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. 2025 Sep 2;124(9):97. doi: 10.1007/s00436-025-08544-7

Restorative potential of melatonin during treatment of severe scabies in an experimental model

Mahmoud S Sharaf 1,✉, Ahmad A Othman 1, Dareen M Ali 2, Abdallah M Hafez 3, Asmaa R Ellakany 1
PMCID: PMC12401764  PMID: 40890376

Abstract

A key limitation of current synthetic treatments of scabies is their focus on eliminating the mites rather than addressing the body’s immune response or tissue healing, potentially fostering drug resistance and prolonging recovery. Melatonin, with its anti-inflammatory, antioxidant, and antimicrobial properties, presents a potential solution. Consequently, this research seeks to assess the value of melatonin supplementation as complementary therapy in Sarcoptes scabiei mite infestation. The study included 25 male crossbreed rabbits, divided into five groups of five rabbits each: group I (a negative control); group II (a positive control); group III (infected and treated with melatonin); group IV (infected and treated with ivermectin); and group V (infected and treated with melatonin and ivermectin). Clinical and parasitological assessments were conducted from day 0 till day 28 post-treatment. Serum and tissue samples were collected at the end of day 28 post-treatment for subsequent histopathological, biochemical, and immunological analyses. Our research indicated that combining melatonin with ivermectin (group V) significantly accelerated clinical improvement compared to using ivermectin alone (group IV). Melatonin also lessened the side effects of ivermectin seen in group IV and effectively alleviated itching in group V. Skin analysis of group V revealed nearly full healing and the absence of mites, unlike group IV, which still showed inflammation and dead mites. Supporting these findings, blood tests in group V demonstrated a significant improvement in biochemical and immunological markers compared to group IV. Infestation with Sarcoptes mites disrupts the balance between oxidants and antioxidants and triggers systemic inflammation. Supplementing melatonin can help restore this balance and reduce inflammation, thereby accelerating cure in affected rabbits. Therefore, melatonin is suggested as an adjunct therapy with ivermectin, particularly in severe scabies cases, and future research should explore optimal dosages and treatment regimens.

Graphical Abstract

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Supplementary Information

The online version contains supplementary material available at 10.1007/s00436-025-08544-7.

Keywords: Scabies, Sarcoptes scabiei, Ivermectin, Melatonin, Treatment

Introduction

Scabies is a skin condition that causes intense itching and affects humans and other mammals. It is caused by the burrowing mite Sarcoptes scabiei. An estimated 200 to 300 million people are affected by scabies worldwide each year, marking an unacceptably high prevalence for a neglected disease (Leung et al. 2020). While scabies can impact individuals of all ages, children and the elderly in low-resource settings are particularly vulnerable (El-Moamly 2021). In 2017, the World Health Organization added scabies to its list of neglected tropical diseases, highlighting the significant health and economic impact it has, especially on low-income populations.

The scabies mites burrow into the stratum corneum of the skin, leading to inflammation and progressive skin hyperkeratinization (Sharaf 2024). Symptoms include severe itching, papules, erythema, scaling, and crusting. Secondary bacterial infections usually complicate the condition, which contributes to the diversity of clinical presentations (Romero et al. 2016; Chiummo et al. 2020). Importantly, scabies has been recognized as a systemic syndrome that can impact organs beyond the skin, particularly in severe cases. Mite antigens and secondary bacterial infections can trigger diverse immune responses and inflammatory reactions, altering the host’s redox status. This oxidative stress can cause tissue damage in different organs, leading to changes in serum biochemical and immunological parameters (Beigh et al. 2016; Sharaf et al. 2023a).

Currently, ivermectin (IVM) is the only approved oral medication available for the treatment of human scabies. It is primarily utilized in mass drug administration during outbreaks and for treating severe crusted forms or non-compliant patients in endemic areas (Romani et al. 2015). Although IVM has been shown to achieve clinical and parasitological cures, some studies have reported that mild to moderate histopathological and biochemical changes may persist (Zahran et al. 2022; Sharaf et al. 2023a). IVM has been linked to oxidative stress that causes tissue injury and inflammation. Notably, Abdel-Rahman and Ali (2021) demonstrated that such induced oxidative stress can last up to three months post-treatment in ewes.

Melatonin, an amphiphilic indoleamine (N-acetyl-5-methoxytryptamine), has garnered significant interest in recent studies. It is a powerful free radical scavenger and antioxidant that targets mitochondria, thereby protecting against oxidative stress by reducing reactive oxygen species (ROS) and reactive nitrogen species (RNS) locally (Aranarochana et al. 2021; Bashandy et al. 2021; Essawy et al. 2023). In addition to its role as an antioxidant, melatonin is a pleiotropic molecule that has a role in a variety of physiological and pathological processes, including circadian rhythms, immune response, and inflammation (Ma et al. 2021; Carretero et al. 2023; Maestroni 2024).

The beneficial effects of melatonin have been described in several parasitic diseases, including infection with Plasmodium species (Singh et al. 2020), Trypanosoma cruzi (Oliveira et al. 2013), Trypanosoma brucei (Grassi-Zucconi et al. 1996), Toxoplasma gondii (Machado et al. 2020), Giardia lamblia (Pereira et al. 2018), Leishmania species (Elmahallawy et al. 2014), Entamoeba histolytica (França-Botelho et al. 2011), Wuchereria bancrofti (Sack 2009), and Opisthorchis viverrini (Wongsena et al. 2018). In this regard, further research into the influence of melatonin on parasitic infections appears to be a promising path (Ribeiro Franco et al. 2024). Given the limited existing literature on its role in treating scabies, this study aimed to explore the effects of melatonin when administered alongside IVM in the treatment of scabies in rabbits.

