 망막을 견인하여 망막을 박리하며, 심한 경우 시력이 완전 소실된다. 주요 선행인자로 미성숙과 산소치료, 산혈증, 고이산화탄소혈증, 수혈, 비타민 E 결핍, 빛 등이 알려져 있으며, 혈관 미성숙의 정도, 산소투여기간 및 산소농도 등이 매우 중요하게 작용하고 있다. 이에 연구자는 신생 흰쥐을 이용하여 생체 내·외 산소유발성 망막병증을 유발하고, 미숙아망막증의 항세포사멸사 기전을 통한 minocycline 의 망막 보호 효과를 알아보고자 하였다. 방법: 생체내 산소유발성 망막증은 생후 1일째의 신생 흰쥐를 생후 2주까지 24시간 주기로 고산소와 정상산소(산소분압 80%와 21%) 환경에 교대로 노출시킨 후(H군, HM군) 정상산소 환경으로 옮겨 사육하였고, 대조군(N군)은 정상산소 환경에서 사육하였다. Minocycline (HM군) 약물을 1주일간씩 투여하였고 생후 3주째 동물을 희생시켜 망막내 신경세포들의 형태학적 변화는 H&E 염색법을 이용하여 전자현미경으로 살펴보았다. 생체외 산소유발성 망막증은 재태기간 0-2일된 신생 흰쥐의 망막세포를 추출하여 정상산소군(N군)은 5% 이산화탄소 배양기에 두고, 고산소군(H군)과 minocycline(HM군) 약물을 투여한 군은 5% 이산화탄소 배양기내 100% 산소 용기에 두어 산소에 의한 망막세포 손상을 유발하였다. 동물모델 및 세포배양 모두 세포사멸사와 관련된 Bcl-2, Bax, caspase-3 항체 및 primer를 이용하여 Western blotting과 실시간 중합효소연쇄반응을 시행하였다. 결과: 산소유발성 망막증의 생체내·외 실험에서 Western blotting 및 실시간 중합효소연쇄반응을 실시한 결과로 Bcl-2, Bax, caspase-3의 발현은 고산소군보다 minocycline을 투여한 군에서 Bcl-2는 증가, Bax 및 caspase-3는 감소하였다. 결론: 본 연구에서 minocycline은 항세포사멸사 기전을 통하여 미숙아망막병증에서 나타나는 비정상적인 혈관 신생을 보호하는 것을 알 수 있었다. Purpose: Retinopathy of prematurity (ROP) is a leading cause of blindness with retinal detachment due to oxygen toxicity in preterm infants. Recently advances in neonatal care had to led improved survival rates in premature infants and ROP re-emerged as a significant clinical problem. In the present study, we aimed to determine the protective abilities of minocycline in a animal model of ROP and a primary retinal cell cultures of neonatal rat via anti-apoptotic actions using Western blotting and real-time PCR with Bcl-2, Bax and caspase-3 antibodies and mRNAs. Methods: In the in vivo oxygen-induced retinopathy (OIR), the cyclic hyperoxia was performed that 80% O2 for 1 day and 21% O2 for 1 day from P1-14 of newborn rats. Minocycline was injected intravitreously for 7 days and sacrificed at P21. In the in vitro OIR, primary retinal cell culture was done using P0-P2 SD rats. Hyperoxia injury was done for 100% O2 exposure for 6 hours. Western blotting and real-time PCR using Bcl-2, Bax and caspase-3 antibody and primer were done in the rat model of ROP and the dispersed retinal cell culture. To identify photoreceptors of retinal cells the immunofluorescence assay photoreceptor marker, IRBP, was used. Results: In the in vivo OIR, the expression of Bcl-2 antibody and mRNA was increased and those of Bax and caspase-3 were reduced in the minocycline-treated group. In the in vitro OIR, the result was the same as above. Conclusion: In conclusion, minocycline was suggested to have retinal protective effects for hyperoxic injury via anti-apoptotic mechanism.

