• 대한약리학회지
• /
• 제32권2호
• /
• pp.211-219
• /
• 1996

The inhibitory effect of cyclosporin A (CsA) on nitric oxide production is not related to the immunosuppressive action of the drug, but to the renal toxicity and arterial hyper-tension. In this study the experimental interventions to reverse the inhibition of nitric oxide production by cyclosporin A in rat aortic smooth muscle cells were examined. CsA inhibited the accumulation of nitrite, the stable end product of nitric oxide, in culture media in a concentration $(0.1{\sim}100{\mu}g/ml)-dependent$ manner. The inhibitory effect of CsA on nitrite accumulation were not antagonized by arginine (10 mM), a substrate of nitric oxide synthase, nor by calcium ionophore A23187 $(7{\mu}M)$. Forskolin, an activator of adenylate cyclase, which enhanced iNOS induction at transcriptional level, completely reversed the inhibitory action of CsA on nitrite accumulation. However, PMA (2 nM) and PDB (50 nM), PKC activators, increased the inhibitory action of CsA on nitrite accumulalion. From these results, it is suggested that cyclic AMP-elevating agents may be candidates of therapeutic agents in prevention and treatment of renal toxicity and arterial hypertension induced by CsA. Among conventional antihypertensive drugs, calcium channel blockers and ${\alpha}-blockers$ are preferred to ${\beta}-blockers$.

• Journal of Chest Surgery
• /
• 제39권10호
• /
• pp.739-748
• /
• 2006

토끼의 25분간의 척수허혈 모델에서 cyclosporin A의 신경보호효과를 신경병리학적 연관성과 면역조직화학적분석을 통하여 알아보고자 하였다. 대상 및 방법: 몸무게가 3.0 kg 전후의 뉴질랜드산 토끼를 이용하였고 복부 대동맥을 25분간 차단하였다. 32마리의 토끼를 무작위로 4군으로 나누어 대조군인 12군(n=8)과 17군(n=8)은 복부 대동맥 차단만 시행한 후 12군은 2일째, 17군은 7일째 희생시켜 신경학적 평가와 조직학적 검사를 시행하였다. 실험군인 Cs2군(n=8)과 Cs7군(n=8)은 복부 대동맥을 차단 후 재관류 15분 후에 cyclosporin A (25 mg/kg)를 정맥 주입한 후 Cs2군은 2일째, Cs7군은 7일째 희생시켜 신경학적 평가와 조직학적 검사를 시행하였다. 결과: 모든 토끼가 술 후 생존하였으며 술 후 2일째 신경학적 평가에 있어서는 군들 간 차이가 얼었으나 술 후 7일째 시행한 평가에서 복부대동맥 허혈 후 cyclosporin A를 투여한 Cs7군의 Tarlov score가 평균 $2.75{\pm}0.89$로 투여하지 않은 17군의 $1.25{\pm}1.39$에 비해 의미 있게 높아 신경학적 평가상 덜 손상을 받았음을 알 수 있었다(p<0.05). 또한 대조군 17군에서는 신경학적 평가가 2일째보다 7일째 악화하는 경향이었으나 통계학적으로 의미 있는 차이는 없었고 실험군 Cs7군에 있어서는 신경학적 평가가 2일째 $1.87{\pm}0.83$에 비해 7일째 $2.75{\pm}0.89$로 의미 있게 호전되었다(p<0.05). 모든 군을 조직학적으로 손상의 정도에 따라 등급을 매겼으며 신경학적 평가와의 상관관계를 분석하였는데 상관계수 -0.44로 조직학적 손상정도와 신경학적 평가사이에 유의한 관계가 있었다(p=0.009). 병리조직학적 등급을 4군 간 비교하였을 때 2일째 희생시킨 대조군과 실험군 사이에는 유의한 차이가 없었으나 7일째 희생시킨 17군은 조직학적 등급이 $2.13{\pm}1.36$이었으나 Cs7군은 $1.0{\pm}0.53$으로 두 군 간 유의한 차이가 있어 병리학적으로도 cyclosporin A를 투여한 실험군 Cs7군이 대조군 17군에 비해 덜 손상을 받았음을 알 수 있었다(p=0.039). 12군과 Cs2군에서 TUNEL 염색에 양성반응을 보이는 신경세포의 수는 12군이 $17.5{\pm}22.6$개였고 Cs2군이 $12.5{\pm}11.1$개로 통계학적으로 유의한 차이가 없었다. Heat shock protein-70 (HSP70)과 neuronal nitric oxide synthase (nNOS)에 대한 면역조직화학검사에서 실험군 Cs2군의 신경세포가 대조군 12군에 비해 HSP70과 nNOS의 과발현을 보였으며, 이는 통계학적으로 유의한 차이를 보였다(p<0.05). nNOS와 HSP70의 발현은 강한 연관성을 보였고(상관계수 0.91, p=0.000), nNOS를 발현하는 세포가 동시에 HSP70도 발현함을 확인할 수 있었다. 결론: 우리는 cyclosporin A가 토끼의 25분간의 척수허혈에 대해 척수보호 효과가 있었으며 이는 HSP70의 과발현과 연관이 있으리라 생각한다.