Materials and methods

Animals

The study included 25 male crossbreed rabbits, aged two months and weighing between 1500 and 2000 g. All rabbits were confirmed to be free of ectoparasites and intestinal parasites through random microscopic examination of skin scrapings and fecal samples. These rabbits had no recent history of drug administration. They were housed in separate cages within a well-ventilated room maintained at 25 ± 2 °C, under a 12-h light/dark cycle, and had unrestricted access to water and standard commercial pellet food. The rabbits were allowed one week to stabilize and acclimate to their new environment before the infection was induced.

Parasite

Three naturally infected rabbits with sarcoptic mange were used to obtain Sarcoptes scabiei var. cuniculi mites for the experimental induction of scabies. Infection with Sarcoptes scabiei mites was affirmed by scraping the edges of the skin lesions with a scalpel blade until capillary bleeding occurred. The collected scales were then placed in petri dishes and incubated at 30 °C for 30 min to promote the migration of mites to the surface (Sharaf et al. 2020). Afterward, a stereoscopic examination of the dishes was conducted to identify the distinct morphological features of the Sarcoptes scabiei mites. The mite-infested skin crusts, which contained approximately 600–800 mites, were transferred into the ear canals of mite-free rabbits to induce infection. The crusts were placed on pieces of gauze, which were then secured to the inner ear surfaces of the rabbits to ensure they stayed in place. After 1 h, the gauze was carefully taken off (Bernigaud et al. 2016).

Drugs

Treated rabbits received oral tablets of Iverzine® 6 mg (UNIPHARMA, Egypt) at a dosage of 0.4 mg/kg body weight once a week for a duration of four weeks, beginning four weeks post-infection (day 0) (Kachhawa et al. 2013). Melatonin (NOW FOODS, USA) was administered as a single daily dose of 3 mg/kg body weight per rabbit at 9 AM for four weeks, starting 4 weeks post-infection (Maestroni 2024).

Study design

The study comprises two phases: the post-infection phase, which involved the progression of the infestation to its crusted form, and the post-treatment phase that followed drug administration. Each phase lasted 4 weeks. The rabbits were divided into five groups of five rabbits each: group I (non-infected, non-treated, as a negative control); group II (infected, non-treated, as a positive control); group III (infected and treated with melatonin); group IV (infected and treated with IVM); and group V (infected and treated with both melatonin and IVM).

Throughout the study period, all rabbit cages and the breeding area were disinfected with deltamethrin once a week to mitigate the risk of mite reinfection (Sharaf et al. 2020). Clinical and parasitological assessments began on day 0 and continued on days 2, 4, 6, 8, 10, 12, 14, 21, and 28 post-treatment. Following blood sample collection at the end of day 28 post-treatment, rabbits were humanely euthanized by cervical decapitation, and tissue samples were subsequently harvested.

Clinical evaluation

Rabbits were assessed using the scoring criteria developed by Sharaf et al. (2023b). The evaluation of skin lesions was based on several factors, including the types of lesions, the extent of crusting on the limbs and head, the degree of pruritus, and the severity of alopecia. Each rabbit was individually scored across these parameters, and a total clinical score was calculated. The highest possible clinical score for a rabbit was 17.

Parasitological evaluation

Viable mites were counted by examining skin scrapings obtained from a 2 cm2 area of skin lesions in each rabbit under a stereomicroscope.

Histopathological evaluation

Skin tissue samples (2 cm) were collected from the ear pinna of each rabbit and preserved in 10% formol saline for subsequent histopathological assessment. Slides were prepared following standard protocols for staining with hematoxylin and eosin and were evaluated microscopically for changes in the dermis and epidermis using a modified scoring system based on the criteria described by Sharaf et al. (2023b) (Table 1). The evaluation was conducted using eight distinct high-power fields (400 × magnification) per tissue section for each animal within every group, selected randomly without any overlap. The pathologist was blinded to the allocated group.

Table 1.

Histopathological scoring system

Parameter Grades
1 2 3 4
Crust thickness (mm) No crust Less than 2.5 mm Between 2.5 and 3.5 mm Greater than 3.5 mm
Percentage of hair follicles containing hairs More than 90% More than 55% Between 45 and 55% Less than 45%
Stratum corneum thickness Normal thickness Double thickness Three times the normal thickness Exceeding three times the normal
Stratum spinosum layers Normal 3 to 4 layers 5 to 6 layers More than 6 layers
Average mite counts observed at × 400 high-power field No mites 1 or 2 mites 3 to 6 mites More than 6 mites
Inflammatory cells count in the epidermis at × 400 high-power field Fewer than 5 cells 5–25 cells 26–50 cells  > 50
Inflammatory cells count in the dermis at × 400 high-power field Fewer than 5 cells 5–25 cells 26–50 cells  > 50
Total score 7–28
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Immunohistochemical evaluation of skin sections

Matrix metalloproteinase-9 (MMP-9) expression was immunohistochemically assessed following the manufacturer’s guidelines, using MMP-9 mouse monoclonal antibodies (Cat. No. ab58803, Abcam, USA) and rabbit HRP/DAB detection IHC kits (Cat. No. ab64264, Abcam, USA). Immunoreactivity was scored based on the proportion of positively stained cells and the staining intensity. The percentage of immunoreactive cells was graded from 0 to 4: 0 (no stained cells); 1 (1–9%); 2 (10–49%); 3 (50–70%); and 4 (> 70%). Staining intensity was graded from 0 to 3: 0 (none); 1 (pale); 2 (moderate); and 3 (strong) (Mohamed et al. 2022). The assessment was performed in two non-overlapping high-power fields (× 400) per section, with three sections analyzed per animal per group. The final score was obtained by multiplying the intensity grade by the percentage grade for each field. Expression was categorized as minimal for scores from 0 to 4, moderate for scores more than 4 and less than 8, and high for scores from 8 to 12.

