INTRODUCTION:

The world population suffers from inflammatory skin diseases atopic dermatitis and psoriasis almost 3%, of which 1-3% affects the adult population with various extra-cutaneous manifestations¹. This disease is very commonly known because of its significant effect on patients' quality of life². As a result, more than a cosmetic nuisance, psoriasis is associated with psychosocial effects that seriously affect quality of life and social relations³. Psoriasis is a long-term autoimmune condition where both genetic and environmental factors play significant roles. It originates from the Greek words 'psora,' meaning itch, and 'isis,' meaning inflammation⁴. This immune-mediated disease requires discorded interactions between immune cells and keratinocytes⁵. Meanwhile, Rouxel and Lehunen stated that society does not fully understand the immune-mediated disease⁶. Hence, comprehensive research into the fundamental structures is done⁷. In recent research, patients who have psoriasis may also express their feelings of consciousness, helplessness, anger, frustration, and embarrassment whi, which is followed by low confidence, poor self-visualize, the absence of self-assurance, and a huge low feeling of prosperity⁸ .

Due to the fact that psoriasis does not normally arise in laboratory animals, thorough study is still ongoing into the disease's pathophysiology⁹. However, specific features of their intricate immune disease can be uncovered in study animals through knockout, transgenic, immunological reconstruction, xenotransplantation, spontaneous mutation or drug-induced¹⁰. Uncontrolled proliferation with differentiation of keratinocytes and dysfunctional is signified by the persistent inflammation. Epidermal hyperplasia and an inflammatory infiltration made up of neutrophils, dermal dendritic cells, T cells, and macrophages are visible in the histology of psoriatic plaques¹¹.

Research animals, particularly mice, help study the prevalence of inflammation and cellular reactions of innate adaptive immune systems. Psoriasis occurs due to dysregulation, the relationship between the adaptive immune and innate systems as well as the complexity of immune systems. Evidence suggests that autoimmune and autoinflammatory pathways are the root of this illness. In psoriasis, T cells and adaptive immune cells are involved¹².

The IMQ-induced psoriasis mice model provides a powerful tool for understanding early events during psoriasiform plaque formation and the role of various cytokines, cell types, and cellular pathways involved in disease formation¹³. Imiquimod (IMQ) is an immune activator often used as a ligand for Toll-Like Receptors 7 (TLR7) and TLR 8. It was also recently reported to have an inflammatory effect similar to psoriasis. Wolfram, Morandi, Eberhart, Hautz, Hackl, Zelger, Riede, Wachter, Dubrac, Ploner, Pierer, and Schneeberger¹⁴ IMQ’s immunomodulatory action in inducing psoriasis was observed due to TLR7 stimulation in plasmacytoid dendritic cells and upregulation of the Type I interferon pathway, adenosine receptors, and increased inflammation. Previous studies where rats were given IMQ as an experimental model resulted in disruption of the adenosine receptor signaling pathway and increased inflammation¹⁵. A study describing interleukin role (IL)-23/IL-17 in IMQ-induced the inflammation in rats skin was also confirmed through histopathological examination, showing characteristics similar to psoriasis¹⁶. Therefore, IMQ is considered easy and convenient as a psoriasis-inducing agent in animal models for studying the mechanistic evaluation of the acute inflammatory response in animals and humans¹⁷.

Parmar et al.¹⁸ examined the administration of IMQ at doses of 80 mg, 100 mg, and 120mg for the occurrence of psoriasis. It found that erythema signs, thickening, and scaling was given IMQ 120mg and 100mg with thickening of the ears and back of the rats. Previous research explains that the steric energy for imiquimod was calculated to be 59.09kcal/mol. It was concluded that the lowest energy and most stable conformation of imiquimod was 59.09kcal/mol. The most energetically favorable conformation of imiquimod was found to have a heat of formation of 908.38kcal/mol. So, conducting further research on IMQ in experimental animals is necessary¹⁹. The biochemical evaluating a significant increase of granulation tissue weight, decreased collagen, and hexosamine levels. In skin lesions, nitric oxide and lipid peroxidation rapidly increased. although superoxide dismutase and catalase antioxidant characteristics decreased. Increasing expression of pro-inflammatory cytokines has supported by (IL)-1 β, IL-6, IL-17, VEGF and tumour necrosis factor-α. Psoriasis skin tissue histopathology indicated damage structural elements, increasing the epidermal expansion and aberrant differences with increase keratinocytes²⁰.

