KARYA TULIS AKHIR
PENGARUH EKSTRAK KULIT MANGGIS (Garcinia mangostana Linn) SEBAGAI ANTI INFLAMASI PADA TIKUS MODEL ATEROSKLEROTIK
Oleh :
RP SALVA REVERENTIA YURISTA 08020113
UNIVERSITAS MUHAMMADIYAH MALANG FAKULTAS KEDOKTERAN 2011
HASIL PENELITIAN
PENGARUH EKSTRAK KULIT MANGGIS (Garcinia mangostana Linn) SEBAGAI ANTI INFLAMASI PADA TIKUS MODEL ATEROSKLEROTIK
KARYA TULIS AKHIR
Diajukan kepada Universitas Muhammadiyah Malang untuk memenuhi Salah Satu Persyaratan dalam menyelesaikan Program Sarjana Fakultas Kedokteran
Oleh : RP SALVA REVERENTIA YURISTA 08020113
UNIVERSITAS MUHAMMADIYAH MALANG FAKULTAS KEDOKTERAN 2011
LEMBAR PENGESAHAN LAPORAN HASIL PENELITIAN Telah disetujui sebagai hasil penelitian untuk memenuhi persyaratan Pendidikan Sarjana Fakultas Kedokteran Universitas Muhammadiyah Malang
12 Oktober 2011
Pembimbing I
Prof. Dr. dr. Djanggan Sargowo, Sp.PD, Sp.JP(K)
Pembimbing II
dr. Fathiyah Safithri, M.Kes
Mengetahui, Dekan Fakultas Kedokteran Universitas Muhammadiyah Malang
dr. Irma Suswati, M.Kes
LEMBAR PENGUJIAN
Karya Tulis Akhir oleh RP Salva Reverentia Yurista ini telah diuji dan dipertahankan di depan Tim Penguji pada tanggal 12 Oktober 2011.
Tim Penguji
Prof. Dr. dr. Djanggan Sargowo, Sp.PD, Sp.JP(K)
Ketua
dr. Fathiyah Safithri, M.Kes
Anggota
Prof. Dr. dr. Djoni Djunaedi, Sp.PD, KPTI
Anggota
KATA PENGANTAR
Puji syukur saya ucapkan kepada Tuhan Yang Maha Esa, karena atas berkat dan rahmat-Nya, penulis telah berhasil menyelesaikan usulan penelitian yang berjudul “Pengaruh Ekstrak Kulit Manggis (Garcinia Mangostana Linn) sebagai Anti Inflamasi pada Tikus Model Aterosklerotik”. Dalam penyelesaian karya tulis akhir ini tidak lepas dari bimbingan dan bantuan dari semua pihak, untuk itu penulis ingin mengucapkan terima kasih yang tak terhingga kepada : 1. dr. Irma Suswati, M.Kes selaku Dekan Fakultas Kedokteran Universitas Muhammadiyah Malang atas kesabaran dan ilmu yang diberikan kepada penulis. 2. dr. Meddy Setiawan, Sp.PD selaku Pembantu Dekan I Fakultas Kedokteran UMM yang telah membekali ilmu hingga terselesaikannya karya tulis akhir ini. 3. dr. Fathiyah Safithri, M.Kes selaku Pembantu Dekan II Fakultas Kedokteran UMM sekaligus pembimbing II atas bimbingan, ilmu, dukungan, dan saran yang telah diberikan dalam penyusunan karya tulis akhir ini. 4. dr. Iwan Sys Indrawanto, Sp.KJ selaku Pembantu Dekan III Fakultas Kedokteran UMM yang terus memberi semangat dan ilmu bagi penulis. 5. Prof. Dr. dr. Djanggan Sargowo, Sp.PD, Sp.JP(K) selaku pembimbing I yang berkenan memberikan waktu untuk memberikan bimbingan, semangat, ilmu, dan pengarahan dari awal hingga terselesaikannya karya tulis akhir ini.