Biochemical and immunological assessment

By the end of day 28 post-treatment, blood samples were drawn from each rabbit via cardiac puncture, collecting 2 ml into serum-separating vacutainer tubes. The samples were allowed to clot at room temperature for 1 h before being centrifuged for 20 min at 3000 rpm. The resulting serum was then transferred into Eppendorf tubes and stored at – 80 °C until use.

Serum concentrations of various biomarkers were measured, including C-reactive protein (CRP) (Cat. No. MBS166122, MyBioSource, San Diego, USA), malondialdehyde (MDA) (Cat. No. MBS2602584, MyBioSource, San Diego, USA), total antioxidant capacity (TAC) (Cat. No. MBS2548432, MyBioSource, San Diego, USA), interleukin-4 (IL-4) (Cat. No. MBS9305049, MyBioSource, San Diego, USA), interleukin-10 (IL-10) (Cat. No. MBS764535, MyBioSource, San Diego, USA), interleukin-12 (IL-12) (Cat. No. MBS2504364, MyBioSource, San Diego, USA), and interferon gamma (IFN-γ) (Cat. No. MBS2601171, MyBioSource, San Diego, USA). These were quantified following the manufacturer’s guidelines, utilizing a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) technique, except for serum TAC, which was determined using a colorimetric method.

Statistical analysis

The data analysis was performed using the Statistical Package for the Social Sciences (IBM SPSS) version 22.0 (Armonk, NY: IBM Corp., USA). Quantitative data were expressed as means with standard deviation (SD). The Shapiro–Wilk test was utilized to assess the normality of variable distributions. Given that the data followed a normal distribution, parametric tests were employed, specifically ANOVA (F-test) for comparing means across multiple groups, followed by Tukey’s post hoc test for pairwise comparisons. Results were deemed significant if the P-value was less than or equal to 0.05.

Results

Clinical evaluation

On day 0, all infected groups displayed typical signs of severe scabies, including alopecia, hemorrhagic thick crusts, and fissures, primarily located on the limbs, ears, face, nose, and eyelids. These lesions were accompanied by pruritus, leading to intermittent scratching of the affected areas with their front paws. Following day 0, both group II and group III exhibited a progressive increase in clinical scores till the end of the experiment. Group III generally showed lower clinical scores throughout most of the study, with a significant difference when compared to group II (P = 0.045* on day 10 and 0.001* later till day 28) (Table 2).

Table 2.

Clinical evaluation

Group I Group II Group III Group IV Group V F-test P-value
Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD
D0 0.00 ± 0.00 13.80 ± 0.84 13.80 ± 1.00 14.00 ± 0.71 14.00 ± 0.71 333.206 0.001*
D2 0.00 ± 0.00 14.20 ± 0.45 13.80 ± 1.09 14.00 ± 0.71 14.00 ± 0.71 408.541 0.001*
D4 0.00 ± 0.00 14.40 ± 0.89 13.80 ± 1.00 13.20 ± 0.84 12.80 ± 0.45 346.222 0.001*
D6 0.00 ± 0.00 15.00 ± 0.71 13.80 ± 1.09 12.00 ± 1.22 10.40 ± 0.54 255.914 0.001*
D8 0.00 ± 0.00 15.40 ± 1.14 13.80 ± 1.09 10.80 ± 1.09 7.60 ± 1.51 155.050 0.001*
D10 0.00 ± 0.00 16.20 ± 0.84 13.80 ± 1.09 9.80 ± 0.83 5.20 ± 2.28 136.987 0.001*
D12 0.00 ± 0.00 16.80 ± 0.45 14.20 ± 0.83 8.80 ± 0.83 2.80 ± 1.30 390.545 0.001*
D14 0.00 ± 0.00 16.80 ± 0.45 14.20 ± 0.83 8.20 ± 0.83 2.20 ± 0.83 579.260 0.001*
D21 0.00 ± 0.00 17.00 ± 0.00 14.80 ± 1.30 6.80 ± 0.83 0.00 ± 0.00 667.416 0.001*
D28 0.00 ± 0.00 17.00 ± 0.00 14.60 ± 1.51 3.60 ± 0.54 0.00 ± 0.00 642.576 0.001*
Post hoc test
P1 P2 P3 P4 P5 P6 P7 P8 P9 P10
D0 0.001* 0.001* 0.001* 0.001* 0.899a 0.899a 0.899a 0.899a 0.899a 0.899a
D2 0.001* 0.001* 0.001* 0.001* 0.893a 0.899a 0.899a 0.899a 0.899a 0.899a
D4 0.001* 0.001* 0.001* 0.001* 0.899a 0.112a 0.019* 0.446a 0.112a 0.899a
D6 0.001* 0.001* 0.001* 0.001* 0.196a 0.001* 0.001* 0.021* 0.001* 0.046*
D8 0.001* 0.001* 0.001* 0.001* 0.182a 0.001* 0.001* 0.002* 0.001* 0.001*
D10 0.001* 0.001* 0.001* 0.001* 0.045* 0.001* 0.001* 0.001* 0.001* 0.001*
D12 0.001* 0.001* 0.001* 0.001* 0.001* 0.001* 0.001* 0.001* 0.001* 0.001*
D14 0.001* 0.001* 0.001* 0.001* 0.001* 0.001* 0.001* 0.001* 0.001* 0.001*
D21 0.001* 0.001* 0.001* 0.899a 0.001* 0.001* 0.001* 0.001* 0.001* 0.001*
D28 0.001* 0.001* 0.001* 0.899a 0.001* 0.001* 0.001* 0.001* 0.001* 0.001*
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Group I, non-infected non-treated rabbits; group II, infected non-treated rabbits; group III, infected and treated with melatonin; group IV, infected and treated with IVM; group V, infected and treated with melatonin and IVM. Superscripts indicate statistical significance:(a) Insignificant: P > 0.05; (*) significant: P ≤ 0.05. P1, group I and group II; P2, group I and group III; P3, group I and group IV; P4, group I and group V; P5, group II and group III; P6, group II and group IV; P7, group II and group V; P8, group III and group IV; P9, group III and group V; P10, group IV and group V. n = 5 in all groups

In group IV, crust separation was first observed as early as day 4 post-treatment. Starting from day 6, the rabbits in this group exhibited a significant improvement in clinical scores throughout the experiment when compared to group II (P = 0.001*) (Table 2). By day 21 post-treatment, crusts were no longer present, and partial hair regrowth was noted in all rabbits; however, complete recovery of the skin lesions had not occurred by the end of the study. Bouts of itching persisted in some rabbits until the end of the study (Online Resource 1). Additionally, all rabbits experienced diarrhea and reduced appetite during the first few days following each dose of IVM.