A study by Lin et al.²⁰ used mice induced with IMQ where the change in the mice’s skin is showing dermatitis lesions that resembled psoriasis lesions. The mice’s skin was found with slight erythema and scaly lesions. The study results stated that Imiquimod increased skin deposition and flux of aminolaevulinic acid (ALA) by 5.6 to 14.4 times, respectively, compared to normal skin. Imiquimod treatment resulted in a decrease in sebum production on the skin's surface, which darkened and significantly reddened the skin. The biotechnological method was utilized to determine the physiological changes brought on by imiquimod, including Trans Epidermal Water Loss (TEWL), skin pH and erythema. In this study, the TEWL rate of 4.24 g/m2/hour for the control group. It significantly increased the TEWL rate (p 0.05; 36.90g/m2/h). TEWL is correlated with the degree of barrier breakdown. The pH level of skin surface with imiquimod showed a significantly decreased (p<0.05) in the group²⁰.

Liu et al.²¹ conducted a study by giving IMQ to mice with 62.6mg dosage every day per 5cm³ consecutively for six days, and the result found that IMQ administration caused by research animals' skin had a severe psoriatic phenotype (scaling and erythema). It has been found that mice that were induced with IMQ become thinner compared to the group of mice that were not induced with IMQ. The study observed the changes on the ear skin where PASI score and ear thickness occurred macroscopically. Histologically, the skin showed that IMQ considerably thickens the epidermis. According to the study, topical IMQ treatment led to a significant drop in levels of the anti-oxidative biomarkers GSH, SOD, and CAT as well as a rise in the levels of inflammatory cytokines TNF-, IL-6, IL-1, IL-17A, and IL-22²¹. Also, no labor-intensive breeding is necessary, and the induced lesions are similar to human psoriatic lesions phenotypically and histologically; moreover, they depend on IL-23 and IL-17²².

Liu et al.²¹ conducted a study on a group of mice C57BL which were constrained by the topical IMQ with 62.5 mg dosage for seven consecutive days on the back and left ear. The results indicated that the experiment caused scaly skin, redness, and thickening of the skin. The study also observed the skin layers, where there was an increase in the thickness of the epidermal layer, and an increase in immune cell infiltration in the dermis layer, while the results of IHC staining were an increase in the IL-6, IL-17, and Ki-67 expression²³.

Therefore, this study aimed to develop psoriasis mice with imiquimod (IMQ), it become the inducing agent. This study assessed histopathology and PASI scores as long as the administration of IMQ in rats’ studies, PASI scores were observed every three days until the ninth day.

MATERIALS AND METHODS:

Materials:

This research was carried out at the Experimental Animal Laboratory, Faculty of Medicine, Abdurrab University, Pekanbaru. The material used in this study was 27 wistar strain rattus novergicus. Slough, Veet ® , and Reckitt Benckiser Group. Treatment for the rat's back used 6,25mg of 5% IMQ cream from brands like Aldara, MEDA Pharmaceuticals, Solna, and Sweden, paraformaldehyde diluting and paraffin phosphate-buffered, Rotary Microtome Model 1212, Germany, and Wetzlar

Methods:

Research Animals Preparation:

This research population was 2-3 months of male rats (Rattus norvegicus strain Wistar) in healthy/active conditions. The selection of using white rats (Rattus norvegicus strain Wistar) was based on genetic similarity to humans, including similarities in anatomical structure. This study used the correct procedure treatments of animals in the 3R principles: Refinement, Replacement, and Reduction. The five freedoms were also used: freedom from discomfort, pain, hunger and thirst, freedom from damage or disease, freedom from fear and anguish, and freedom to exhibit natural behaviour. Additionally, drop-out criteria were used in cases where a research subject's illness or death prevented him from completing the research method. According to the sample criteria, sampling was performed randomly using a straightforward random sampling procedure.

The minimum sample of an experimental group is eight mice. A dropout is added by 20% of the minimum sample size and adding samples based on the statistically permissible sample size and not violating the 3R principles (Reduction, Replacement, Refinement) in experimental animal research, the sample size used is 9 rats for each group.

Imiquimod Induced Psoriasis:

Rats fur backs were shaved with the Brav Mini Clipper razor to remove rat fur using depilatory creams such as; Slough, Veet ®, and Reckitt Benckiser Group. Treatment for the rat's back used 6,25 mg of 5% IMQ cream from brands like Aldara, MEDA Pharmaceuticals, Solna, and Swedia. The results were observed three times on the 3rd, 6th, and 9th days. After observation, the skin cells of the mice were observed histopathologically^20,24.

