Abstract

Psoriasis is a life-long immune-mediated dermatosis with thickened, reddish, and flaky skin patches. Canagliflozin is a gliflozin antidiabetic with non-classical remarkable antioxidative, anti-inflammatory, anti-proliferative, and immune-modulating effects. The aim of this study is to examine the probable effects of topical canagliflozin on a mouse model of imiquimod-provoked psoriasis-like dermatitis. The study evaluated 20 Swiss white mice, sorted haphazardly into 4 groups of 5 animals each. Every mouse, with the exception of the control group, had imiquimod applied topically to their shaved backs for 7 days. The control group included healthy mice that were not given any treatment. Mice in the other three groups underwent topical treatment with vehicle (induction group), 0.05% clobetasol propionate ointment (clobetasol group), or 4% canagliflozin emulgel (canagliflozin 4% group) on exactly the same day as imiquimod cream was administered. Topical canagliflozin markedly lowered the intensity of imiquimod-provoked psoriasis eruptions, featuring redness, glossy-white scales, and acanthosis, while also correcting histopathological aberrations. Canagliflozin administration to imiquimod-exposed animals resulted in significantly decreased cutaneous concentrations of inflammatory mediators such as IL-8, IL-17, IL-23, and TNF-α, with raised levels of IL-10. Canagliflozin further lowered proliferative factors involving Ki-67 and PCNA, diminished oxidative indicators such as MDA and MPO, and augmented the activity of antioxidant markers, notably SOD and CAT. Canagliflozin might alleviate the imiquimod-induced animal model of psoriasis, probably thanks to its profound anti-inflammatory, antioxidant, antiangiogenic, and antiproliferative activities. 

Psoriasis is a common dermatological disease that requires ongoing, lifelong care, distinguishes by the presence of itchy or painful erythematous plaques, usually covered with silver, flaking scales. This disease has no cure and available therapy only to relieve symptoms [1-3]. Although psoriasis is often diagnosed clinically, prominent histological features comprise epidermal acanthosis with vasodilation and lymphocyte infiltration and hyperkeratosis, parakeratosis, and keratosis [4, 5]. Psoriasis has a complicated origin, with immunological and genetic components driving disease progression. Psoriasis is involving innate and adaptive immune system arms in its pathogenesis [6]. Furthermore, environmental and behavioral variables such as skin trauma or damage, infection, injury/Koebner phenomenon, cigarette smoking, alcohol intake, some drugs such as lithium, imiquimod, and interferon, and even stress can aggravate psoriasis [7, 8].

Sodium-glucose co-transporter-2 (SGLT2) inhibitors, often referred to as gliflozins, originated as an innovative category of anti-diabetic medications that facilitate glycosuria by lowering the uptake of glucose in the proximal tubules [35-37]. They consist of the following medications: canagliflozin, dapagliflozin, empagliflozin, luseogliflozin, ipragliflozin, and phlorizin and exhibit variable selectivity towards SGLT1 and SGLT2, along with their structural variations [38, 39]. Notably, canagliflozin is a remarkably selective SGLT2 antagonist; its binding capacity for SGLT2 is around 250 times greater than its propensity for SGLT1 [40]. Notwithstanding their differing selectivity, SGLT2 inhibitors have comparable pharmacokinetics, including fast absorption, a prolonged half-life, profound liver metabolism, minimal renal clearance, and a lack of interactions between drugs [41].
Despite SGLT2 inhibitors being initially investigated for their ability to reduce blood glucose levels, their pleiotropic actions on a variety of targets across the body's tissues were just recently identified, in diabetes and non-diabetes people  [42, 43]. The beneficial actions of SGLT2 blockade extended beyond glycemic regulation include improvements in blood pressure, body weight, uricemia, albuminuria, visceral fat, liver stenosis, cardiac and renal events, oxidative injury, autoimmunity, and inflammation [44-47].
In addition to that, SGLT2 inhibiting agents have been demonstrated to be involved in the regulation of a variety of physiological processes, including osmotic natriuresis and diuresis [48, 49]. However, investigations conducted in vitro and in vivo suggested that SGLT2 inhibitors may have anti-inflammatory capabilities [61, 62]. Remarkably, canagliflozin has advantages in limiting hepatic fibrosis and inflammation in mice with non-alcohol-related steatohepatitis by diminishing macrophage intrusion and lowering nuclear factor kappa B (NF-κB) activation [63]. This medicine also ameliorates cognitive decline in a rat model of scopolamine-aggravated memory impairments through its action on the cholinergic and monoaminergic systems [64]. In the same direction, canagliflozin's stimulation of AMP-activated protein kinase (AMPK) and consequent suppression of mechanistic target of rapamycin (mTOR), p65, and oxidative stress-related genes attenuated inflammasome formation and activation. This resulted in dampening caspase-1 activation and preventing the production of IL-1β and IL-18 [65]. This medication additionally reversed the Th1/Th2 cell unbalance, dampening the deterioration of podocyte autophagy promoted by immunoglobulin G production from B-cells in a rat model of autoimmune membranous nephropathy [66].