Group V also showed crust separation by day 4 post-treatment and demonstrated significant clinical improvement throughout the experiment compared to group II (P = 0.019* on day 4 and 0.001* thereafter until the end of the study). By day 10, no crusts were evident in any rabbits, with partial hair regrowth beginning at that time. Complete clinical resolution was observed as early as day 21 after treatment, with no itching reported until the end of the study (Online Resource 1). This group did not exhibit any significant side effects from IVM throughout the experiment. Overall, group V showed significantly lower clinical scores compared to group IV (P = 0.046* on day 6 and 0.001* thereafter until day 28). When compared with group I, no statistically significant differences in clinical scores were detected in group V starting from day 21 post-treatment (P = 0.899) (Table 2).

Parasitological evaluation

On day 0, skin scrapings from all infected groups revealed a high number of eggs, larvae, nymphs, and adult mites during microscopic examination, with no significant differences in the viable mite counts among the groups (P = 0.899). After day 0, both groups II and III showed a gradual increase in viable mite counts until the end of the experiment, with no significant difference between the two groups (P = 0.899).

Starting from day 2 post-treatment, both groups IV and V displayed a significant decline in viable mite counts compared to group II (P = 0.006* and 0.017* on day 2 for group IV and group V, respectively, and 0.001* later for both groups). Parasitological cure was observed as early as day 10 post-treatment in both groups. There were no significant differences in mite counts between groups IV and V throughout the duration of the experiment, with P-values consistently at 0.899, except for day 6 post-treatment, where P = 0.859 (Table 3).

Table 3.

Mean values (± SD) of viable mite count

Group I Group II Group III Group IV Group V F-test P-value
Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD
D0 0.00 ± 0.00 234.4 ± 66.06 224.4 ± 53.62 242 ± 49.73 227.8 ± 36.37 24.521 0.001*
D2 0.00 ± 0.00 255.4 ± 56.48 249.2 ± 82.94 136.8 ± 21.33 150.6 ± 27.59 23.964 0.001*
D4 0.00 ± 0.00 283.8 ± 58.34 275.2 ± 38.41 97.8 ± 18.65 100.8 ± 23.82 66.031 0.001*
D6 0.00 ± 0.00 312.8 ± 71.52 301.8 ± 35.73 61.8 ± 19.69 39.4 ± 9.07 83.642 0.001*
D8 0.00 ± 0.00 332 ± 70.13 318.4 ± 24.31 19 ± 8.80 7.40 ± 3.04 134.476 0.001*
D10 0.00 ± 0.00 354 ± 58.97 345 ± 13.10 0 ± 0.00 0 ± 0.00 251.097 0.001*
D12 0.00 ± 0.00 376 ± 56.40 366.2 ± 22.26 0 ± 0.00 0 ± 0.00 280.964 0.001*
D14 0.00 ± 0.00 410.6 ± 41.32 399.4 ± 16.77 0 ± 0.00 0 ± 0.00 618.817 0.001*
D21 0.00 ± 0.00 432.6 ± 49.20 422 ± 11.29 0 ± 0.00 0 ± 0.00 537.617 0.001*
D28 0.00 ± 0.00 462 ± 43.15 455.6 ± 16.27 0 ± 0.00 0 ± 0.00 742.363 0.001*
Post hoc test
P1 P2 P3 P4 P5 P6 P7 P8 P9 P10
D0 0.001* 0.001* 0.001* 0.001* 0.899a 0.899a 0.899a 0.899a 0.899a 0.899a
D2 0.001* 0.001* 0.001* 0.001* 0.899a 0.006* 0.017* 0.010* 0.027* 0.899a
D4 0.001* 0.001* 0.001* 0.001* 0.899a 0.001* 0.001* 0.001* 0.001* 0.899a
D6 0.001* 0.001* 0.100a 0.467a 0.899a 0.001* 0.001* 0.001* 0.001* 0.859a
D8 0.001* 0.001* 0.891a 0.899a 0.899a 0.001* 0.001* 0.001* 0.001* 0.899a
D10 0.001* 0.001* 0.899a 0.899a 0.899a 0.001* 0.001* 0.001* 0.001* 0.899a
D12 0.001* 0.001* 0.899a 0.899a 0.899a 0.001* 0.001* 0.001* 0.001* 0.899a
D14 0.001* 0.001* 0.899a 0.899a 0.899a 0.001* 0.001* 0.001* 0.001* 0.899a
D21 0.001* 0.001* 0.899a 0.899a 0.899a 0.001* 0.001* 0.001* 0.001* 0.899a
D28 0.001* 0.001* 0.899a 0.899a 0.899a 0.001* 0.001* 0.001* 0.001* 0.899a
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Group I, non-infected non-treated rabbits; group II, infected non-treated rabbits; group III, infected and treated with melatonin; group IV, infected and treated with IVM; group V, infected and treated with melatonin and IVM. Superscripts indicate statistical significance:(a) Insignificant: P > 0.05; (*) significant: P ≤ 0.05. P1, group I and group II; P2, group I and group III; P3, group I and group IV; P4, group I and group V; P5, group II and group III; P6, group II and group IV; P7, group II and group V; P8, group III and group IV; P9, group III and group V; P10, group IV and group V. n = 5 in all groups

