Biomedical Science Letters 2019, 25(2): 131~138 https://doi.org/10.15616/bsl.2019.25.2.131 eissn : 2288-7415 Original Article Effects of Sea Buckthorn and Boswellia Extracts in Inflammatory Orofacial Pain by Xerostomia in Rats Ja-Hyeong Choi 1,*, Tae-Heon Kim 2,* and Min-Kyung Lee 3,,* 1 Department of Dental Hygiene, Ulsan College, Ulsan 44610, Korea 2 Department of Dental Hygiene, Taegu Science University, Daegu 41453, Korea 3 Department of Dental Hygiene, Dong Eui University, Busan 47340, Korea Xerostomia due to the subjective dry mouth feeling that may occur even when the salivary gland function reduction is not objectively confirmed. The purpose of this study was to investigate whether or not dry mouth is more sensitive to pain in the oral facial area, which is the main cause of dental problems. The natural products used in this study are Boswellia serrata and seabuckthorn, Both natural substances are known as a representative antioxidant substance rich in vitamins. 4-DAMP was injected into the peritoneal cavity of the experimental animals, and 5% formalin was injected into the face to observe the change of inflammatory pain. Boswellia (15, 30 mg/kg) or seabuckthorn (150, 30 mg/kg, 5 mg/kg) after formalin infusion, As a result, pain response was significantly reduced in the drug-infused group compared to the formalininfused group (*P<0.05). It was also found that the two drugs were more effective when administered together. Based on these results, we confirm that natural extract can be an alternative treatment modality for the control of oral facial inflammatory pain. Key Words: Xerostomia, Boswellia serrata, Sea buckthorn, Orofacial pain 서론구강건조증은객관적혹은주관적으로호소하는구강내입마름증으로, 타액선기능의감소에의한타액량부족또는타액선기능감소를동반하지않는상태에서도발생할수있는구강질환이다 (Napenas et al., 2009). 구강건조는구강내통증및저작장애등을포함한조직의감염및병변등의다양한문제를야기하는구강증상중하나이며, 최근에는노인층을비롯한성인의발병률이증가하고있는주요한구강병으로여겨진다. 구강건조증을유발하는다양한원인으로는노화로인한세포기능저 하및세포수감소, 근수축기능감소 (Yasuko et al., 1998) 와같은퇴행성변화등과함께자율신경계기능저하에따른생리적원인뿐만아니라불안감이나스트레스와같은심리적인요인도배제할수없다 (Jang et al., 2006). 또한고령화사회로인하여전신질환환자의증가로고혈압제재나삼환성항우울제의복용, 타액선질환, 방사선치료등이원인이될수있으며현저하게타액선기능감소가증상으로나타날경우에는양대구강질환인치아우식증과치주질환을비롯하여구강캔디다증, 미각변화, 구취등의구강질환이동반되어나타날수있다 (Kim et al., 2011). 