The skin and ear samples were confirmed overnight with 4% v/v paraformaldehyde diluting and paraffin phosphate-buffered. The piece of five μm samples used microtomes such as Leica, Rotary Microtome Model 1212, Germany, and Wetzlar. Rat skin samples were taken 8mm utilizing a clean skin punch, and the samples were liquid nitrogen freezing -80°C²⁵.

Psoriasis Area Severity Index (PASI) Score Evaluation:

The inflammatory state of the rat's back skin was evaluated daily for nine days using the PASI clinical scoring method. This is carried out from the third day to the ninth day, and every third day, sixth day, and ninth day it is evaluated. Erythema (redness), induration (thickness), and desquamation (scaling) of each mouse's back skin were the three parameters that were visually inspected. Parameters score range from 0(none) to 1 (slightly), 2(moderate), 3(signified), and 4 (highly marked). That cumulative score leads from 0 to 12. Two researchers conducted the evaluation (n = 3 for each parameter) and then calculated the average value independently.

According to inflammatory cell infiltration and epidermal thickness, a representative region for each segment was chosen to evaluate the inflammatory characteristics of the skin. Daily values of epidermal thickness were calculated for the three rats using ImageJ software by measuring area and length. The two researchers performed the measurements separately and then statistically examined the data using one-way ANOVA and post hoc analysis.

RESULT:

Skin Exposure Level:

Erythema, thickening, and scaling marks on the rat back skins after administration of IMQ were seen on the third and sixth days. The cumulative score with three parameters showed an increment of gradual. The physical factors were observed with the maximum score on time.

In psoriasis-like dermatitis, the PASI score was assessed during IMQ induction. The criteria observed were thickness, skin redness, total PASI score and presence of scales. During nine days, it was found that the scales, thickness, scales and total PASI score increased. Meanwhile, on the sixth day, the thickness decreased, but scales began to appear.

Based on the observation, on the third day, the PASI Thickness score is 1, the PASI Redness score is 0, the PASI Scales score is 1, and the total PASI score is 0.25. On the sixth day, the PASI Thickness score is 2, the PASI redness score is 2, the PASI Scales score is 3, and the total PASI score is 1.5. On the ninth day, the PASI Thickness score is 4, the PASI Redness score is 4, the PASI Scales score is 4, and the total PASI score is 4.

Histological Observation:

Day 3

Day 6

Figure 3. Histopathological examination with HE staining on the back skin of rats given IMQ every three day

Microscopically, figure 2 shows the thickening stratum corneum (hyperkeratosis), epidermal hyperplasia (acanthosis), and enhancement of vascularity skin. Figure 2 was analysed with one-way ANOVA followed by Tukey’s multiple comparison tests **: p <0,01; ****: p <0,0001 and a prominent inflammatory contained mast cells, lymphocytes, and abundant macrophages.

The ANOVA results of the intergroup are p<0.01, indicating an impact of IMQ administration on the occurrence of psoriasis in the experimental animal in this study. Multiple comparison test was carried out for each group (day-3 group (P1), day-6 group (P2), and day-9 group (P3)) using post-hoc analysis. The average PASI score of the P1 group is 3±0.5, the average PASI score of the P2 group is 9±0.5, the average PASI score of P3 is 16±0. The post-hoc analysis of P1 and P2 resulted in p=0.064, P1 and P3 resulted in p=0.012, P2 and P3 resulted in p=0.033. The results demonstrated differences between P1, P2, and P3. This indicates a significant result in the observation results of the PASI score on each group.

DISCUSSION:

This study found that the administration of IMQ on the experimental animal can cause psoriasis lesions where IMQ is an agonist-specific Toll-Like Receptor (TLR) 7/8, which activates the cells of immune and dendritic causes the production of inflammatory cytokines and epidermal hyperplasia. The results of IMQ administration is the phenotypic symptoms and histology that resemble psoriasis lesions in humans. The study's findings indicate that lesions and histology that resemble psoriasis lesions exhibit epidermal hyperplasia (acanthosis), stratum corneum thickening (hyperkeratosis), increased skin vascularization, and a noticeable inflammatory infiltrate made up of lymphocytes, macrophages, and mast cells. The theory is in line with the results of this study where the significant difference (p=0.033) in the occurrence of psoriasis lesions in the P2 and P3 groups is evidenced by the groups’ PASI score which increased on the ninth day after the IMQ administration on the laboratory mice²⁶.