6. Prof. Dr. dr. Djoni Djunaedi, Sp.PD, KPTI selaku penguji yang telah banyak memberikan waktu, ilmu, arahan, dan saran demi kesempurnaan karya tulis akhir ini. 7. dr. Mochamad Bahrudin, Sp.S selaku dosen wali atas saran, ilmu, dan arahan studi yang diberikan selama ini. 8. Seluruh dosen Fakultas Kedokteran UMM yang telah membekali penulis berbagai ilmu hingga terselesaikannya karya tulis ini. 9. Papa Dr. RP Henky, SH, MH dan mama yang tidak pernah berhenti memberikan dukungan dan doa bagi penulis. Terimakasih telah menjadi orang tua yang sempurna. 10. Kakak, adik, dan seluruh keluarga besar S. Hadikoesumo. 11. Ir. Adlis Achir Abdullah, MS dan keluarga atas segala bantuan dan dukungan yang diberikan kepada penulis. 12. Staf TU dan para laboran FK UMM yang telah banyak membantu penulis. 13. Seluruh staf CVCU RSU dr. Saiful Anwar Malang dan staf Laboraturium Farmakologi FK Universitas Brawijaya yang telah memberikan banyak bantuan bagi penulis. 14. Dicky dan Elok selaku tim terbaik. 15. Teman-teman terbaik angkatan 2008 yang selalu memberikan motivasi bagi penulis. 16. Semua pihak yang tidak mungkin disebutkan satu-persatu.
Karya tulis akhir ini masih jauh dari kesempurnaan. Dengan kerendahan hati penulis mohon maaf yang sebesar-besarnya dan mengharapkan saran dan kritik yang membangun. Semoga karya tulis ini dapat menambah wawasan dan bermanfaat bagi semua pihak. Malang, Oktober 2011
Penulis
ABSTRAK Yurista, RP Salva Reverentia. 2011. Pengaruh Ekstrak Kulit Manggis (Garcinia mangostana Linn) sebagai Anti Inflamasi pada Tikus Model Aterosklerotik. Fakultas Kedokteran, Universitas Muhammadiyah Malang. Pembimbing: (1) Prof. Dr. dr. Djanggan Sargowo, Sp.PD, Sp.JP (K) , (2) dr. Fathiyah Safithri, M.Kes. Latar Belakang: Aterosklerosis merupakan penyakit inflamasi yang ditandai dengan peningkatan aktivitas imunologis, dimana respon imun berperan pada setiap fase aterosklerosis. Hal terpenting pada aterogenesis adalah nuclear factorκB (NF- κB) yang meregulasi aktivasi molekul adhesi (ICAM-1) dan sekresi sitokin pro-inflamasi seperti tumor necrosis factor (TNF-α) interleukin-1 (IL-1), dan interleukin-6 (IL-6) Tujuan : Membuktikan aktivitas anti inflamasi dari esktrak kulit manggis pada tikus model aterosklerotik. Metode : Sampel penelitian ini menggunakan 30 ekor tikus putih (Rattus novergicus Strain wistar), dibagi dalam 5 kelompok dengan enam tikus di masing-masing kelompok. Kelompok I merupakan kelompok normal; Kelompok II merupakan kelompok tikus yang diberi diet aterosklerotik selama 90 hari; kelompok III, IV, dan V merupakan kelompok perlakuan tikus yang diberi diet aterosklerotik dan ekstrak kulit manggis per oral (200mg/kg; 400 mg/kg, 800 mg/kg) selama 90 hari. Setelah 90 hari perlakuan, dilakukan pengambilan sampel darah untuk pemeriksaan kadar TNF-α dan IL-1 menggunakan metoda Elisa. Pengambilan jaringan aorta juga dilakukan untuk mengamati ekspresi NF-kB, ICAM-1, dan IL-6 menggunakan teknik immunohistokimia. Hasil : Pemberian ekstrak kulit manggis (800 mg/kg) signifikan menurunkan kadar TNF-α, dan IL-1, serta menurunkan ekspresi NF-kB, ICAM-1, dan IL-6. Kesimpulan: Ekstrak kulit manggis (Garcinia mangostana Linn) memiliki aktivitas anti inflamasi dengan menurunkan kadar TNF-α dan IL-1, serta menurunkan ekspresi NF-kB, ICAM-1, and IL-6 yang mencegah perkembangan aterosklerosis. Kata kunci: Aterosklerosis, Garcinia mangostana Linn, anti inflamasi, TNF-α, IL-1, IL-6, NF-kB, ICAM-1.