또한구강건조증이발생하면구강기능이제한되고저작및연하능력이감소하여소화불량등의전신적증상으로 Received: May 2, 2019 / Revised: June 17, 2019 / Accepted: June 17, 2019 * Professor. Corresponding author: Min-Kyung Lee. Department of Biomedical Health Science, Dong Eui University, 176 Eongwangno (Gayadong san24), Busanjin-gu, Busan 47340, Korea. Tel: +82-51-890-4238, Fax: +82-0505-182-6878, e-mail: lmk849@deu.ac.kr C The Korean Society for Biomedical Laboratory Sciences. All rights reserved. CC This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. - 131 -
이어지기도하며신체적, 사회적및심리적안녕에도심각한영향을줄수있다 (Gerdin et al., 2005; Thomson et al., 2006). 이러한구강건조증의치료를위하여미국식품의약국 (FDA) 의승인을받은약물인필로카르핀 (Pilocarpine) 과세비멜린 (Cevimeline) 이대표적인타액분비촉진제로써주로처방되고있다. 필로카르핀은무스카린수용체 (Muscarinic receptor, M) 에작용하여부교감신경을자극하고, 세비멜린은무스카린수용체중 M3와높은결합력을나타내는타액선자극제로알려져있다 (Choi and Lim, 2016). 필로카르핀은 5 mg, 세비멜린의경우 30 mg을각각하루세번복용하는것이일반적이며, 투약기간은최소 3개월이상복용하는것을권장한다 (Braga et al., 2009). 두약물은구강건조증개선을위한긍정적인효능이우수한반면부작용도적지않은데, 현재까지보고된주요부작용으로는샘 (gland) 기능의증가로땀증가, 혈관확장, 오심이나구토, 딸꾹질, 기관지축소, 저혈압, 빈맥등의증상들이동반되는것으로알려져있다 (Aframian et al., 2007). 이처럼장기간에걸쳐질환의증상개선및완화를위해투여되는의약품의부작용발생을감소시키기위해최근에는구강건조증뿐만아니라다양한질환을대상으로천연약물에대한관심과연구가증가하고있으며, 의약품의효능에준하는약리적인효능을나타내면서상대적으로독성이낮은천연물들이지속적으로개발되고있다 (Braga et al., 2009). 본연구에서는보스웰리아 (Boswellia Serrata) 와비타민나무로일컬어지는산자나무 (Hippophae rhamnoides L., seabuckthorn) 를이용하였고, 두천연물질모두비타민이풍부하게함유된대표적인항산화물질로알려져있으며현재건강보조및질환예방목적으로널리사용되고있다. 보스웰리아는중등도크기정도의분지나무로주요성분은테르페노이드및보스웰릭산이며, 보스웰릭산은소염및진통효과를나타내는유효한성분으로알려져있다 (Sailer et al., 1996). 보스웰릭산은 5-lipoxygenase (5-LO) 의활성을저해시켜생체내에서염증에반응하는물질및염증을유발하는물질인 interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α) 등에의한 cytokine 생성을억제하게되면서염증성질환이나자기면역질환에효과적인것으로보고되고있다 (Ammon, 2006; Siddiqui, 2011). 한편, 산자나무는보리수과 (Elaeagnaceae) 에포함된낙엽성관목으로비타민 C가풍부하고필수지방산의일종인 α-linoleic acid 및 linoleic acid 가다량함유되어있는것으로알려져있는데 (Chen et al., 1990), 이는화상을비롯한피부질환이나상 처치유제, 염증및궤양치료에효과적인것으로알려져있다 (Yang et al., 2002). 또한산자나무잎의추출물은 p38 mitogen-activated protein kinase (MAPK) 를비롯하여 NF-κB 활성억제를통해 LPS에의한 cyclooxygenase-2, TNF-α, inducible nitric oxide synthase, nitric oxide (NO), IL-6 등의단백질발현의억제에작용된다고보고되었다 (Jiang et al., 2017). 