• The Korean Journal of Physiology and Pharmacology
• /
• 제2권4호
• /
• pp.471-477
• /
• 1998

Cyclosporin A (CsA), a widely used immunosuppressant, is well known to cause nephrotoxicity and hypertension as major side effects. The present study was aimed at investigating the effects of CsA-pretreatment on the activities of cytosolic guanylate cyclase (cGC) in relation to the alteration of relaxant responses in the rat thoracic aorta. CsA $(10\;{\mu}M)-preincubation$ for 90 min significantly attenuated the vasodilatation induced by sodium nitroprusside (SNP), a cytosolic guanylate cyclase activator, shifting the dose-response curve to the right. The increase in cGMP contents induced by SNP was markedly attenuated by CsA. SNP ($1\;{\mu}M{\sim}\;mM$) increased the cGC activity dose-dependently, and the increase was completely abolished by CsA. CsA attenuated the SNP-induced cGC activation dose-dependently. The abolishing effect of CsA-pretreatment on the SNP-induced cGC activation was not affected by washing the preparation, suggesting that the inhibition is irreversible. When CsA was added simultaneously with SNP, cGC activation was not attenuated. 1-(5-isoquinolinylsulfonyl)-2-methyl piperazine (H-7), a protein kinase C (PKC) inhibitor, decreased SNP-induced cGC activation and blocked the CsA-attenuation of cGC activation. These results suggest that CsA directly inhibits cGC participating in the CsA-induced impairment of vasodilatation, and that PKC is involved in the inhibitory action of CsA on cGC.

• Childhood Kidney Diseases
• /
• 제9권1호
• /
• pp.91-96
• /
• 2005

CsA 유발성 중추 신경독성은 신증후군 환자에서 드물게 보고되고 있다. 저자들은 신 증후군환아에서 CsA 치료 중에 뇌 자기공명 영상으로 확진한 급성 백색질 뇌증 1례를 경험하였기에 보고하는 바이다.

• Journal of Periodontal and Implant Science
• /
• 제30권4호
• /
• pp.747-757
• /
• 2000

Cyclosporin A(CsA) is an immunosuppressive agent widely used for preventing graft rejecting response in organ transplantation. The basic properties of CsA to osteoblast has not been well known yet. A better understanding of the mechanisms of CsA function on bone could provide valuable information regarding basic properties of bone remodeling, pharmacotherapeutic intervention in metabolic bone disease, and the consequences of immunosuppression in bone physiology. The purpose of this study was to investigate the effect of CsA on osteoblast by evaluating parameters of proliferation, collagen synthetic activity, alkaline phosphatase activity, and ALP mRNA expression in mouse calvarial cell. 1. CsA ($3{\mu}g/m{\ell}$) treated mouse calvarial cell showed statistically significant increase in cell proliferation.(P<0.05) 2. CsA($1,\; 3{\mu}g/m{\ell}$) treated MC3T3 cell line showed statistically significant increase in cell proliferation. 3. The amount of collagen of CsA($3{\mu}g/m{\ell}$) treated mouse calvarial cell was decreased statistically significantly. 4. Alkaline phosphatase activity was increased statistically significantly in CsA treated group($1{\mu}g/m{\ell}$). 5. mRNA expression of ALP was increased in CsA treated group These results suggest that CsA could affect bone remodeling by modulating proliferation & differentiation of osteoblast.