ABSTRACT Yurista, RP Salva Reverentia. 2011. Effect of Extract from Pericarp of Mangosteen (Garcinia Mangostana Linn) as Anti-Inflammatory Agent in Rat Models with Atherosclerosis. Faculty of Medicine, University of Muhammadiyah Malang. Advisors: (1) Prof. Dr. dr. Djanggan Sargowo, Sp.PD, Sp.JP (K), (2) dr. Fathiyah Safithri, M.Kes Background : Atherosclerosis is an inflammatory disease characterized by intense immunological activity, which immune responses participate in every phase of atherosclerosis. On fundamental importance in atherogenesis is nuclear factor-κB (NF- κB) that regulates activation of adhesion molecules (ICAM-1) and secretion of pro-inflammatory cytokines such as tumor necrosis factor (TNF-α) interleukin-1 (IL-1), and interleukin-6 (IL-6). Objectives : The extract from pericarp of mangosteen (Garcinia mangostana Linn ) were carried out to investigate for anti-inflammatory activity in rat models with atherosclerosis. Methods: The subjects of the study were 30 albino rats of (Rattus novergicus Strain wistar), divided into 5 groups with six rats in each group. Group I comprises normal healthy rats remains untreated for 90 days; Group II comprises of high cholesterol diet induced atherosclerotic rats for 90 days; Group III, IV, and V comprise of high cholesterol diet induced atherosclerosis and were administered extract from pericarp of mangosteen orally (200mg/kg; 400 mg/kg, 800 mg/kg) daily for 90 days. After 90 days treatment, rats were decapitated and blood was sample collected from the aorta for determination level of TNF-α and IL-1 by ELISA. Aorta was taken to observe the expression of NF-kB, ICAM-1, and IL-6 using immunohistochemical techniques. Results : Oral administration (800 mg/kg) of the extract from pericarp of mangosteen significantly decreased the level of TNF-α, and IL-1 and also reduced the expression of NF-kB, ICAM-1, and IL-6. Conclusion: These results suggest that the extract from pericarp of mangosteen (Garcinia mangostana Linn) possess anti-inflammatory actions by reducing level of TNF-α, IL-1, and also reduce the expression of NF-kB, ICAM-1, and IL-6 that prevent the development of atherosclerosis. Keywords: Atherosclerosis, Garcinia mangostana Linn, anti-inflammatory, TNFα, IL-1, IL-6, NF-kB, ICAM-1.
DAFTAR ISI HALAMAN JUDUL ....................................................................................... i LEMBAR PENGESAHAN ............................................................................. ii LEMBAR PENGUJIAN .................................................................................. iii KATA PENGANTAR ..................................................................................... iv ABSTRAK. ...................................................................................................... vii ABSTRACT.. ................................................................................................... viii DAFTAR ISI .................................................................................................... ix DAFTAR TABEL ............................................................................................ xiii DAFTAR GAMBAR. ...................................................................................... xiv DAFTAR SINGKATAN. ................................................................................ xvi DAFTAR LAMPIRAN .................................................................................... xviii BAB 1 PENDAHULUAN .............................................................................. 1 1.1 Latar Belakang ................................................................................ 1 1.2 Rumusan Masalah ........................................................................... 4 1.3 Tujuan Penelitian ............................................................................ 4 1.3.1 Tujuan Umum ........................................................................ 4 1.3.2 Tujuan Khusus ....................................................................... 4 1.4 Manfaat Penelitian ........................................................................... 4 1.4.1 Manfaat Akademik ................................................................. 4 1.4.2 Manfaat Klinis ....................................................................... 4 BAB 2 TINJAUAN PUSTAKA..................................................................... 6 2.1 Aterosklerosis .................................................................................. 5 2.1.1 Definisi Aterosklerosis ........................................................... 5
2.1.2 Patogenesis Aterosklerosis..................................................... 7 2.1.3 Dislipidemia dan Aterosklerosis ............................................ 8 2.1.4 Proses Inflamasi pada Aterosklerosis karena Peningkatan LDL ........................................................................................ 12 2.1.5 Peran Makrofag pada Pembentukan Plak Aterosklerosis ...... 14 2.1.6 Aktivasi Sel T dan Aterogenesis ............................................ 17 2.1.7 Peran Nuclear Faktor kappa B (NF-κB) pada Disfungsi Endotel ................................................................... 20 2.1.8 Peran TNF-α, IL-1, dan IL-6 pada Disfungsi Endotel ........... 22 2.1.9 Inflamasi sebagai Target Terapi Aterosklerosis .................... 24 2.2 Manggis (Garcinia mangostana Linn) ............................................ 