이상의다양한연구결과를통해두천연물질은공통적으로항산화및항염증작용을나타낸다는것을알수있다. 이러한연구결과와마찬가지로, 최근본연구의선행연구를통하여보스웰리아를경구투여한뒤 5% formalin 을실험동물의안면부피하및측두하악관절내로주입한실험에서안면부및측두하악관절염증성통증행위반응감소에보스웰리아투여가효과적임을입증하였고 (Lee et al., 2017), 동일한실험모델에서산자나무추출물을경구투여한경우에도유사한통증경감효과를확인할수있었다 (Kim et al., 2017). 이러한선행연구결과를기초로하여구강건조증에의해향상된안면부통증조절에서두가지의천연물의효과를확인하고자실험을고안하였고, 4-DAMP 를복강내로주입하여구강건조증을유발시킨실험동물을대상으로 5% formalin 을안면부에주입하여향상된염증성통증의변화를관찰하고, 단독혹은병용하여경구투여한보스웰리아와산자나무가구강건조증에의해향상된안면부통증조절에효과적인지를확인하고자하였다. 재료및방법실험동물본실험은 Sprague-Dawley 계의 200~230 g의생후 6~7 주령의수컷흰쥐를사용하였으며효창사이언스 ( 대구 ) 에서공급받아동의대학교동물실험윤리위원회의승인 (R2018-011) 을받아진행하였다. 12시간주 야빛의순환주기를주었으며 23~26 온도를일정하게유지하였다. 또한실험동물용사료와물을자유롭게공급하였으며행동적인억압등에의한스트레스를최소화시켰고의식이있는실험동물에관한통증연구학회의윤리적규정을준수하여실험하였다. 구강건조증모델구강건조증을유발하기위하여사용된 4-DAMP 는시그마알드리치사 (Sigma-Aldrich Co., St. Luis, U.S.A) 에서구입하여사용하였다. 4-DAMP 를생리식염수에희석하여사 - 132 -
용하였으며 1 mg/kg 의농도로 1 ml의용량으로실험동물에복강 (intraperitoneal) 투여하였다. 투여후 1시간경과시점에서 20% urethane (0.5 ml/kg) 을복강투여하여안정위상태로마취시킨다음면구 (cotton ball) 를구강내악하선의분비도관부에위치시키고면구의타액흡수전후의무게차이를분비된타액량으로간주하여 30분간측정한결과타액분비량이현저하게감소된것을확인하여구강건조증이유발되었음을확인하였다. 시약준비 보스웰리아추출물 ( 보스웰리아추출물열매분말 ; Bioprex Labs Co., Ltd., Pune Maharashtra, India) 은 15, 30 mg/kg 의농도로희석하여 1 ml의용량으로경구에투여하였다. 산자나무추출물 ( 비타민나무추출물열매분말 ; Shanghai Brichtolinternatilnal Co., Ltd., Tibet, China) 역시 150, 300 mg/ kg의농도로희석하여동일하게 1 ml의용량으로경구투여하였다. 또한두약물의병용효과를확인하기위하여보스웰리아 (15 mg) 와산자나무 (150 mg) 추출물을함께투여하였다. 각각의약물을주입한후 30분경과한뒤에안면부통증유발을위해 5% formalin 을투여하였다. 안면부염증성통증유발구강안면부의염증성통증모델의이전실험방법을참고하여동일하게진행하였다 (Lee et al., 2017). 구강건조증이유발된실험동물의안면부피하에 5% formalin (50 μl) 을 31 gauge 의인슐린주사기를사용하여주입하였고, 약물이투여된부위를문지르거나긁는행위를통증지표로간주하여진행하였다. 주입직후부터총 45분간 5분단위로행위반응을관찰하였으며, 통증행위반응은포르말린주입으로유발되는말초감작 1차통증행위반응 (0~10 분, first phase) 과중추감작 2차통증행위반응 (11~45 분, second phase) 으로구분하여평가하였으며 (Lee et al., 2014), 실험이진행되는동안은물과사료섭취를제한하였다. 통계분석실험결과는 IBM SPSS Statistic ver. 22.0 (IBM Co., Armonk, NY, USA) 을이용하여 least significant difference 사후분석법을적용한일원배치분산분석을하였고, Sigmaplot 2001 (SPSS Inc., Chicago, IL, USA) 을이용하여그래프를나타내었다. 