The results of the observation on the day of third, sixth, and ninth were demonstrated by the thickening of the mice’s skin on the ninth day compared to the previous observations which can be identified through the PASI score of Thickness and Scales. Based on the study by Liu et al.²¹ on the administration of IMQ with the same dosage (6.25mg) on psoriasis occurrence that was only carried out until the sixth day, the results demonstrated by PASI score observation showing that the Thickness and Scales score of psoriasis were not as thick compared to the ninth day²¹.

A study by Jabeen et al.²⁷ on the inducing of psoriasis using IMQ with the same dosage as this study (62.5 mg IMQ 5%) on the mice back end. The total of PASI was recorded on the day second, third, fourth, sixth and eighth. The average PASI score is as follows: PASI Redness; 0 (second day), 0.5(third day), 2(fourth day), 2.8(sixth day) and 3(eighth day). The PASI Thickness score was zero on the second day, 0.2(third day), 1.2 (fourth day) and 3 on the day sixth and eighth. The PASI Scales score was zero (second day), zero (third day), 0.02 (fourth day), 2 (sixth day) and 2.8 (eighth day). We can diagnose psoriasis with skin biopsy, PASI scoring study and physical examination of patients, which include patient history and lifestyle etc²⁸.The previous study was different from this study, where on the eighth day, the PASI score is lower compared to this study which was carried out on the ninth day and demonstrated a clearer view of the psoriasis thickness to be observed and intervened²⁷.

A study conducted by Wu H et al.²⁹concerning 5% IMQ with 50 mg dosage administration with nine days of observation found that the PASI score of Scales was zero in the day first to second, 0.5 (third day), 1.5 (fourth day), 3 (fifth day), 1.5 (sixth day), 1 (seventh day), 0.78 (eighth day) and 0.5 (ninth day). PASI score of Redness was 0.5 (first day), 1 (second day), 2 (third day), 3 on the day fourth and fifth, 1 (sixth day) and 0.57 (seventh, eighth, and ninth day). PASI score of Thickness was 0.5 (first day), 2 on the day second and third, 2.3 (fourth day), 2.1 (fifth day), 2 on the day sixth and seventh and 1.9 on the day eighth and ninth. The peak PASI score was decreased on the day fourth until the ninth after the administration of 5% IMQ with a 50mg dosage²⁹.

Mouse model administered with erythema of skin, thickness, neo-angiogenesis, scaling and epidermal alterations (acanthosis, parakeratosis), as well as enhanced inflammatory infiltration, IMQ is quite similar to human plaque-type psoriasis. It is made up of T lymphocytes, neutrophils, and dendritic cells³⁰.

In this condition, oxidative stress occurs, which is a critical response to skin disorders. Reactive oxygen species' (ROS') and antioxidants' interactions can lead to the development of oxidative stress. Generally, it can increase the ROS production levels of oxidant factors, such as malondialdehyde (MDA), decrease antioxidant enzymes, such as glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). The results of previous studies demonstrated that IMQ can increase MDA levels, decrease SOD, GSH and CAT levels between vitro models and vivo²⁰.

The administration of IMQ may cause oxidative damage, which may activate T cells and keratinocytes and release proinflammatory cytokines, leading to an inflammatory reaction in psoriasis. Previous studies have looked at changes in proinflammatory cytokines. Th17 and Th1 cells are suspected to play an important role in the psoriasis pathogenesis. The result of oxidative damage causes cytokines released by the Th17 (IL-17A, IL-17F, IL-22, IL-26, and TNF-α) and Th1 cells (TNF-α, IFNγ, and IL-2) to increase the serum. Previous studies have shown that pro-inflammatory cytokines which includes IL-6, IL-1β, IL-22, TNF-α, and IL-17A are organize in skin tissue and psoriatic serum, and the IL-23/IL-17 axis is recognized. Participates in the regulation of IMQ-induced psoriasis-like skin inflammation. ICAM-1 is an essential molecules in recruiting immunocytes to the skin and contributes for psoriasis, which TNF-α can trigger in a variety of cell types³¹.

The important signalling routes are NF-B and MAPK; in a variety of inflammatory disorders. MAPKs take part in activating NF-B signalling pathways. The regulation of several extracellular signals to affect the inflammatory response has ramifications for the MAPK and NF-B signalling cascades. MAPKs and NF-B may encourage inflammation, epidermal hyperproliferation, and worsen the pathogenesis of psoriasis²⁵.

The results of histological examination are total epidermal hyperplasia (acanthosis), stratum corneum thickening (hyperkeratosis), increased skin vascularity, and a noticeable inflammatory infiltrate with many macrophages, mast cells and lymphocytes. In accordance with the study of Pietrzak et al.³² acanthosis, hyperkeratosis, and inflammatory cell infiltration into the epidermis signed with psoriatic inflammation, which eventually results in the development of erythematous plaques and the destruction of the skin barrier.