25 2.2.1 Taksonomi.............................................................................. 25 2.2.2 Morfologi Tanaman ................................................................ 26 2.2.3 Komponen Manggis (Garcinia mangostana Linn) ................ 27 2.2.4 Penelitian Mengenai Manfaat Kulit Manggis ........................ 30 2.2.5 Peran Manggis sebagai Anti Inflamasi Alami ....................... 31 BAB 3 KERANGKA KONSEP DAN HIPOTESIS .................................... 34 3.1 Kerangka Konsep ............................................................................ 34 3.2 Hipotesis .......................................................................................... 35 BAB 4 METODE PENELITIAN .................................................................. 36 4.1 Rancangan Penelitian ...................................................................... 36 4.2 Tempat dan Waktu Penelitian ......................................................... 36 4.3 Populasi dan Sampel ....................................................................... 36 4.3.1 Populasi .................................................................................. 36
4.3.2 Sampel.................................................................................... 36 4.3.3 Estimasi Besar Sampel ........................................................... 36 4.3.4 Karakteristik Sampel Penelitian ............................................. 38 4.4 Bahan dan Alat Penelitian ............................................................... 38 4.4.1 Bahan ..................................................................................... 38 4.4.2 Alat ......................................................................................... 39 4.5 Variabel dan Definisi Operasional .................................................. 40 4.5.1 Variabel .................................................................................. 40 4.5.2 Definisi Operasional .............................................................. 41 4.6 Alur Penelitian ................................................................................. 43 4.7 Prosedur Penelitian .......................................................................... 44 4.7.1 Pembagian Kelompok Tikus .................................................. 44 4.7.2 Adaptasi ................................................................................. 44 4.7.3 Pemberian Diet Aterosklerotik............................................... 44 4.7.4 Pemberian Ekstrak Kulit Manggis (Garcinia Mangostana Linn) ....................................................................................... 45 4.7.5 Proses Anastesi dan Pembedahan Hewan Coba .................... 47 4.7.6 Pemeriksaan Pemeriksaan Kadar IL-1, IL-6 dan TNF-α ....... 48 4.7.7 Pengamatan ekspresi ICAM-1 ............................................... 49 4.7.8 Pengamatan Hasil ................................................................... 52 4.7.9 Analisis Data .......................................................................... 52 BAB 5
HASIL PENELITIAN DAN ANALISA DATA. ......................... 54 5.1 Pemeriksaan Kadar IL-1 . ......................................................... 55 5.2 Pemeriksaan Kadar TNF-α. ...................................................... 57
5.3 Pengamatan Ekspresi IL-6........................................................ 59 5.4 Pengamatan Ekspresi ICAM-1. ................................................ 61 5.5 Pengamatan Ekspresi NF-κB ................................................... 63 BAB 6
PEMBAHASAN. ............................................................................ 67
BAB 7
KESIMPULAN DAN SARAN. .................................................... 73
DAFTAR PUSTAKA. .................................................................................... 74 LAMPIRAN…. ............................................................................................... 80
DAFTAR TABEL Tabel
Halaman
5.1 Pengaruh pemberian ekstrak kulit manggis terhadap rerata kadar IL-1(pg/ml) ............................................................................................... 55 5.2 Pengaruh pemberian ekstrak kulit manggis terhadap rerata kadar TNF-α (pg/ml) .......................................................................................... 57 5.3 Pengaruh pemberian ekstrak kulit manggis terhadap ekspresi IL-6 (sel/ lapang pandang) ........................................................................................ 59 5.4 Pengaruh pemberian ekstrak kulit manggis terhadap ekspresi ICAM-1 (sel/lapang pandang) ................................................................................. 61 5.5 Pengaruh pemberian ekstrak kulit manggis terhadap eskpresi NF-κB (sel/lapang pandang) ................................................................................. 63
DAFTAR GAMBAR
Gambar
Halaman