결과는유의수준을 0.05를기준으로하여평균 ± 표준오차 (standard error of the mean) 로표시하였다. Fig. 1. The effect of the boswellia extract (15, 30 mg/kg, BW) on behavioral responses following injection of formalin (5%, 50 μl) into vibrissa pad. BW reduced behavioral responses during the second phase compared with 5% formalin-treated group. * P<0.05, vs 4-DAMP+F 결 구강건조증으로유발된안면부염증성통증모델에서보 스웰리아추출물의효과 과 4-DAMP 를복강투여하여구강건조증을유발시킨흰 쥐의안면부염증성통증모델에서보스웰리아추출물의 경구투여에따른통증행위반응의변화를살펴보았다. 보 스웰리아투여시 1 차통증행위반응은 4-DAMP + 포르 말린주입군, 대조군 (4-DAMP + veh + 포르말린주입군 ) 그리고약물주입군간의뚜렷한차이가없었으나, 2 차 통증행위반응에서는포르말린투여군에비해약물주입 군 (BW 15 mg/kg, 30mg/kg) 에서통증행위반응이농도의존 적으로유의하게감소되었다 (*P<0.05) (Fig. 1). 시간의경 과에따른통증행위반응의변화는 BW 15 mg/kg 투여시 에는약물주입 25 분경과시점에서가장효과적으로통 증행위반응이감소되었고, BW 30 mg/kg 투여군에서는 2 차통증행위반응대부분의시점에효과적이었다 (Fig. 2). 이러한결과를통해구강건조증으로인하여향상된안면 부염증성통증조절에보스웰리아가효과가있음을확인 할수있었다. 구강건조증으로유발된안면부염증성통증모델에서산 자나무추출물의효과 산자나무추출물에의한통증경감효과는보스웰리아와 마찬가지로투여된산자나무의농도에의존적으로통증 - 133 -
Fig. 2. Time response curve for the number of scratches responses following injection of formalin (5%, 50 μl) into vibrissa pad 30 minutes after oral administration of boswellia extract. * P<0.05, vs 4-DAMP+F. Fig. 3. The effect of the sea buckthorn extract (150, 300 mg/kg, SB) on behavioral responses following injection of formalin (5%, 50 μl) into vibrissa pad. SB reduced behavioral responses during the second phase compared with 5% formalin-treated group. * P<0.05, vs 4- DAMP+F. 행위반응의감소를확인할수있었다. 포르말린주입후 1차통증행위반응에서는약물주입군간의유의한차이가없었으나, 2차통증행위반응에서는포르말린주입군에비해약물주입군 (SB 150 mg/kg, 300 mg/kg) 모두통증행위반응이유의하게감소되었다 (*P<0.05) (Fig. 3). 이러한통증행위반응을시간의경과에따른변화로확인하였을때, SB 150 mg/kg 투여시에는포르말린주입 25분이후에통증경감효과가관찰된반면에, SB 300 mg/kg 투여군에서는 2차행위반응의대부분의시점에서유의한통증경감효과를확인하였다 (Fig. 4). 이러한결과를통해산자나무도보스웰리아와마찬가지로구강건조증으로인하여향상된안면부염증성통증조절에효과적임을알수있었다. 안면부염증성통증모델에서보스웰리아와산자나무추출물의병용효과 Fig. 5와 Fig. 6은 4-DAMP 를복강투여하여구강건조증을유발시킨안면부염증성통증모델에서저농도의보스웰리아와산자나무추출물의병용투여에의한통증행위반응의변화를관찰한결과각각의약물을주입하고관찰한통증경감의효과에비해두약물을병용투여했을경우에훨씬효과적인통증경감효과를확인할수있었다 (Fig 4, 5). 이러한결과를통해각각의보스웰리아와산자나무추출물의투여는구강건조증으로인하여발생된안면부염 Fig. 4. Time response curve for the number of scratches responses following injection of formalin (5%, 50 μl) into vibrissa pad 30 minutes after oral administration of sea buckthorn extract. * P<0.05, vs 4-DAMP+F. 증성통증조절에효과적이며, 저농도로두가지물질을 병용투여하였을때통증조절효과가더우수함을알수 있었다. 고 찰 구강안면부통증 (orofacial pain) 은구강내경조직및연 조직과관련된통증을포함하는것으로, 개구및저작장 - 134 -