• Biomolecules & Therapeutics
• /
• 제6권2호
• /
• pp.130-138
• /
• 1998

In this study, the effect of verapamil (VER) on cyclosporin A (CsA)-induced nephrotoxicity was investigated in uninephrectomized rats. Male Wistar rats were administered CsA (50 mg/kg/day, p.o.) or VER (0.5 mg/kg/day, i.p.) with CsA (50 mg/kg/day, p.o.) for 20 days. The urinary N-acetyl-$\beta$-D-glucosaminidase (NAG) activity along with BUN, serum creatinine, creatinine clearance (CLcr), body weight, and 24 hr-urine output were measured and histopathologic changes of kidney were evaluated by light and electron microscopy. The results obtained from this study can be summarized as follows: While NAG activity, BUN and serum creatinine was progressively increased and CLcr significantly decreased in CsA group, VER almost signifi-cantly (p<0.05) suppressed and normalized CsA-induced changes in VER+CSA group. While urine output increased until 12th days and thereafter progressively decreased in CsA group, it gradually increased in control and VER+CSA group. While body weight progressively made a gain in control and VER+CSA groups, it significantly (p<0.05) lost in CsA group. On light microscopy, the glomerular hyperemia and proximal convoluted tubular (PCT) dilatation, focal tubular cell vacuolation and necrosis were clearly evident in CsA group, but, were not seen in other groups. Ultrastructural studies revealed thickened glomerular endothelium and basal lamina of capillary, irregular shaped pedicels of podocytes, indistinct slit pores and narrowed bowman's space. The large oval vacuoles with dense debris and phagosome were distributed in apical zone and deformed microvilli and mitochondria were seen in the PCT cell of CsA group. But, glomeruli and PCT cell were relatively preserved in normal apperance in other groups. In conclusion, it is suggested that verapamil has a protective effect on cyclosporine-induced nephrotoxicity in uninephrectomized rats.

• 약학회지
• /
• 제59권4호
• /
• pp.177-183
• /
• 2015

The mechanism of melanogenesis induced by cyclosporin A (CsA) was investigated in B16 melanoma cells. CsA stimulated the production of melanin in a dose-dependent manner in the cells. In addition, CsA increased intracellular $Ca^{2+}$ concentration in a dose-related fashion. Treatment with BAPTA/AM, an intracellular $Ca^{2+}$ chelator significantly inhibited the CsA-induced intracellular melanin synthesis. CsA profoundly induced $Cl^-$ efflux, which was significantly blocked by niflumic acid (NFA) and flufenamic acid (FFA), specific and nonspecific inhibitors of $Ca^{2+}$-activated $Cl^-$ channels (CaCCs), respectively. Furthermore, these inhibitors of CaCCs significantly inhibited the CsA-induced stimulation of melanin synthesis. Taken together, these results suggest that the activation of CaCCs may play an important role in the CsA-induced stimulation of melanin synthesis in B16 cells. These results further suggest that CaCCs may be a good target for the management of hyperpigmentation of the skin reported in the patients treated with CsA.

• Journal of Periodontal and Implant Science
• /
• 제33권4호
• /
• pp.643-650
• /
• 2003

Cyclosporin-A(CsA)는 장기와 조직 이식에 따른 거부반응을 조절하기 위해 사용되는 면역억제제로, 이식의학의 발달과 더불어 사용량이 증가하고 있다. CsA의 부작용중의 하나인 치은과증식은 30-50%의 빈도로 발발하고 있다. 최근 macrolide 계열의 항생제인 azithromycin을 이용하여 이런 부작용을 억제시킨다는 임상 보고가 있어서, 이를 실험적으로 확인하고자 하였다. 이를 위해 CsA를 투여한 적이 없는 환자에서 정상 치은조직을 채취, 치은섬유아세포를 배양하였다. 우선 CsA에 대한 치은섬유아세포의 반응을 보기 위해 다양한 농도($10^{-8}-10^{-10}$g/ml)로 처치하여, 세포 증식량과 교원질 합성량을 MTT assay와 Sirol Collagen Assay를 이용하여 측정하였다. 이에 반응을 보인 조건과 세포를 대상으로 다양한 농도($10^{-8}-10^{-10}$g/ml)의 azithromycin을 CsA와 동시 처치하여 아래와 같은 결과를 얻었다. 1. CsA는 일부 치은섬유모세포의 증식을 증가시켰다. 그러나 Collagen 합성능에는 변화를 주지 않았다. 2. Azithromycin은 정상 치은섬유아세포의 증식능에 영향을 미치지 않았다. 3. Azithromycin은 CsA 에 반응을 보인 세포의 증식을 감소시켰으며, 이는 정상 수준과 유사하였다. 이상의 결과에서 azithromycin이 CsA에 의한 치은과증식 치료에 유익하다고 사료된다.