Pulsed Dye Laser Treatment Combined with Oral Minocycline Reduces Recurrence Rate of Rosacea

( Hye Soo Ko ),( Young Ju Suh ),( Ji Won Byun ),( Gwang Seong Choi ),( Jeonghyun Shin ) 대한피부과학회 2017 Annals of Dermatology Vol.29 No.5

Background: The recurrence rate of rosacea was not known very well, but has been reported as 60% in 6 months after withdrawal of the drug. It is not known which treatment can reduce relapses of rosacea effectively. Objective: The objective was to identify whether 595 nm-pulsed dye laser (PDL) treatment reduced recurrence rate among rosacea patients who were treated with oral minocycline. Methods: One hundred and seven Korean patients with rosacea who started treatment with oral minocycline (100 mg/d) with or without PDL (2∼4 sessions) were evaluated retrospectively. The recurrence rate was estimated using the Kaplan-Meier method, and difference was evaluated using the log-rank test. Cox proportional hazards model was used to estimate hazard ratios and 95% confidence intervals (CIs) of risk factors for the recurrence of rosacea. Results: The recurrencefree survival analysis revealed that the group with oral minocycline plus PDL was significantly different compared with the group with oral minocycline alone (p=0.011). Cox proportional hazards model showed that the combined use of PDL with oral minocycline appeared to be a significant protective factor for the hazard of recurrence of rosacea (hazard ratio, 0.492; 95% CI, 0.257∼0.941; p=0.032). Conclusion: PDL can be used added to oral minocycline to reduce relapses among rosacea patients who are undergoing oral minocycline treatment. (Ann Dermatol 29(5) 543∼547, 2017)

Minocycline-induced Periarticular Black Bones in Inflamed Joints Which Underwent Arthroplastic Reconstruction

Suran Yang,Yuya Takakubo,Shinji Kobayashi,Tamon Asano,Akiko Sasaki,Kan Sasaki,Hiroharu Ohki,Yasunobu Tamaki,Michiaki Takagi 대한정형외과학회 2012 Clinics in Orthopedic Surgery Vol.4 No.3

Background: Minocycline-induced pigmentation of bone (black bone) is well described in tooth-bearing intra-oral bone, but is less known in periarticular bone in patients who have undergone total joint arthroplasty. On a retrospective basis, we investigated the short-term clinico-radiological results of total joint arthroplasties in which the patient developed minocycline-induced periarticular black bone. Methods: We found 5 cases (0.08%), in 4 patients, of periarticular bone pigmentation revealed during total joint arthroplasties (2 hips, 2 knees, and 1 ankle) in our series of total joint surgeries (6,548 cases) over a 10-year time period in our 3 institutes. Their mean age was 56 years at surgery. All patients had received long-term minocycline treatment. Mean dosage and duration of minocycline was 160 mg/day and 2.2 years, respectively. Minocycline had been prescribed for reactive arthritis (one), rheumatoid arthritis (two) and late infection after total joint arthroplasty (two patients). Mean follow-up period was 3.4 years after the surgeries. Results: All cases had black or brown pigmentation in the periarticular bones during the surgery. There was no pigmentation in the cartilage or soft tissues of the joints. The mean Japanese Orthopaedic Association (JOA) score or Japanese Society for Surgery of the Foot (JSSF) scale for rheumatoid arthritis foot and ankle joints at latest follow-up (case 1, 66; case 2, 87; case 3, 77; case 4, 77; case 5, 80) improved compared to those of pre-surgery (case 1, 47; case 2, 45; case 3, 55; case 4, 34; case 5, 55). No implant loosening was noted on radiographic examination during the follow-up period. No abnormal bone formation, bone necrosis, hemosiderin deposition, malignancy or metallic debris was found on histological examination. Conclusions: No clinico-radiological symptoms of total joint arthroplasties showed in the patients with minocycline-induced periariticular black bone in the short-term. Systemic minocycline treatment has the potential to induce significant black pigmentation of many tissues. In particular, minocycline-induced pigmentation of periarticular bone may be accelerated by inflammation due to rheumatic or pyogenic arthritis. Surgeons should recognize the risk of bone pigmentation in inflamed joints due to the systemic treatment of minocycline and explore its influence on periarticular bone and total joint arthroplasty in the long-term.