Fig. 5. 4-DAMP was administered intraperitoneally to the oral cavity, changes in the pain behavior response to oral administration of low concentrations of boswellia and sea buckthorn in the modified acute pain model. * P<0.05, vs 4-DAMP+F. Fig. 6. BW 15 mg/kg and SB 150 mg/kg were administered, the response was found to be effective at 25~40 minutes after administration of BW+SB, The orofacial pain relief effect was higher at the time of the minute. * P<0.05, vs 4-DAMP+F. 애를초래하며, 측두하악관절장애 (temporomandibular disorder, TMD) 나삼차신경통과같은신경병증성통증뿐아니라두통이나근골격성, 신경계등의동통으로나타나는것으로알려져있다 (Rhodus, 1988). 이러한치료를위하여대개비스테로이드성약물 (nonsteroidal antiinflammatory drug, NSAID) 을처방받아복용하는데, 이약물은뛰어난진통효과를기대할수있지만위장관독성이나장기간복용으로인한혈전증등의부작용이발생할수있어복용에주의가필요하다 (Kim and Lee, 2015). 이러한부작용을최소화하기위해최근에는비교적부작용이적은천연물질에대한관심이증가하고있는실정이다. 본연구에서는최근항산화및항염증등다양한효능으로주목받고있는보스웰리아및산자나무추출물을구강건조증에의해유발된안면부염증성통증모델에서역할을규명하고자하였다. 먼저, 보스웰리아및산자나무추출물을경구투여하여나타나는안면부통증에미치는영향을확인한결과, 대조군에비해보스웰리아및산자나무추출물투여군에서농도의존적으로통증이감소하였다. 이러한결과는최근보고되고있는천연물에의한안면부통증조절연구결과들과유사한것으로, 포르말린으로유도한흰쥐의안면부통증모델에서커피생콩추출물을 30, 60 mg/ml 의농도로투여하였을때농도의존적으로통증행위반응이유의하게감소된다는것을보고하였고 (Lee et al., 2018), 홍삼및흑삼추출물이간과신장에부작용이발생되지않으면서안면부통증모델에서통증반 응을유의하게감소시켰으며, 이는 Nrf2 의발현의조절을통해서라고보고하였다 (Lee et al., 2017). 이러한결과들을바탕으로천연물은안면부통증의직접적인조절에관한연구뿐만아니라, 구강의다양한질병에서유의한역할을한다는보고가꾸준히발표되고있다. 최근한연구에따르면, 성인을대상으로씀바귀및갈근추출물의투여후타액분비효과를비교한연구에서, 증류수를머금고있을때타액분비는 0.41±0.021 ml/min, 씀바귀추출물투여시에는 20% 정도증가한 0.49±0.029 ml/min 이였으며갈근추출물은 0.54±0.014 ml/min으로약 32% 가증가한다는것이보고되었다 (Jung et al., 2018). 구강건조증은인구의증가와함께유병률이급증하고있는구강의주요질환으로구강의건조감은치아우식증이나치주질환을가속화시키는원인이되고, 본연구에서처럼안면부의통증을향상시키는기저질환으로작용할수도있다. Fox (1987) 의연구에의하면구강건조증을호소하는환자군에서타액분비의감소로인한기능저하로이차적지환인치아우식이발병되는비율이높다고발표하였다. 또한대조군에비하여구강건조감을호소하는군에서소화불량, 불면증, 위장염등과같은질환을호소하는비율이많았다는 Oh 등의 (2001) 연구를통하여구강건조증과통증이관련되어있음을확인할수있었다. 따라서, 타액의유출량, 점도및 ph 등의조절을위해다양한연구가이루어져야할것이고, 지속적인효과를나타내기위해장기간사용함에있어서비교적부작용이적은천연물이연구대상이 - 135 -