Histopathological and immunohistochemical evaluation

Sections from group II displayed damaged skin characterized by a wavy epidermis with multiple epidermal burrows containing different stages of scabies mites and necrotic debris. Additionally, the epidermis showed significant hyperkeratosis, acanthosis, irregular hypertrophy of rete pegs, ulceration, microabscesses, and mild to moderate spongiosis. The dermis exhibited congestion and marked diffuse inflammatory infiltrates, predominantly comprised of lymphocytes, neutrophils, eosinophils, and plasma cells, with mast cells present to a lesser extent. Hyperplasia of sebaceous glands was also observed (Fig. 1B, C). Although skin sections from group III showed similar alterations, these changes were less pronounced, resulting in a significantly lower histopathological score compared to group II (P = 0.001*) (Table 4, Fig. 1D).

Fig. 1.

Fig. 1

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Photomicrographs of ear skin sections (H&E). A Normal skin from group I. B, C (Group II) heavy mite infestation (“yellow circles”), hypertrophy of rete ridges (“yellow arrows”), congested dermal blood vessels (“yellow stars”), hyperplasia of sebaceous glands (“black arrowheads”), and heavy dermal inflammation. D (Group III) similar but milder changes. E (Group IV) absence of motile mite stages, mild epidermal thickening, and moderate dermal inflammation. F (Group V) mite-free skin with normal epidermal and dermal structure (scale bar = 100 μm)

Table 4.

Histopathological score in different groups

Mean ± SD F-test P-value Post hock test
Group I 7 ± 0.00 P1 0.001* P6 0.001*
Group II 27.2 ± 1.30 P2 0.001* P7 0.001*
Group III 24 ± 1.58 389.068 0.001* P3 0.001* P8 0.001*
Group IV 11.8 ± 1.30 P4 0.899a P9 0.001*
Group V 7 ± 0.00 P5 0.001* P10 0.001*
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Group I, non-infected non-treated rabbits; group II, infected non-treated rabbits; group III, infected and treated with melatonin; group IV, infected and treated with IVM; group V, infected and treated with melatonin and IVM. Superscripts indicate statistical significance:(a) Insignificant: P > 0.05; (*) significant: P ≤ 0.05. P1, group I and group II; P2, group I and group III; P3, group I and group IV; P4, group I and group V; P5, group II and group III; P6, group II and group IV; P7, group II and group V; P8, group III and group IV; P9, group III and group V; P10, group IV and group V. n = 5 in all groups.

In group IV, marked improvement was noted, evidenced by the absence of mites and the resolution of most epidermal and dermal changes observed in groups II and III. However, the improvement was not complete, as the epidermal thickness remained mildly increased, with occasional trapping of dead mite eggs. Moreover, there was still a mild to moderate (and occasionally severe) inflammatory infiltrate in the dermis, mainly comprising lymphocytes and plasma cells (Fig. 1E). When compared to group I, a significantly higher histopathological score was still noted (P = 0.001*) (Table 4). In contrast, skin sections from group V showed complete resolution of epidermal and dermal lesions, with restoration of normal skin histological architecture (Fig. 1F). There were no significant differences in the histopathological score when compared to group I (P = 0.899). Additionally, group V had a significantly lower histopathological score compared to group IV (P = 0.001*) (Table 4).

Analysis of MMP-9 expression within skin sections revealed distinct patterns across the experimental groups. Group I exhibited minimal MMP-9 expression, localized primarily to the endothelium of dermal blood vessels (Fig. 2A). In contrast, group II demonstrated high MMP-9 expression, predominantly originating from dermal fibroblasts and collagen fibers, infiltrating inflammatory cells, and vascular endothelial cells (Fig. 2B). Group III displayed moderate MMP-9 expression, a level significantly lower than that observed in group II (P = 0.025*) (Table 5, Fig. 2C). Group IV showed moderate to occasionally severe MMP-9 expression, with no statistically significant difference when compared to group III (P = 0.899) (Table 5, Fig. 2D, E). Finally, group V presented minimal MMP-9 expression, comparable to group I (P = 0.899), but significantly lower than that in group IV (P = 0.001*) (Table 5, Fig. 2F).

Fig. 2.

Fig. 2

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Photomicrograph illustrating MMP-9 expression in ear skin sections. A Low expression in group I. B (Group II), there is high expression throughout both the dermis and epidermis. C (Group III) moderate expression. D, E (Group IV) varying levels, from moderate (“D”) to high (“E”) expression. F (Group V) minimal expression (scale bar = 50 μm)

Table 5.

Immunohistochemical score in different groups (MMP-9 expression in skin sections)

Mean ± SD F-test P-value Post hock test
Group I 0.60 ± 0.24 P1 0.001* P6 0.011*
Group II 11.40 ± 0.60 P2 0.001* P7 0.001*
Group III 7.80 ± 0.73 37.905 0.001* P3 0.001* P8 0.899a
Group IV 7.40 ± 1.40 P4 0.899a P9 0.001*
Group V 0.80 ± 0.20 P5 0.025* P10 0.001*
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Group I, non-infected non-treated rabbits; group II, infected non-treated rabbits; group III, infected and treated with melatonin; group IV, infected and treated with IVM; group V, infected and treated with melatonin and IVM. Superscripts indicate statistical significance:(a) Insignificant: P > 0.05; (*) significant: P ≤ 0.05. P1, group I and group II; P2, group I and group III; P3, group I and group IV; P4, group I and group V; P5, group II and group III; P6, group II and group IV; P7, group II and group V; P8, group III and group IV; P9, group III and group V; P10, group IV and group V. n = 5 in all groups

Biochemical evaluation

When compared to group I, both groups II and III exhibited a statistically significant increase in serum levels of MDA (P = 0.001* for both) and CRP (P = 0.001* for both), along with a significant decrease in serum TAC (P = 0.001* for both). However, serum levels of MDA and CRP remained significantly lower in group III compared to group II (P = 0.046* and 0.001*, respectively). Likewise, serum levels of TAC were significantly higher in group III compared to group II (P = 0.023*).