A study by Creamer et al.³³ found that dermal hypervascularization and angiogenesis were evidenced by histopathological examination found a blood cell infiltration in the skin. Increased CD31 and CD34 signals are vascular and endothelial markers, respectively. It was found in skin samples from mice that had been given IMQ to induce psoriasis. It has been demonstrated that vascular endothelial cells and epidermal keratinocytes play a key role in the psoriasis inflammatory process through the secretion of cytokines and growth factors, as well as the upregulation of signalling molecules and adherence to their surface.

According to the results, rat treatment using IMQ can show epidermal changes (acanthosis, parakeratosis), skin erythema, and neo-angiogenesis. The inflammatory infiltrate comprises dendritic cells, neutrophils, and T cells that match human plaque-type psoriasis²⁹.

In animal models, the psoriasis treatment used a 5% imiquimod (IMQ) cream. Initially, IMQ was a skin treatment caused by human papillomavirus³⁵. The effectiveness of IMQ can treat cancer is proven by up to 90% of instances with tumour regression. In addition, IMQ cream patients reported that psoriatic lesions in the application and remote areas were unaffected³⁶. IMQ is a receptor ligand for plasmacytoid dendritic cells (pDCs), macrophages, and monocytes. Therefore, this activity can contribute to a strong immune such as increasing Langerhans cell migration and Th1 response. The researchers can develop mouse models of psoriasis (Ps) to target induction³⁷. The skin formation lesions are similar to psoriatic plaques induced by IMQ applications. The alteration of epidermal proliferation, impaired keratinocyte differentiation erythema, and vascular changes due to neutrophil accumulation in the epidermis IMQ produces an epidermal expression of the IL-17F, IL-23 and IL-17A genes³⁸.

The various mediators in psoriasis include dendritic cells and T-cells. The inflammatory myeloid cells stimulate IL-17 and IL-23, which will trigger an increase in the production of Th22 cells, Th1 cells, and T cells, which will stimulate IL-17 and the production of more cytokines that cause inflammatory skin diseases such as IL-17, IL-22, and tumor necrosis factor-alpha (TNF-α)³⁹. IL-23 comprises p19 and p40 sub-units produced by antigen-presenting cells. In developing skin inflammation need to distinguish naive lymphocytes into Th22 cells and Th17 in IL-23. An intradermal injection of 1 μg of IL-23 into rats’ skin induces the synthesis of IL-24 and IL-19, which affects keratinocyte differentiation and proliferation via a TNF-dependent mechanism (but not IL-17A). This was consistent with the results of the current study. There was a significant decrease in the concentration of TNF-α in the serum of the infected and treated Etanercept (Enbrel), indicating a reduction in the effect of one of the factors leading to inflammation and common in the increase of disease in psoriasis⁴⁰.

It causes histological alterations such as parakeratosis, acanthosis, and follicular hyperplasia. Dendritic cells, the influx of CD4+ lymphocytes, neutrophils and macrophages caused the rat's skin to become erythematous. The severe Ps symptoms in the rat model highlighted the significance of IL-23 in developing psoriatic plaques⁴¹.

CONCLUSION:

Based on the research findings, Wistar rats have been successfully developed as research model animals for studying the causes of skin inflammation, such as psoriasis, induced by IMQ 5% as an inducing agent to psoriasis. Wistar rats are an inexpensive and suitable choice of experimental animal for in vivo screening of novel research topics. To sum it up, the PASI score on the ninth day was higher than the previous day when compared to previous studies with lower PASI scores which did not reach the ninth day of administration.

The limitation of this study was that it only examined the PASI score and histopathology and did not carry out other tests on the ninth day such as Expression of pSTAT3 Proteins, Skin Barrier Disruption, and Systemic Inflammatory Response. Hence, future studies could carry out these tests until the ninth day to see different results from previous studies.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

Thanks to the Indonesian Ministry of Education, Culture, Research and Technology at DRTPM with contract 23/UN16.19/PT.01.03/PL/2024 through LPPM Universitas Andalas for funding this research through the Doctoral Dissertation Research scheme.

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Received on 01.04.2024 Revised on 07.10.2024

Accepted on 08.01.2025 Published on 02.05.2025

Available online from May 07, 2025

Research J. Pharmacy and Technology. 2025;18(5):1975-1982.

DOI: 10.52711/0974-360X.2025.00282

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