되어야한다고생각된다. 본연구에서사용된천연물인보스웰리아의효능은 11- keto-b-boswellic acid (KBA) 와 acetyl-11-keto-b-boswellic acid (AKBA) 을포함한선택적 5-lipoxygenase (5-LO) 의조절에의한것으로알려져있는데, Kiela 등의연구에의하면 KBA 또는 AKBA가증가하면염증성질환의발생및진행에서사이토카인의조절에관여하는인자인 The nuclear transcription factor (NF-κB) 의발현이감소된다는것이보고되었다 (Abdel-Tawab et al., 2011). 또한위장및심혈관계통의통증모델에서비스테로이드성항염증제 (NSAIDs) 에비하여보스웰리아의통증저항력이더효과적이라는연구결과 (Prabhavathi et al., 2014) 도이러한보스웰리아의통증조절제로써의가능성을입증하는것으로보여진다. 본실험에서도보스웰리아의주입은구강건조증에의해유발된안면부염증성통증경감에효과적인것을확인하였고, 이러한결과를바탕으로보스웰리아가염증질환이나통증의발생및조절에효과적인약물로적용될수있음을시사한다. 이와마찬가지로, 산자나무추출물역시염증및통증조절에효과적이라는것을입증한다양한연구결과들이보고되었다. 산자나무의생화학적구성에관한연구에따르면산자나무가함유하고있는다양한종류의비타민, 미량원소, 아미노산및다양한생리활성물질이다용도의약리학적활동을담당하고있으며, 산자나무추출물은감염을방지하고항산화물질이풍부하여염증상태를개선시키는것으로보고되었다 (Xing et al., 2002). 또한, 산자나무는 linoleic 과 linolenic acid의함량이높고항산화특성에상응하는카로티노이드, flavonoids 및 phytosterols 를포함한높은 pyhtochemical material 을다량으로함유하고있어서감소된 glutathione (GSH) 과 glutathione peroxidase (GPx) 와같은세포내항산화물질을회복시켜 ROS/free 의라디칼생산의억제한다고알려져있다 (Geetha et al., 2003). 마찬가지로, Richa 등 (2013) 의연구에의하면, 중형잡종성견 20마리를대상으로덱사메타손 (dexamethasone) 1 mg/kg 을투여하여위궤양을유발한모델에서산자나무추출물투여에의한유의한통증경감효과가입증되었다. 이와더불어식욕의현저한개선이관찰되었으며, 대변잠혈검사에서도양성이었으며혈청생화학검사는연구전반에걸쳐정상적인생리학적한계내에서유지되었다. 또다른연구에의하면, 실험동물의피부조직에상처를내어산자나무잎추출물을해당조직에도포하면육아조직의항산화수준이증가되어상처치유효과가나타난다는것이보고되었다 (Gupta et al., 2005). 이를결과들과마찬가 지로본연구에서도산자나무추출물이구강건조증에의해향상된안면부염증성통증을유의하게조절함을밝혔고, 이러한결과는산자나무의통증및염증조절제로서의가능성을보여주는것으로생각된다. 본연구에서흥미로운점은, 두가지의약물을저농도로병용했을때각각의단독투여효과에비해훨씬유의한통증경감효과를확인한것이다. 약물의효과를극대화하기위해고농도의단독주입은조직과신경의손상을유발하거나오히려약효의반전을나타내는경우도있다. 최근에는울트라셋정과같은약리작용기전이명확한약물의혼합제제가개발되는등부작용의범위를줄이면서유효한약효를확보하려는연구및개발이증가되고있다. 실험적으로보고된한예로, 신경병증성통증동물모델을이용하여 gabapentin 과 milnacipran 의병용투여는각각의단독투여에의해효과적으로증가된통증경감효과를나타내었음이보고되었다. 일부연구에서는유효한화학약제와천연물의병용을시도하여좋은연구결과를보여주기도하는데, 최근에미역순나무의주요성분인트립톨리드 (triptolide) 와 nitric oxide (NO) 의합성억제제인 N- nitro-l-arginine Methyl Ester의병용투여가흰쥐의측두하악관절통증조절에효과적이라는것이확인되었다 (Kim and Lee, 2015). 이러한결과와유사하게, 본연구에서도두가지천연물의병용투여에의해안면부염증성통증이효과적으로감소되는것을확인하였다. 물론향후천연물의작용기전에관한구체적인연구가추가되어야하며, 지속적인투여를위해서는안정적인적용범위를확보하는것이필수적이라고생각된다. 이상의연구결과를종합해보면, 보스웰리아와산자나무추출물은구강건조증으로인하여향상된안면부염증성통증을유의하게감소시켰으며, 두약물의저농도병용투여시에는각각의단독투여에비해더욱효과적으로통증조절효과를나타내었다. 이러한결과들을통해안면부염증성통증조절을위한약물로써보스웰리아및산자나무추출물이치료제로제시될수있으며, 약물의병용투여에의한상호작용은약리학적가치를더욱증가시킬수있을것으로사료된다. ACKNOWLEDGEMENT This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2017R1C1B5076722). - 136 -
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