For group IV, serum levels of MDA and CRP significantly decreased (P = 0.001*), while TAC significantly increased (P = 0.001*) when compared to those in group II. Nevertheless, the serum levels of MDA and CRP were still significantly elevated compared to group I (P = 0.019* and 0.001*, respectively). Similarly, TAC levels in group IV were significantly higher compared to those in group I (P = 0.038*). In group V, there was a significant improvement in all parameters compared to group II (P = 0.001* for all), with no statistically significant differences when compared to group I (P = 0.899, 0.899, and 0.472 for MDA, CRP, and TAC, respectively) (Fig. 3A–C).

Fig. 3.

Fig. 3

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Biochemical and immunological serum parameters (mean ± SD). A, serum malondaldehyde (MDA); B, serum total antioxidant capacity (TAC); C, serum C-reactive protein (CRP); D, serum IL-4; E, serum IL-10 and IL-12; F, serum IFN-γ  (a–e indicate a significant difference versus groups I, II, III, IV, and V, respectively)

Immunological evaluation

When compared to group I, both groups II and III exhibited a significant increase in serum levels of IL-4, IL-10, IL-12, and IFN-γ (P = 0.001* for all). However, these levels were still significantly lower in group III compared to group II (P = 0.001* for all). In group IV, serum levels of these parameters showed a significant decrease (P = 0.001* for all) compared to those in group II. Nevertheless, the serum levels of IL-10, IL-12, and IFN-γ remained significantly elevated compared to those in group I (P = 0.035*, 0.040*, and 0.001*, respectively). For group V, significant improvements were observed in all parameters compared to group II (P = 0.001* for all), with no statistically significant differences when compared to group I (P = 0.899 for all) (Fig. 3D–F).

Discussion

The pathogenesis of scabies is complex and involves several mechanisms, including the persistence of the mite and its antigens, dysfunction of small blood vessels and the lining endothelium, an aggravated immune response, bacterial superinfection, and ongoing oxidative stress. These factors negatively impact the structure and function of the skin (Sharaf 2024). These combined factors make effective treatment difficult, particularly because most conventional scabicides target killing the mites rather than adjusting the immune system or aiding tissue repair, which can contribute to drug resistance and delay in treatment (Abd El-Ghany 2022; Obaid et al. 2022; Zahran et al. 2022).

Owing to its modulatory effects on the immune response, as well as its anti-inflammatory, antioxidant, and antimicrobial properties, melatonin has the potential to enhance the therapeutic efficacy of drugs while reducing their toxicity (Maestroni 2024). Additionally, various studies have indicated that melatonin can facilitate and enhance wound healing (Pugazhenthi et al. 2008; Aqa and Albanna 2022; de Souza et al. 2022; Yu et al. 2025). To date, there has been no investigation into the application of melatonin in the context of scabies. Therefore, the current study aims to evaluate the effectiveness of melatonin supplementation as an adjuvant to standard treatment in promoting improvement in rabbits affected by Sarcoptes mite infestation.

Based on existing evidence regarding the potential therapeutic effects of melatonin in addressing infections, various treatment regimens have been proposed, specifically comparing non-circadian high doses to circadian low doses. Maestroni (2024) suggests the evaluation of different melatonin dosage ranges, with low doses potentially between 10 μg and 1000 μg/kg administered in a circadian rhythm during the evening, and high doses ranging from 3 to 50 mg/kg given in the morning. Following this recommendation, our study implemented a dosage of 3 mg/kg, administered in the morning.

Our study demonstrated that melatonin supplementation substantially hindered the progression of clinical lesions associated with scabies in the rabbits that received melatonin only and accelerated clinical recovery in the group receiving both IVM and melatonin. This was evidenced by a significantly lower clinical score in animals treated solely with melatonin compared to the infected non-treated animals, as well as improved rates of clinical recovery and an earlier onset of clinical resolution in the group treated with both IVM and melatonin compared to IVM alone. Furthermore, melatonin supplementation reduced the clinical side effects of IVM observed in the group treated with IVM only and had a positive impact on pruritus in the group that received combined treatment.

Melatonin’s enhancement of skin healing observed in this study may be attributed to its capacity to reduce oxidative stress and inflammation, as indicated by the significant improvements in redox status markers (MDA and TAC) and levels of serum CRP, IL-4, IL-12, and IFN-γ in the combined therapy group compared to the group singly treated with IVM. Additionally, the positive effects of melatonin on pruritus may also stem from its ameliorative and antioxidant activities. Notably, Zhang et al. (2022) demonstrated that melatonin treatment alleviated acute itch as well as chronic pruritus associated with psoriasis and dry skin in mice, attributing these effects to its interaction with melatonin receptors and its antioxidant and anti-inflammatory properties.

Given that there is no significant difference in the viable mite count between the positive control group and the group receiving melatonin only, it appears that melatonin does not influence mite populations, at least at the administered dose. Although melatonin’s potential to enhance tissue healing might theoretically aid in the detachment of crusts and result in a reduced mite count in skin scrapings, no significant difference in mite counts was observed between the IVM-treated group and the group that received both IVM and melatonin. This could be attributed to the early onset of parasitological cure, which may not have allowed sufficient time for the healing process to produce a significant impact on mite counts.