2.1 Komposisi Selular Plak Aterosklerosis ...................................................... 6 2.2 Karakteristik Kelas Lipoprotein Utama. .................................................... 9 2.3 Klasifikasi Lipoprotein .............................................................................. 10 2.4 Klasifikasi Fraksi Lipid menurut NCEP ATP III 2001.............................. 11 2.5 Dislipidemia dan Aterosklerosis ................................................................ 11 2.6 Penyakit yang Terkait dengan Aktivasi NF-κB ......................................... 14 2.7 Rekruitmen dan Aktivasi Sel Imun ............................................................ 15 2.8 Peran Makrofag pada Inflamasi Arteri....................................................... 17 2.9 Efek Aktivasi Sel T pada Inflamasi Plak ................................................... 19 2.10 Peran Translokasi NF-κB pada Aterogenesis .......................................... 20 2.11 Struktur NF-κB/DNA complex : p50 dan p65 ......................................... 21 2.12 Skema NF-κB pada Inflamasi .................................................................. 21 2.13 Ilustrasi NF-κB pathways terhadap respon LPS,TNF dan Antigen ......... 22 2.14 Peran Agen Inflamasi pada Disfungsi Endotel ........................................ 23 2.15 Kaskade Sitokin ....................................................................................... 24 2.16 Target Terapi Aterosklerosis .................................................................... 25 2.17 Buah Manggis .......................................................................................... 26 2.18 Struktur Buah dan Pohon Manggis .......................................................... 26 2.19 Kandungan Nutrisi Manggis. ................................................................... 28 2.20 Struktur Kimia Xanthone pada Kulit Manggis ........................................ 29 2.21 Isolasi Xanthone pada Kulit Manggis. ..................................................... 30 2.22 Aktivitas Anti Inflamasi dan Anti Alergi pada Manggis. ........................ 33
5.1 Grafik Rerata Kadar IL-1 pada Berbagai Kelompok. ................................ 55 5.2 Kurva Persamaan Dosis ekstrak kulit manggis terhadap Kadar IL-1......... 56
5.3 Grafik Rerata Kadar TNF-α pada Berbagai Kelompok. ............................ 57 5.4 Kurva Persamaan Dosis ekstrak kulit manggis terhadap Kadar TNF-α. ... 58 5.5 Grafik Rerata Ekspresi IL-6 pada Berbagai Kelompok ............................. 59 5.6 Kurva Persamaan Dosis ekstrak kulit manggis terhadap Ekspresi IL-6 .... 60 5.7 Gambaran mikroskopis aorta tikus putih dengan perbesaran 200 kali. ..... 61 5.8 Grafik Rerata Ekspresi ICAM-1 pada Berbagai Kelompok. ..................... 62 5.9 Kurva Persamaan Dosis ekstrak kulit manggis terhadap Ekspresi ICAM-1. ................................................................................................. 63 5.10 Gambaran mikroskopis aorta tikus putih dengan perbesaran 200 kali. ... 64 5.11 Grafik Rerata Ekspresi NF-κB pada Berbagai Kelompok. ...................... 64 5.12 Kurva Persamaan Dosis ekstrak kulit manggis terhadap Ekspresi NF-κB ..................................................................................................... 65
DAFTAR SINGKATAN AGE APC ATP BSA CD40 CD40L CD154 COX CRP CXCL CX3CR-1 DAB DNA ELISA HSP HRP ICAM-1 IFN- γ IKK α IKK β IkB IDL IL-1 IL-4 IL-6 IL-10 iNOS IP-10 ITAC-11 kDa LDL LOX-1 LPS M-CSF mRNA MCP-1 Mig MMPs NF-kB NKT
: Advance glycation endproduct : Antigen presenting cell : Adenosine triphosphat : Bovine serum albumin : Cluster of differentiation 40 : CD40 ligand : Cluster of differentiation 154 : Cyclooxygenase : C-reactive protein : CXC-chemokine ligand : CX3-chemokine receptor-1 : Diamino benzidine : Deoxyribonucleic acid : Enzyme linked immunosorbent assay : Heat-shock protein : Horseradish peroxidase : Intracellular adhesion molecule-1 : Interferon gamma : Inhibitor kappa B kinase alpha : Inhibitor kappa B kinase beta : Inhibitor kappa B : Intermediate density lipoprotein : Interleukin-1 : Interleukin-4 : Interleukin-6 : Interleukin-10 : inducible nitric oxide synthase : Inducible protein-10 : IFN-inducible T-cell α-chemoattractant : kilo Dalton : Low density lipoprotein : Lectin-like receptor for oxidized LDL : Lipopolysaccharide : Macrophage colony-stimulating factor : messenger RNA : Monocyte chemoattractant protein-1 : Monokine induced by IFN- γ : Matrix metalloproteinases : Nuclear factor kappa B : Natural killer-T cell
NO ox-LDL PBS PGE2 RANTES ROS TF TG TGF-β Th1 Th2 TLR TMB TNF-α Treg VCAM VLA4 VLDL VEGF
: Nitric oxide : Oxidized low density lipoprotein : Phosphate buffered saline : Prostaglandins E2 : Regulated and T-cell expressed secreted : Reactive oxygen species : Tissue factor : Trigliserida : Transforming growth factor- β : Type 1 helper cell : Type 2 helper cell : Toll-like receptor : Tetra methyl benzidine : Tumor necrosis factor alpha : regulatory T cell : Vascular cell adhesion molecule : Very late antigen 4 : Very low density lipoprotein : Vascular endothelial growth factor
DAFTAR LAMPIRAN Lampiran
Halaman
1. Analisis Kadar IL-1 ..................................................................................... 80 2. Analisis Kadar TNF-α ................................................................................. 83 3. Analisis Ekspresi IL-6 .................................................................................. 86 4. Analisis Ekspresi ICAM-1 .......................................................................... 89 5. Analisis Ekspresi NF-κB.............................................................................. 92 6. Confirmation Dr.Salva Reverentia FK Muhammadiyah ............................. 95 7. Indonesian Oral Acceptance Letter .............................................................. 96 8. Kosultasi Tugas Akhir ................................................................................. 97
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