Učinci pentadekapeptida BPC 157 na posttraumatski osteoartritis koljena u štakora [Effects of pentadecapeptide BPC 157 on post-traumatic knee osteoarthritis in the rat]

Krstonijević, Zoran (2018) Učinci pentadekapeptida BPC 157 na posttraumatski osteoartritis koljena u štakora [Effects of pentadecapeptide BPC 157 on post-traumatic knee osteoarthritis in the rat]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Introduction. Osteoarthritis (OA) is the most common joint disease and among the most important causes of pain, disability and economic loss in all populations. A substantial fraction (12 %) of the overall burden of disease of OA arises secondary to joint trauma. With the best current care of significant joint injuries, the risk of post-traumatic OA (PTOA) ranges from about 20 % to more than 50 %. Considering that disease-modifying OA therapies are presently not available, and numerous positive effects of pentadecapeptide BPC 157 on healing of different injuries and tissues, the need for this investigation is imposed. Materials and methods. Research was conducted on surgical model of knee PTOA in the rat (female Wistar albino rats weighing an average of 200 g and aged 8-10 weeks, kept in standard conditions) after MCL transection, medial meniscectomy and ACL transection of the right knee. Pentadecapeptide BPC 157 was administred in doses of 10 μg/kg or 10 ng/kg, dissolved in drinking water, perorally (0,16 μg/ml or 0,16 ng/ml, 12 ml/rat/day, dailly till sacrifice), and dissolved in saline solution, intraarticularly (20 μg/ml or 20 ng/ml, 0,1 ml/aplication, two weeks interval, first aplication immediately after surgery, last aplication two weeks before sacrifice). Control groups received pure drinking water or 0,1 ml of saline solution intraarticularly. Considering route of administration and administred dose, after surgery animals were distributed in 12 treated and 6 control groups (each group with 5 animals), randomly (cotreatment 4 weeks, cotreatment 8 weeks, post-treatment 8 weeks - treatment started after 4 weeks). Throughout whole duration of experiment, functional measurements (gait analysis, extensor postural thrust, assessment test for knee contracture) were conducted on day 1, 7, 14, 28, 42 and 56 after surgery. Sacrifice was conducted on day 28 for cotreatment 4 weeks, and on day 56 for cotreatment 8 weeks and post-treatment. Immediately after sacrifice radiological interpretation and macroscopical assessment were conducted, as well as preparing of samples for histological interpretation. Results. Functional indicators in all control groups clearly indicated significant loss of function of operated leg immediately after surgery. As opposed to control groups, all cotreated groups showed substantially faster and more complete functional recovery. In post-treated groups contrary to control groups improvement of function was visible throughout time, however definitive values differed significantly from normal values. Macroscopical and histological, as well as radiological indicators in control groups showed clearly expressed signs of moderate PTOA after 4 weeks, and clearly expressed signs of heavily, advanced PTOA after 8 weeks. As opposed to control groups, all cotreated groups showed substantially better results. In post-treated groups in comparison with control groups differences were significantly lower. Effectiveness of pentadecapeptide BPC 157 is clearly visible at peroral and intraarticular administration, and at doses of 10 μg/kg and 10 ng/kg. Statistical analysis showed results statistically significant (P<0,05). Conclusion. Pentadecapeptide BPC 157 administration have substantial effect on prevention of developement and progression of PTOA, and on regression of already developed PTOA on surgical model of knee PTOA in the rat, independently of admistration route and administred dose.

Abstract in Croatian

Uvod. Osteoartritis (OA) je najčešća bolest zglobova i jedan od najvažnijih uzroka bolnosti, onesposobljenja i ekonomskih gubitaka u svim populacijama. Znatan udio (12 %) ukupne pojavnosti OA posljedica je zglobnih ozljeda. Uz najbolju trenutno moguću skrb značajnih zglobnih ozljeda, rizik za razvoj posttraumatskog OA (PTOA) kreće se od oko 20 % do više od 50 %. S obzirom da trenutno ne postoji farmakološki agens za terapiju osteoartritisa koji mijenja tijek bolesti, te na brojne pozitivne učinke pentadekapeptida BPC 157 na cijeljenje različitih ozljeda i tkiva, nametnuta je potreba za ovim istraživanjem. Materijali i metode. Istraživanje je provedeno na kirurškom modelu PTOA koljena u štakora (ženke Wistar albino štakora prosječne težine 200g i dobi 8-10 tjedana držane u standardnim uvjetima) nakon transekcije MCL-a, medijalne meniscektomije i transekcije ACL-a desnog koljena. Pentadekapeptid BPC 157 primjenjen je u dozi 10 μg/kg ili 10 ng/kg, otopljen u vodi za piće, peroralno (0,16 μg/ml ili 0,16 ng/ml, 12 ml/štakor/dan, svakodnevno do žrtvovanja), te otopljen u fiziološkoj otopini, intraartikularno (20 μg/ml ili 20 ng/ml, 0,1 ml/aplikacija, dvotjedni intervali, prva aplikacija neposredno nakon operacije, zadnja aplikacija dva tjedna prije žrtvovanja). Kontrolne skupine dobivale su čistu vodu za piće ili 0,1 ml fiziološke otopine intraartikularno. S obzirom na način primjene i primjenjenu dozu BPC 157 životinje su nakon operacije raspoređene u 12 tretiranih i 6 kontrolnih skupina (svaka sa po 5 životinja) metodom slučajnog odabira (kotretman 4 tjedna, kotretman 8 tjedana, posttretman 8 tjedana - tretiranje je počelo nakon 4 tjedna). Tijekom trajanja pokusa funkcionalna testiranja (analiza hoda, test pritiska ekstenzora, test za procjenu kontrakture koljena) vršena su 1., 7., 14., 21., 28., 42. i 56. poslijeoperacijski dan. Žrtvovanje je provedeno 28. dan za kotretman 4 tjedna i 56. dan za kotretman 8 tjedana i posttretman. Neposredno nakon žrtvovanja provedena je RTG obrada i makroskopska procjena, te priprema preparata za histološku obradu. Rezultati. Funkcionalni pokazatelji u svim kontrolnim skupinama jasno su ukazali na značajan gubitak funkcije operirane noge neposredno nakon operacijskog zahvata. Nasuprot kontrolnim skupinama sve kotretirane skupine pokazale su znatno brži i potpuniji funkcijski oporavak. Kod posttretiranih skupina vidljivo je poboljšanje funkcije u odnosu na kontrolne skupine protekom vremena, međutim konačne vrijednosti značajno zaostaju za normalnim vrijednostima. Makroskopski i histološki, te radiološki pokazatelji u kontrolnim skupinama pokazali su jasno izražene znakove umjerenog PTOA nakon 4 tjedna praćenja, dok su nakon 8 tjedana pokazali izražene znakove teškog, uznapredovalog PTOA. Nasuprot kontrolnim skupinama sve kotretirane skupine pokazale su značajno bolje rezultate. Kod posttretiranih skupina razlike u odnosu na kontrolne skupine bile su znatno manje. Vidljiva je učinkovitost pentadekapeptida BPC 157 kod peroralne i intraartikularne primjene, te u dozi 10 μg/kg i 10 ng/kg. Statističkom obradom rezultati su potvrđeni kao statistički značajni (P<0,05). Zaključak. Primjena pentadekapeptida BPC 157 ima značajan učinak na sprječavanje razvoja i progresije PTOA, te na regresiju već razvijenog PTOA na kirurškom modelu PTOA koljena u štakora, neovisno o načinu primjene i primjenjenoj dozi.

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