The direct impact of melatonin on parasitic organisms remains an area requiring thorough investigation. In vitro studies by Alves et al. (2011) indicated that melatonin stimulated the proliferation of Plasmodium falciparum by activating specific membrane receptors, leading to enhanced schizogony and increased parasitemia. Conversely, Machado et al. (2020) found that melatonin reduced the proliferation of Toxoplasma gondii in infected monkey kidney epithelial cells (LLC-MK2), inducing morphological alterations such as ruptured plasma membranes and cytoplasmic leakage in tachyzoites, suggesting its potential as a therapeutic agent for toxoplasmosis. These contrasting findings underscore the complex nature of melatonin’s interaction with parasites. Hence, meticulous in vitro and in vivo studies employing a spectrum of dose regimens are warranted to elucidate the potential direct effect of melatonin on Sarcoptes scabiei mites.

Our study highlights that the death of mites appears to be essential for the progression of the healing process. Although rabbits treated with melatonin only exhibited a lower histopathological score compared to the infected non-treated group, melatonin supplementation did not eliminate the skin changes associated with Sarcoptes infestation. In fact, the death of mites appeared to positively influence the pathological changes in the skin of rabbits in both the IVM-treated group and the group treated with both IVM and melatonin, leading to the emergence of clear signs of recovery, such as a reduction in inflammation and hyperkeratosis, the formation of new skin layers, and hair regrowth.

The expression of MMP-9, a zinc-dependent endopeptidase secreted by various cells, including neutrophils, macrophages, and fibroblasts, was significantly elevated in the rabbits treated with melatonin only, although to a lesser extent than in the positive control. This observation aligns with previous findings by Darwish and Eldakroury (2020) and Darwish (2025), who reported a substantial increase in serum MMP-9 levels in camels and sheep infected with Sarcoptes, respectively. MMP-9 plays a crucial role in the degradation of the extracellular matrix during both physiological tissue remodeling and various pathophysiological processes. Notably, MMP-9 is upregulated in conditions involving inflammation and tissue repair, where its proteolytic activity can contribute to the initiation of pathogenesis and the exacerbation of disease progression by influencing the immune response (Yabluchanskiy et al. 2013; Mondal et al. 2020).

Notably, complete healing was not achieved by the end of our experiment in the group singly treated with IVM, where inflammatory cells and remnants of dead mites were still present. Even following the death of the mites, immunohistochemical analysis revealed the continued presence of MMP-9 expression within skin tissue sections, with instances of severe expression still observed, indicating ongoing extracellular matrix remodeling. This could be due to the targeted effects of IVM on mites, as well as ongoing itching and oxidative stress, which prolong inflammation and hinder the development of healthy skin (Zahran et al. 2022). Conversely, the combined therapy group exhibited complete resolution of both the epidermis and dermis, with a complete absence of dead mite remnants and only minimal expression of MMP-9. These findings underscore the beneficial effects of melatonin when administered alongside IVM. Such results could be explained by the absence of mite remnants in the skin layers, the cessation of pruritus and its damaging effects on the skin, along with the anti-inflammatory, immunomodulatory, and antioxidant properties of melatonin in this group.

Oxidative stress refers to the imbalance between reactive oxygen and nitrogen species (ROS/RNS) and an organism’s ability to detoxify these reactive intermediates. Endogenous antioxidants, such as catalase, superoxide dismutase, and glutathione peroxidase, along with dietary antioxidants like vitamins C and E, zinc, folate, selenium, and carotenoids, play crucial roles in scavenging ROS to maintain their levels within normal ranges. However, certain pathological conditions can overwhelm these antioxidant defenses, leading to cellular oxidative stress (Wang et al. 2016; Zhou et al. 2018). Severe oxidative stress can cause cellular damage and death, contributing to various adverse skin effects, including erythema, edema, wrinkling, inflammation, hypersensitivity, and keratinization (Papaccio et al. 2022).

Our data revealed a state of systemic inflammation and oxidative stress in both positive control rabbits and those treated with melatonin only. Importantly, administering melatonin solely to rabbits with severe scabies could not abolish the recorded disturbance in serum cytokines, CRP, and redox status markers, indicating that eradication of mites is a prerequisite for reversal of such changes. When live scabies mites burrow into the skin or release their products like saliva or eggs, various skin cells become activated. These include keratinocytes, lymphocytes, endothelial cells, Langerhans cells, and dendritic cells, which interact in a complex way in response to the scabies infestation. This interaction leads to the development of inflammation and oxidative stress (Rebholz et al. 2007; Dai et al. 2011; Nwufoh et al. 2020; Zahran et al. 2022). This process can increase the production of reactive oxygen species, such as hydrogen peroxide (H2O2), which can damage the skin by causing lipid peroxidation and altering its structure and permeability. Importantly, the measurement of malondialdehyde (MDA) in our study is a common way to assess oxidative stress in medical research and serves as a key indicator of lipid peroxidation (Singh et al. 2014).

In this context, our results showed that rabbits treated with IVM only exhibited persistent systemic oxidative stress and inflammation, despite being at significantly lower levels than those observed in the positive control rabbits. In contrast, rabbits that received both IVM and melatonin exhibited almost complete normalization of all the biochemical and immunological parameters assessed. It is worth noting that Abdel-Rahman and Ali (2021) indicated that ewes treated with IVM still showed signs of oxidative stress for three months following treatment. Furthermore, another study showed that adding vitamin E and selenium alongside standard scabies therapy could enhance the recovery of affected dogs, indicating their potential as supportive therapies alongside mite-killing medications for canine scabies (Kubesy et al. 2020). Interestingly, melatonin is believed to provide a significantly stronger antioxidant effect compared to vitamins E, C, and glutathione, a property that could enhance its positive role in supporting tissue healing. Unlike conventional antioxidants that neutralize one ROS at a time, a single melatonin molecule can capture up to ten (Tan et al. 2007; Aqa and Albanna 2022).

