الفهرس 
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Abstract
In The Present Study, The Anti-Arthritic Effects Of Nicorandil And Theophylline Were Examined With Focus On The Role Of JAK/STAT/RANKL Signaling Pathway. AIA Model Was Used To Induce RA And GH Was Used To Activate JAK/STAT/RANKL Signaling Pathway.
Induction Of RA Was Performed By S.C. Injection Of A Single Dose Of CFA (0.3 Ml) In The Planter Surface Of The Rat Hind Limb.
To Study The Possible Effects Of Drugs On RA And JAK/STAT/RANKL Signaling Pathway Four Sets Of Experiments Were Performed. In The First Set, Effects Of Test Agents On Normal Animals Were Examined. Animals Were Randomly Assigned Into Three Groups; A Normal Control group Receiving Vehicles, A Nicorandil group And A Theophylline Group. In The Second Set, Effects Of Test Agents On CFA-Induced RA Were Examined. Animals Were Allocated Into Four Groups, Namely A Normal Control group (Receiving Vehicles Alone), An Arthritis Control group (Receiving CFA Alone) And Two Treatment Groups Receiving Nicorandil Or Theophylline Plus CFA. In The Third Set, Effects Of Test Agents On GH-Induced Stimulation Of JAK/STAT/RANKL Signaling Pathway Were Examined. Animals Were Allocated Into Four Groups, Namely A Normal Control Group, A GH Control group Receiving Only GH, And Two Treatment Groups Receiving Nicorandil Or Theophylline Plus GH. In The Fourth Set, Effects Of Test Agents On CFA/GH-Induced RA Were Examined. Animals Were Allocated Into Four Groups, Namely A CFA Control Group, A CFA/GH Control group And Two Treatment Groups Receiving Nicorandil Or Theophylline Plus CFA/GH Combination.
Test Agents Were Administered On A Daily Basis For 14 Days Starting from Day 12 After A Single Dose Of CFA Or Respective Vehicle. Nicorandil Was Given In A Dose Of 15 Mg/Kg/Day, P.O. Theophylline Was Given In A Dose Of 20 Mg/Kg/Day, I.P. GH Was Given In A Daily Dose Of 2 Mg/Kg/Day, S.C. For 12 Days Starting from The Day Of CFA Administration.
Estimation Of RA Induction, JAK/STAT/RANKL Signaling Pathway Activation And Effect Of Drugs Was Performed By Determination Of Serum Levels Of ACPA And COMP As Rheumatoid Markers, Furthermore, Tissue Levels Of JAK2, STAT3, RANKL, And Serum IL-6 Level As Signaling Pathway Markers As Well As Tissue Levels Of Enos, Inos And MIP1α As Inflammatory Markers. Finally The Knee Joints Were Cut For Histopathological Study.
The Main Findings Of The Present Investigation Can Be Summarized As Follow:
1. Effect Of Test Agents On Normal Animals
Nicorandil And Theophylline Showed No Effect On Serum Levels Of ACPA, IL-6 And COMP, Or Joint Tissue Levels Of JAK2, STAT3, RANKL, Inos, Enos And MIP1α In Normal Animals.
2. Effect Of Test Agents On CFA-Induced RA
Rats Subjected To CFA Alone Showed Significantly Higher Levels Of Serum ACPA, IL-6 And COMP, Significantly Higher Levels Of Tissue JAK2, STAT3, RANKL, Inos And MIP1α, And Significantly Lower Levels Of Tissue Enos Compared With Normal Animals. Alternatively, Administration Of Nicorandil Or Theophylline Caused Significant Correction Of All Biomarkers Compared With CFA Control Values.
3. Effect Of Test Agents On GH-Induced Stimulation Of JAK/STAT/RANKL Signaling Pathway
Administration Of GH To Normal Animals Significantly Increased JAK2, STAT3, RANKL, Inos And MIP1α Expression Together With Serum Levels Of ACPA, IL-6 And COMP Level And Significantly Decreased Tissue Level Of Enos. Nicorandil And Theophylline Significantly Decreased Both Values, With The Effect Of Nicorandil Being Significantly Better Compared With Theophylline Regarding RANKL Expression.
4. Effect Of Test Agents On CFA/GH-Induced RA
Combination Of GH With CFA Showed Significantly Higher Serum Levels Of ACPA (144%), IL-6 (176%) And COMP (149%), As Well As Joint Tissue Levels Of JAK2 (148%), STAT3 (143%), RANKL (132%), Inos (163%) And MIP1α (175%), Coupled With Decreased Tissue Levels Of Enos (62%) As Compared With Animals Receiving CFA Alone. Nicorandil Or Theophylline Administration Significantly Corrected All The Measured Biomarkers Compared With CFA/GH Control Rats.
Depending On The Previous Findings, It Could Be Concluded That:
1. Ncorandil And Theophylline May Be Promising Drugs In The RA Management As They Have A Potent Anti-Inflammatory And Immune-Modulator Effects, Which Are Mediated, At Least Partly, By Modulation Of Janus Kinase Signaling Pathway.
2. Further Clinical Trials Are Needed To Confirm The Value Of Such Pre-Clinical Studies.