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Title:	Combined effects of delta tocotrienol and lovastatin on bone metabolism in ovariectomised rats
Authors:	Saif Saad Abdul Mejeed (P59331)
Supervisor:	Ima-Nirwana Soelaiman, Professor Dr.
Keywords:	Bone metabolism Dissertations, Academic -- Malaysia
Issue Date:	29-May-2014
Description:	Osteoporosis merupakan masalah kesihatan dan ekonomi yang membimbangkan. Osteoporosis jenis pasca-menopaus ialah osteoporosis yang paling lazim dijumpai dan kejadian ini adalah disebabkan oleh kekurangan estrogen. Tapak jalan mevalonate telah dibuktikan mempengaruhi kesihatan tulang. Statin merupakan perencat enzim penurun 3-hidroksi-3-metil-glutaril-koA (HMG-CoA), yakni langkah penentu kadar tindak balas dalam tapak jalan mevalonat. Berbeza dengan statin, vitamin E delta-tokotrienol ialah pengawal turun enzim penurun HMG-CoA. Kajian-kajian terdahulu menunjukkan manfaat statin dan tokotrienol ke atas kesihatan tulang. Bagaimanapun, dos statin yang tinggi diperlukan untuk memperlihatkan kesan dadah ini. Dos statin yang tinggi telah dikaitkan dengan hepatotoksisiti dan miopati. Tujuan kajian ini adalah untuk menentukan kesan gabungan delta-tokotrienol dan lovastatin dalam dos yang selamat secara klinikal ke atas metabolisme dan kekuatan tulang dalam model tikus pasca-menopaus, dan membandingkan kesan dadah-dadah tersebut diberi secara bersama dan secara berasingan. Empat puluh lapan tikus betina Sprague Dawley telah dibahagikan secara rawak kepada enam kumpulan dengan setiap kumpulan mempunyai lapan ekor tikus: kawalan asas; kawalan sham; kawalan ovariektomi; ovariektomi + 11mg / kg lovastatin; ovariektomi + 60 mg/ kg delta-tokotrienol dan ovariektomi + 60 mg / kg delta-tokotrienol + 11 mg / kg lovastatin. Kumpulan-kumpulan ini diberi rawatan secara paksa-oral selama lapan minggu. Selepas dikorbankan, serum, femur kiri dan kanan, tibia kiri tikus diproses untuk ujian biokimia tulang, analisis histomorfometri tulang, ujian kekuatan mekanikal tulang dan asai ekspresi protein morfogenetik tulang. Keputusan menunjukkan tikus yang mengalami kekurangan estrogen mengalami penurunan pembentukan tulang, peningkatan resorpsi tulang dan kerapuhan tulang. Penggunaan delta-tokotrienol sahaja mampu meningkatkan pembentukan tulang, menurunkan resorpsi tulang dan meningkatkan kekuatan tulang bagi menentang fraktur tulang. Penggunaan lovastatin sahaja tidak dapat menentang kesan negatif kekurangan estrogen ke atas metabolisme tulang. Rawatan gabungan delta-tokotrienol dan lovastatin meningkatkan pembentukan tulang, menurunkan resorpsi tulang dan meningkatkan kekuatan tulang serta menentang fraktur tulang secara signifikan. Tambahan pula, rawatan gabungan kedua-dua dadah adalah lebih berkesan berbanding dengan rawatan secara berasingan. Kesan positif rawatan gabungan ke atas status kesihatan tulang mungkin disebabkan oleh kesan sinergistik ataupun tambahan dadah-dadah ini ke atas tapak jalan mevalonat. Rawatan gabungan delta-tokotrienol dan lovastatin dalam dos yang selamat secara klinikal berpotensi digunakan sebagai agen antiosteoporotik, khususnya pada pesakit yang berisiko tinggi menghidapi kedua-dua masalah kesihatan, yakni osteoporosis dan hiperkolesterolemia seperti golongan wanita pasca-menopaus.,Osteoporosis is a grievous health problem as well as an economic burden. Postmenopausal osteoporosis is the commonest type and is due to estrogen deficiency. The mevalonate pathway had been shown to negatively regulate bone health. Statins are potent inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-COA) reductase, the rate limiting step in the mevalonate pathway. Unlike statins, vitamin E delta-tocotrienol is a down-regulator of HMG-COA reductase. Previous studies had clearly demonstrated the beneficial effects of statins or tocotrienols on bone health. However, higher doses of statins were required to exert their effects. Hepatotoxicity and myopathy were associated with high statin doses. The aim of this study was to determine the effect of combining delta-tocotrienol and lovastatin on bone metabolism and strength in a postmenopausal rat model at a clinically tolerable statin dose and to compare it with the effect of individually supplemented delta-tocotrienol and lovastatin in estrogen-deficient ovariectomised rats. Forty eight Sprague Dawley female rats were randomly divided into six groups of eight rats: baseline control; sham-operated control; ovariectomised control; ovariectomised + 11 mg / kg lovastatin; ovariectomised + 60 mg / kg delta-tocotrienol and ovariectomised + 60 mg / kg delta-tocotrienol + 11 mg / kg lovastatin. These treatments were given daily via oral gavage for eight weeks. Following sacrifice; serum, left and right femurs and left tibia were processed for bone biochemical markers, bone histomorphometric analysis, bone biomechanical strength test and bone morphogenetic protein expression respectively. The results showed that long term estrogen deficiency had significantly reduced bone formation, increased bone resorption and increased bone fragility of the ovariectomised rats. The use of delta tocotrienol alone enhanced bone formation, decreased bone resorption, and strengthened the bone against fracture. The use of lovastatin alone did not prevent nor restore the deleterious effects of estrogen deficiency on bone metabolism. The use of delta-tocotrienol in combination with lovastatin significantly augmented bone formation, reduced bone resorption, and strengthened the bone against fracture. Moreover, the combination therapy was more effective than the mono therapies. The positive effects of the combined treatment on bone health status might be in a synergistic or additive manner by suppressing the mevalonate pathway. Combination of delta-tocotrienol plus lovastatin at clinically tolerable doses has the potential to be used as an anti-osteoporotic agent especially in patients who are at risk of both conditions, that is, osteoporosis and hypercholesterolemia. This is especially true for postmenopausal women.,PhD
Pages:	280
Publisher:	UKM, Kuala Lumpur
Appears in Collections:	Faculty of Medicine / Fakulti Perubatan

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