Melatonin is regarded as a key component of antioxidant machinery. It directly neutralizes harmful ROS and boosts the activity of antioxidant enzymes while reducing the activity of enzymes that promote oxidation (Reiter et al. 2016). Its direct scavenging effect on free radicals has been clearly demonstrated in cell cultures, where melatonin and its metabolites, typically used in high concentrations, can function through various mechanisms, including electron transfer, hydrogen transfer, and metal chelation (Galano and Reiter 2018). Additionally, it is well established that the activation of melatonin receptors like MT1 and MT2 promotes the expression of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase (Hardeland and Pandi-Perumal 2005; Reiter et al. 2016; Ferlazzo et al. 2020). Moreover, melatonin’s binding to quinone reductase (QR2) inhibits its enzymatic activity, thereby decreasing ROS production (Boutin 2016).

The normalization of serum IL-12, IL-10, and IFN-γ observed in our study in the combined therapy group compared to the group singly treated with IVM, along with the significant differences noted for these parameters together with serum IL-4 between animals treated with melatonin only and the positive control group, supported the immunomodulatory and anti-inflammatory effect of melatonin supplementation. However, the complete understanding of melatonin’s impact on the immune system is complex and somewhat unclear. Various studies suggest that melatonin is a potent immunoenhancing factor, advocating its use as a therapeutic agent when there is a need to enhance humoral and/or cellular immune responses, while others highlight its anti-inflammatory properties (Cardinali et al. 2008; Carrillo-Vico et al. 2013; Claustrat and Leston 2015; Hardeland 2019; Moslehi et al. 2022; Horodincu and Solcan 2023). This apparent controversy might arise from the diverse concentrations and dosages of melatonin used across studies, possibly reflecting the molecule’s pleiotropic nature. Moreover, it could be attributed to the fact that the immune effects resulting from melatonin’s daily rhythm-related actions through its specific receptors are often not distinguished from its other non-circadian effects (Hardeland 2022).

In the same context, the anti-inflammatory effects of melatonin involve several mechanisms, partly associated with its antioxidant properties. Melatonin can hinder the activation of NF-kB, upregulate Nrf2, and suppress TLR4 signaling pathways. Some of these effects of melatonin appear to be connected to the activation of sirtuin 1 (SIRT1) (Deng et al. 2006). Lastly, melatonin’s influence on the immune system might also stem from its well-documented role in promoting sleep. Sleep and immunity are closely interconnected; regular sleep is essential for immune function, while immune-related factors are important for healthy sleep. Therefore, melatonin’s effect on inflammatory cytokines could be linked to its sleep-promoting properties, which, in turn, help maintain a robust immune system (Maestroni 2023).

While this study did not include microbiological investigations, the role of bacteria in the pathogenesis of scabies cannot be ignored. In humans, Staphylococcus aureus and group A hemolytic streptococci are the most commonly reported bacteria among scabies patients (DeCandia et al. 2019; Sharaf 2024). A noteworthy recent study in mice found that polymicrobial sepsis increased the presence of MT2 receptors on neutrophils. Administering melatonin to these mice helped protect them by boosting the bacteria-killing ability of these neutrophils (Xu et al. 2019). Additionally, another study indicated that melatonin treatment in mice subjected to short periods of light and infected with Staphylococcus aureus led to a more effective removal of bacteria from their bloodstream (Bishayi et al. 2016).

The limitations of the current study primarily stem from two methodological aspects. Firstly, the relatively small sample size employed, while sufficient to generate compelling preliminary data, inherently limits the statistical power and, consequently, the generalizability of our findings. Future investigations involving a larger cohort of animals are essential to robustly validate these initial observations and to enhance the external validity of our conclusions. Secondly, the assessment of immunohistochemical staining intensity for MMP-9 expression utilized a semi-quantitative scoring system. While this methodology is a widely accepted practice in histopathological evaluation, its inherent subjectivity can introduce variability in interpretation. We acknowledge that more objective quantification through advanced digital image analysis would significantly enhance the reproducibility and precision of these measurements in future studies.

Conclusions

Infestation by Sarcoptes mites creates a state of oxidative stress, leading to systemic inflammation. Relying solely on IVM for treatment can delay full recovery, as IVM may induce oxidative stress on its own. Administering melatonin alongside IVM has the potential to restore normal biochemical and immunological profiles and accelerate recovery in diseased rabbits. Therefore, melatonin is recommended as an adjunct therapy with IVM, particularly in severe scabies cases. Furthermore, future research is needed to explore optimal doses and treatment schedules.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 24 KB) (24.4KB, docx)

Abbreviations

CRP

C-reactive protein

IFN-γ

Interferon gamma

IL

Interleukin

IVM

Ivermectin

MDA

Malondialdehyde

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

TAC

Total antioxidant capacity

Author contribution

Mahmoud S. Sharaf and Ahmad A. Othman conceived and designed the experiment. Mahmoud S. Sharaf and Asmaa R. Ellakany conducted the experiment. Abdallah M. Hafez carried out the biochemical tests. Histopathological examinations were performed by Dareen M. Ali. All the authors analyzed the results. Statistical analyses were conducted by Mahmoud S. Sharaf and Asmaa R. Ellakany. The initial draft of the manuscript was written by Mahmoud S. Sharaf, after which all authors reviewed and approved the final version for publication.

Data availability

The authors confirm that the data supporting the findings in this study are available within the article. Raw data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethical approval

Animals were housed and managed in accordance with the International Council for Laboratory Animal Science (ICLAS) guidelines. All animal procedures were evaluated and approved by the Research Ethics Committee and Quality Assurance Unit at Tanta University (Approval code: 36264PR1080/2/25).

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

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Supplementary Materials

Supplementary file1 (DOCX 24 KB) (24.4KB, docx)

Data Availability Statement

The authors confirm that the data supporting the findings in this study are available within the article. Raw data that support the findings of this study are available from the corresponding author upon reasonable request.

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