저산소 상태로 유도된 백서 뇌세포 배양에서 Minocycline의 뇌보호 효과

하경아,양범석,김진경,김홍태,하성진,이종원,정혜리,김우택,Ha, Kyung A,Yang, Bum Seok,Kim, Jin Kyung,Kim, Hong Tae,Ha, Sung Jin,Lee, Jong Won,Chung, Hai Lee,Kim, Woo Taek 대한소아청소년과학회 2003 Clinical and Experimental Pediatrics (CEP) Vol.46 No.11

목 적 : 미노사이클린이 in vivo 연구에서 뇌보호 효과가 있는것으로 알려져 있어 본 연구에서는 미노사이클린이 저산소 상태로 유발된 백서 뇌세포 배양에서 고사를 억제하는 뇌보호 효과가 있는지를 알아보고자 하였다. 방 법: 임신 18일된 백서의 대뇌피질 신경세포를 배양하여 정상산소 상태군과 저산소 상태군으로 두 군으로 나누고, 정상산소 상태는 5% $CO_2$ 배양기에, 저산소 상태는 1% $CO_2$ 배양기에서 세포 수를 세면서 수일간 처리하여 현미경하에서 충분한 손상이 있다고 판단되면 두 군을 각각 대조군, 미노사이클린 $1{\mu}g/mL$, $10{\mu}g/mL$로 처리한 군으로 나누어서 실험하였다. TUNEL 및 DAPI 염색으로 세포 고사 상태를 통계학적으로 처리하였다. 결 과: 정상산소 상태군에서 대조군과 미노사이클린 $1{\mu}g/mL$ 투여군, 미노사이클린 $10{\mu}g/mL$ 투여군 3군 모두에서 통계학적으로 유의한 차이가 있었다(P<0.01). 저산소 상태군에서 대조군과 미노사이클린 투여군에서 통계학적으로 유의한 차이가 있었으나(P<0.01), 미노사이클린 투여군 간에는 통계학적으로 유의한 차이가 없었다(P>0.05). 정상산소 상태군과 저산소 상태군간의 대조군과 미노사이클린 $1{\mu}g/mL$ 투여군의 비교에서는 정상산소 상태군이 저산소 상태군보다 평균이 낮아 통계학적으로 유의한 차이가 있었다(P<0.01). 정상산소 상태군과 저산소 상태군간의 미노사이클린 $10{\mu}g/mL$ 투여군의 비교에서는 정상산소 상태군이 저산소 상태군보다 다소 평균이 낮았으나 통계학적으로 유의성은 없었다(P>0.05). 결 론 : 결론적으로 미노사이클린은 고사를 억제하는 기전으로 저 산소 상태나 정상 산소 상태에서 뇌보호 효과가 있었다. Purpose : In vivo, minocycline appears to be neuroprotective. Thus, the neuroprotective effects of minocycline were studied in a rat brain cortical cell culture induced by hypoxia. Methods : Cultured cells from the brains of Sprague-Dawley rats were divided into two sets of groups : normoxia groups treated with 5% $CO_2$ and hypoxia groups treated with 1% $CO_2$. After several days of incubation, the control groups were not treated with minocycline, while the sample groups were treated with either 1 or $10{\mu}g/mL$ of minocycline. The damaged cells were observed under a microscope, while apoptosis was detected using a TUNEL assay control-stained with DAPI. Results : Among the normoxia groups, the control and sample groups treated with 1 and $10{\mu}g/mL$ of minocycline were all statistically significantly different from each other. Meanwhile, among the hypoxia groups, although the control was significantly different from the sample groups, there was no statistically significant difference between the sample groups. When comparing the normoxia and hypoxia groups, there was a statistically significant difference between the control groups and sample groups treated with $1{\mu}g/mL$ of minocycline, yet no significant difference between the sample groups treated with $10{\mu}g/mL$ of minocycline. Conclusion : Minocycline was found to be neuroprotective in normoxia and hypoxia induced rat brain cortical cell cultures.

Effect of Minocycline on Activation of Glia and Nuclear Factor kappa B in an Animal Nerve Injury Model

Eun Young Gu,Hyung Soo Han,Jae-Sik Park 대한생리학회-대한약리학회 2004 The Korean Journal of Physiology & Pharmacology Vol.8 No.5

Glial cells are activated in neuropathy and play a key role in hyperalgesia and allodynia. This study was performed to determine whether minocycline could attenuate heat hyperalgesia and mechanical allodynia, and how glial cell activation and nuclear factor kappa B (NF-kappaB) were regulated by minocycline in a model of chronic constriction of sciatic nerve (CCI). When minocycline (50 mg/kg, oral) was daily administered from 1 day before to 9 days after ligation, heat hyperalgesia and mechanical allodynia were attenuated. Furthermore, when minocycline treatment was initiated 1 or 3 days after ligation, attenuation of the hypersensitive behavior was still robust. However, the effect of attenuation was less when minocycline was started from day 5. In order to elucidate the mechanism of pain attenuation by minocycline, we examined the changes of glia and NF-kappaB, and found that attenuated hyperalgesia and allodynia by minocycline was accompanied by reduced microglial activation. Furthermore, the number of NF-kappaB immunoreactive cells increased after CCI treatment and this increase was attenuated by minocycline. We also observed translocation of NF-kappaB into the nuclei of activated glial cells. These results suggest that minocycline inhibits activation of glial cells and NF-kappaB, thereby attenuating the development of behavioral hypersensitivity to stimuli.

