## 4 Discussion
Measurement of paw volumes after edema induction by carrageenanan revealed that administration of Summer Savory extract impaired the increase in paw volume by 46.5% when compared to animals administered with vehicle. Additionally, the magnitude of that effect was not statistically different when compared to positive control groups administered with known antioxidant and anti-inflammatory properties (49% for indomethacin, 48% for Trolox, and 45.5% for tempol), indicating a potential benefit of this extract in inflammatory-mediated diseases. The analgesic and anti-inflammatory effects of Summer Savory seed essential oil and hydroalcoholic and polyphenic extracts was evaluated by [PERSON] and colleagues [9]. Anti-nociceptive activity was evaluated in the mouse models of acetic acid and formalin-induced pain. Appraisement of anti-inflammatory activity was performed in the carrageenanan-induced rat paw edema model was. Animals were pretreated with 50, 100, or 200 mg/kg, i.p. and 100 or 200 \(\mu\)L/kg, p.o, in the anti-nociceptive and anti-inflammatory models, respectively. Administration of hydroalcoholic and polyphenic extracts or essential oil significantly decreased acetic acid-induced abdominal twitches, while hydroalcoholic extract additionally decreased pain responses in both early and late phases of the formalin test. In this test, the polyphenic extract and essential oil only demonstrated beneficial effect in the late phase of the formalin test, while all three fractions reduced paw edema in the carrageenanan model. However, even though one of the fractions tested was a polyphenic extract, it was a seed extract which corresponds to a very different chemical constitution from a leave extract. After the anti-inflammatory effect of Summer Savory was confirmed in an acute local model of inflammation, we aimed to access the positive effect of the extract in an experimental colitis mouse model. Administration of Summer Savory extract to animals with TNBS-induced colitis drove to a decrease of multiple markers of colon injury and inflammation: impairment of colon length decrease, reduction of injury extent, decrease of diarrhea severity, and reduction of mortality rate. Additionally, both macroscopical and histological signs of colon inflammation were decreased in animals administered with Summer Savory extract compared to colitis animals. Surprisingly, even though no preclinical animal study was published until now that evaluated the beneficial effects of Summer Savory in experimental IBD, there is one publication reporting the results of a small clinical trial studying the administration of a commercial preparation of Summer Savory in Ulcerative Colitis patients [53]. This trial was a randomized, double-blind, placebo-controlled study that assessed the clinical benefit of commercial tablets of dried leaves of Summer Savory (500 mg daily) in Ulcerative Colitis. After 4 months, 85% (12/14) of patients that received supplementation with Summer Savory extract were in complete remission when compared to 46.2% (6/13) of patients on placebo. The flare up frequency was also statistically lower for patients treated with Summer Savory extract. This trial was very limited in terms of dimension, given that included only 27 patients total; nevertheless, it suggests a beneficial effect of Summer Savory in inflammatory bowel disease patients. In our study, a relatively low dose phenolic extract of 15 mg/kg was used, which was derived from previous studies from our group that have been assessing the positive effects of different phenolic extracts in multiple models of inflammation with this dose of phenolic acids having generated matching results and is also within the dose-range of clinical translation [44; 45; 46; 54]. Lately, we have been evaluating the protective effect of phenolic extracts originating from aromatic herbs and have demonstrated a beneficial effect of the administration of spearmint and pennyroyal phenolic extracts in this animal model of TNBS-induced Ulcerative Colitis [14; 15].