All of the research listed above implies that gliflozins have pleiotropic anti-inflammatory, antioxidant, and antiproliferative effects, but to date, their antipsoriatic potential has not been examined. As a result, the objective of this experiment was to investigate the anti-psoriatic activity of canagliflozin in murine model of imiquimod-aggravated psoriasis under normal glucose levels.

The current 7-day observation was designed to explore the therapeutic efficacy of canagliflozin in combating an experimental mouse model of imiquimod-aggravated psoriasiform dermatitis. This was achieved through exploring the impacts of canagliflozin on cutaneous lesions as well as the concentrations of biological indicators associated with oxidation, inflammation, proliferation, and histopathological transformations of skin tissues. 
The prototype of imiquimod-exacerbated psoriasis in mice is increasingly being employed for investigations on molecular mechanisms, antipsoriatic medicine advancement, and transdermal drug uptake [156, 160-165]. Imiquimod is a selective activator of TLR7/8 ligands detected on dendritic cell membranes. Imiquimod-exacerbated dendritic cell proliferation triggers an enormous inflow of lymphocytes from the immune system into the tissue beneath the skin This, in turn, prompts the TNF-α/IL-23/IL-17 axis to produce incendiary cytokine proteins, outwardly observable as redness, scaling development, and skin thickening [30, 31, 166-168]. Furthermore, imiquimod can induce psoriasis by activating Langerhans cells, which in turn releases NF-κB, the primary transcription factor, and cytokines, namely IFN-γ, IL-6, IL-8, and TNF-α [164, 169, 170].
The traditional medicine utilized in this research, clobetasol, demonstrated major improvements in the clinical signs of psoriasis thanks to its anti-inflammatory, anti-mitotic, vasoconstrictive, and immunosuppressive capabilities, which actually mitigated the amount of skin proliferating behavior and lessened lymphocytic infiltration [171, 172].
A decline in mast cell numbers may be the reason for a reduction in the redness grades, while hindering keratinocytic proliferation and lowered melanocytic production may be the explanation for the improvements in the scaling grades [3, 163]. The antiproliferative impact of clobetasol treatment provides an invaluable function in minimizing cutaneous patch thicknesses via boosting lipocortin output, thereby attenuating epidermal multiplication [173, 174]. 
This study found that topically applied canagliflozin profoundly mitigated imiquimod-driven psoriasiform inflammation by attenuating PASI scores, correcting histopathological aberrations, and minimizing the expression of inflammatory, oxidative, and proliferative biochemical markers while boosting the expression of anti-inflammatory and anti-oxidant markers. 
Interestingly, preliminary clinical investigations demonstrated that gliflozins had anti-inflammatory properties irrespective of their hypoglycemic impact. This suggests the potential presence of additional pathways via which gliflozins may be regarded as an effective option for treating a broader range of inflammatory disorders [175, 176]. Studies in this vein have revealed that the mechanisms underpinning the additional advantages of SGLT2 inhibitors are likely multifaceted and consist of diminution of inflammatory cytokine release, alleviation of oxidative stress, amelioration of macrophage invasion, enhancement of autophagy, and suppression of endothelial damage, independent of their glucose-lowering actions [177-179]. In light of the latest research, SGLT-2 suppression by canagliflozin, dapagliflozin, and empagliflozin substantially attenuated biomarkers of inflammation and oxidative stress as well as macroscopic and microscopic bowel injury in a rat model of acetic-acid-exacerbated colitis [180-182]. In this regard, canagliflozin effectively halted acetic acid-aggravated colitis and oxidative damage by substantially lowering amounts of MDA, total nitrite, NF-κB, IL-1β, and TNF-α and considerably elevating amounts of GSH, SOD, and IL-10 [181]. Beyond that, intrarectal application of a canagliflozin-loaded chitosan hyaluronic acid formulation ameliorated acetic acid-driven colitis in rats by substantially suppressing the TLR4/NF-κB/NLRP3 axes, downregulating IL-1β and IL-18, stimulating autophagy, and modifying the AMPK/mTOR axes [183]. Additionally, a new analysis provided solid evidence that canagliflozin, dapagliflozin, and remogliflozin all possess long-lasting anti-inflammatory and wound-healing characteristics, with canagliflozin being the most effective of the three drugs tested [184]. Significantly, SGLT2 inhibitors are capable of blocking the production of inflammatory markers such as MCP-1, TGF-β, TNF-α, IL-6, and NF-kB [185, 186]. Besides, canagliflozin use in animals hinders fibrosis, and oxidation biomarkers and boosts antioxidant and anti-inflammatory signaling via AMPK, Akt, endothelial nitric oxide synthase (eNOS), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Moreover, pro-oxidative, pro-inflammatory, and pro-apoptotic signaling generated by TGF-β, NADPH oxidase isoform 4 (Nox4), and inducible nitric oxide synthase (iNOS) is also attenuated by canagliflozin administration [187]. Importantly, canagliflozin was correlated with a substantial diminution in blood IL-6 concentrations in diabetic individuals [188-190]. Besides, canagliflozin alleviates severe hepatic impairment caused by thioacetamide via blocking oxidative and inflammatory parameters, notably mitogen-activated protein kinase (MAPK), NF-κB, and TNF-α [191].