Effect of Minocycline on Activation of Glia and Nuclear Factor kappa B in an Animal Nerve Injury Model

Gu, Eun-Young,Han, Hyung-Soo,Park, Jae-Sik The Korean Society of Pharmacology 2004 The Korean Journal of Physiology & Pharmacology Vol.8 No.5

Glial cells are activated in neuropathy and play a key role in hyperalgesia and allodynia. This study was performed to determine whether minocycline could attenuate heat hyperalgesia and mechanical allodynia, and how glial cell activation and nuclear factor kappa B (NF-kappaB) were regulated by minocycline in a model of chronic constriction of sciatic nerve (CCl). When minocycline (50 mg/kg, oral) was daily administered from 1 day before to 9 days after ligation, heat hyperalgesia and mechanical allodynia were attenuated. Furthermore, when minocycline treatment was initiated 1 or 3 days after ligation, attenuation of the hypersensitive behavior was still robust. However, the effect of attenuation was less when minocycline was started from day 5. In order to elucidate the mechanism of pain attenuation by minocycline, we examined the changes of glia and NF-kappaB, and found that attenuated hyperalgesia and allodynia by minocycline was accompanied by reduced microglial activation. Furthermore, the number of NF-kappaB immunoreactive cells increased after CCI treatment and this increase was attenuated by minocycline. We also observed translocation of NF-kappaB into the nuclei of activated glial cells. These results suggest that minocycline inhibits activation of glial cells and NF-kappaB, thereby attenuating the development of behavioral hypersensitivity to stimuli.

Minocycline-Induced Autoimmune Hepatitis: A Rare But Important Cause of Drug-Induced Autoimmune Hepatitis

Elizabeth G. Harmon,Randolph McConnie,Anil Kesavan 대한소아소화기영양학회 2018 Pediatric gastroenterology, hepatology & nutrition Vol.21 No.4

Drug-induced autoimmune hepatitis (DIAIH) is an increasingly recognized form of drug-induced liver injury that leads to a condition similar to idiopathic autoimmune hepatitis. A number of drugs have been associated with DIAIH, minocycline is one of the most well characterized. Minocycline is a semisynthetic tetracycline antibiotic used in the treatment of acne vulgaris. Minocycline-induced autoimmune hepatitis presents with serologic and histologic features similar to idiopathic autoimmune hepatitis. However, the natural history and outcomes of these two conditions differ significantly. The majority of patients with minocycline-induced autoimmune hepatitis experience complete resolution of symptoms after withdrawal of the medication. Some patients may require a short course of steroids and rarely use of an immunomodulator to achieve resolution of disease. Recurrence of symptoms is rare and typically only occurs with reintroduction of minocycline. It is important for primary care providers to consider minocycline-induced autoimmune hepatitis when liver injury develops during minocycline therapy.

Blue-gray nail discoloration due to minocycline

( Jae Seong Joo ),( Sook Jung Yun ),( Seung-chul Lee ),( Young Ho Won ),( Jee-bum Lee ) 대한피부과학회 2018 대한피부과학회 학술발표대회집 Vol.70 No.1

Minocycline-induced nail pigmentation is an uncommon side-effect. Most of the cases show blue-black or slate-gray discoloration of the proximal nail beds, and some cases reveal longitudinal melanonychia. These symptoms usually occur after prolonged minocycline therapy, mostly longer than a few years, and coincide with other pigmented sites. We report herein two patients developing blue-gray nail discoloration alone after short term minocycline therapy. One patient is a 56-year-old female and the other patients is a 21-year old female. Both patients with rosacea had been treated with 100mg minocycline twice daily for 8 weeks when they developed a change in the color of their proximal fingernails. No pigmentation was found elsewhere on the skin, mucous membranes, teeth or sclera. These cases demonstrate that nail pigmentation can also occur after relatively short term minocycline therapy. In addition, our cases suggest the possibility that nail discoloration may occasionally precede other pigmentary changes. It is important to observe nails of patients taking minocycline.