• 동국한의학연구소논문집
• /
• 제6권2호
• /
• pp.99-107
• /
• 1998

본 실험은 cyclosporin A(CsA)에 의한 시간의 경과에 따른 림프절에서의 세포성 면역억제를 조사하기 위해서 시행된 것으로 BALB/C계 생쥐에 10일동안 CsA(45mg/kg/day) 투여 후 림프절에서의 T 림프구, IL-2 수용기 그리고 자연살해(NK)세포의 분포 변화를 관찰하였다. 대조군의 림프절에서는 L3T4(CD4)에 양성반응을 보이는 도움 T림프구, Ly2(CD8)에 양성반응을 보이는 세포독성 T 림프구 그리고 CD25R에 양성반응을 보이는 IL-2 수용기를 가진 세포는 곁피질(paracortex)과 수질동(medullary sinus)에서 분포하였다. CsA 투여 후 처음 3일까지는 이들 양성반응세포의 분포 변화는 없었으며 양성반응성의 변화도 없었다. 그러나 CsA 투여 7일부터 양성반응 세포수의 감소와 양성반응성의 약화가 관찰되기 시작하였으며 이러한 변화는 시간이 경과하여 14일에 이르렀을 때 가장 큰 감소추세로 나타났다. 한편 NK1.1(CD56)에 양성반응을 보이는 자연살해세포는 피질과 수질에 분포하였으며 CsA 투여 후 시간의 경과에 따라 양성반응 세포수가 감소하였으며, 이러한 감소는 14일에서 가장 큰 것으로 나타났다. 이상의 결과로 미루어보아 CsA 투여는 림프절에서의 IL-2 분비저해를 통해 T 림프구와 NK세포의 활성을 차단하여 선택적이면서 효과적인 세포성 면역억제작용을 하고 있는 것으로 사료된다.

• Journal of Periodontal and Implant Science
• /
• 제28권1호
• /
• pp.71-86
• /
• 1998

The purpose of this study was to evaluate clinically and histopathologically the effects to the periodontal tissue in rats after Cyclosporin A (CsA) administration and to determine whether there is a relationship between dosage of CsA or blood CsA level and the seventy of gingival overgrowth in rats. Twenty 6-week-old Sprauge-Dawley Fats were randomized into 4groups. The control group received olive oil only and the test group received daily CsA in olive oil via gastric feeding for 6weeks at a 3,10, and 30mg/kg. Rats were weighed to evaluate the systemic effect of drug and stone models were made from alginate impressions of upper and lover anterior region at 2 week interval. On completion of offal CsA administration, blood were collected and blood CsA levels were quantitated by TDxFLx analyzer. Rats were sacrificed an6 their upper and lower jaws were removed together with the surrounding gingiva and soft tissue for light microscopic examination. The results were as follows : 1. The weight gain of GsA-treated rats was much less than of the control group and central incisors were gradually displaced and separated in the test groups. 2. The extensive fibrovascular proliferation and scattered inflammatoy infiltrates in an edematous stroma were observed in enlarged gingiva of CsA-treated rats. 3. The increase in buccolingual, mesiodistal dimension of the anterior teeth and vertical height of the interdental papilla showed dose-dependent manner in CsA-treated rats. 4. Significant positive correlation exists between blood CsA level and the severity of gingival overgrowth in anterior teeth. This result indicates that the severity of gingival enlargement in CsA treated rats is correlated with dosage of CsA administration and blood CsA level.