الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
The present study evaluated the gastroprotective effect of individual and combined use of vitamin D, simvastatin and α-lipoic acid against indomethacin-induced gastric ulcer in adult male rats.
The protective effect of these drugs was evaluated by checking the stomach of rats both macroscopically and microscopically.
Furthermore, the levels of some biochemical markers of oxidative stress, inflammation and gene expression of angiogenic and anti-apoptotic factors were assessed.
The main results and conclusions are summarized and outlined below:
1. The oral administration of indomethacin induced multiple ulcers in gastric mucosa.
Indomethacin-induced gastric ulcer was associated with increased levels of inflammatory markers (increased serum CRP, gastric mucosal TNF-α, and TGF-β1) and
augmentation of gastric mucosal oxidative stress (increased MDA and nitic oxide and
decreased GSH levels, SOD and catalase activities).
On the other hand, the gene
expression of VEGF (angiogenic factor) and miR-21 and mir-210 (anti-apoptotic
regulatory microRNA) were increased in the gastric mucosa as indicies of endogenous
repair.
<2. The administration of vitamin D orally for 6 days, prior to the induction of gastric
ulcer by indomethacin, partially reduced the incidence and severity (ulcer index) of
indomethacin-induced gastric ulcer.
The anti-ulcerogenic action of vitamin D could be
attributed to its anti-inflammatory action manifested as reduced serum CRP and mucosal
TNF-α and TGF-β1.
This is in addition to its well-known antioxidant effect manifested as
decreased gastric MDA, nitric oxide and increased the levels of GSH, SOD and catalase
activities.
<3. Administration of simvastatin for 6 days, prior to the induction of gastric ulcer by
indomethacin, partially ameliorated the ulcerogenic action of indomethacin and showed
ulcer index equivalent to that of vitamin D. Nonetheless, the anti-inflammatory and
antioxidant effects of simvastatin were superior to that of vitamin D. Notably, unlike
vitamin D, simvastatin increased the gene expression of VEGF and mir-21.
<99<
4. Alpha-lipoic acid administration for 6 days, prior to the induction of gastric ulcer
by indomethacin, partially reduced indomethacin-induced gastric lesions via reduction of
inflammatory markers as well as oxidative stress.
<However, the reducion in gastric ulcer
index was significantly less than that induced by vitamin D or simvastatin.
Although α-
lipoic acid was able to restore normal mir-21 and mir-210 (even in presence of evident
ulceration in the stomach), the gene expression of VEGF gene expression was increased
tremendously possibly to increase blood flow to accelerate healing in absence of the
ability of α-lipoic acid to increase the gene expression of anti-apoptotic regulatory genes
as mir-21 and mir-210.
<5. Morphologically as represented by the ulcer index, combined treatment with
vitamin D and simvastatin did not revealed a better protective effect on indomethacininduced
ulcer compared to groups treated with vitamin D or simvastatin alone.
Nonetheless, this combination showed significantly more anti-inflammatory and
antioxidative action compared to its individual drugs.
< Notably, this combination showed
the least nitrate/nitrite content in the gastric mucosa indicating the lowest production in
nitric oxide in the mucosal tissue.
< Also, this combination showed a universal heightened
increase in the gene expression of the cellular proliferative markers assessed in this work (VEGF, mir-21 and mir-210), which dictate caution in dealing with simvastatin and
vitamin D combination and warrant further research.
<6. Combined treatment with vitamin D and α-lipoic acid showed a greater protective
effect on indomethacin-induced ulcer compared to groups treated with α-lipoic acid
alone.
This combination showed a better anti-inflammatory and antioxidant effects
compared to the individual drugs.
Interesting, this combination showed the greatest
capacity in restoring the level of GSH to near normal levels compared to all other tested
individual drugs or combinations.
The increase in GSH can explain the ability of vitamin
D to mitigate the increased in VEGF gene expression induced by α-lipoic acid.
<7. Clinically, it is crucial to identify the molecular
mechanisms involved in gastric
ulcer to design new strategies for gastric ulcer treatment.
<The use of vitamin D,
simvastatin, α-lipoic acid, or their combinations in the current study plays an important
role in protection against gastric ulcer and could clarify the contribution of oxidative
stress and inflammation as well as angiogenic and anti-apoptotic factors in modulating
gastric ulcer course.
Subsequently, the present data emphasizes on the prospective drug
interactions revealed upon using novel therapy of drug combinations in gastric ulcer
treatment, which necessitates further studies prior to implementing new combined
treatment.