Introduction
Psoriasis is a chronic autoimmune human skin disorder that is characterized by excessive
proliferation of keratinocytes, scaly plaques, severe inflammation, and erythema [1]. A wide range of conventional medical therapies to treat psoriasis is established,
from topical therapies [steroids, vitamin D analogues, psoralen, 5-aminolevulinic
acid, salicylates, fumaric acid esters, anthralins (dithranol), tacrolimus, retinoids
– e.g tazarotene] and systemic medications (methotrexate, cyclosporine, retinoids,
6-thioguanine, mycophenolate mofetil, troglitazone and new biologic agents, such as
adalimumab, alefacept, efalizumab, etanercept, infliximab), through to phototherapy
or combinations of those [2]. However, most of these therapies cause a number of side effects, and limited in
efficacy, inconvenience, cutaneous atrophy, organ toxicity (hepatotoxicity, nephrotoxicity,
teratogenicity), carcinogenicity, and broadband immunosuppression, which are limiting
their long-term use [3], [4]. In turn, a short-term treatment of psoriasis causes its remission after finishing
the treatment or only relieves the patientʼs condition. Moreover, psoriasis is often
accompanied by other diseases, such as depressive illness, cardiovascular disease,
and a seronegative arthritis known as psoriatic arthritis [5]. Therefore, the invention of new alternative treatments for psoriasis causing fewer
side effects would be desirable. It seems that several herbal drugs can meet these
requirements and have to be seen as promising new agents for psoriasis treatment [6]. Herbal products are greatly accepted by patients because they are believed to be
safer than conventional therapeutics. Moreover, herbal products present a great structural
diversity and multidirectional mechanisms of action, which is not commonly seen in
synthetic compounds. Herbal drugs may become an effective treatment for psoriasis,
causing lower costs and less side- or toxic effects in comparison to other therapies.
Therefore, researchers are still looking for novel herbal products and/or their active
constituents, which potentially could be used for the treatment of psoriasis instead
of synthetic drugs.
The goal of this review is to summarize the knowledge based on animal studies and
clinical trials regarding herbal products used for the topical treatment of psoriasis
and to characterize their mechanisms of action. Penetration of herbal products through
the psoriatic skin barrier, novel herbal drug delivery systems in psoriasis treatment,
and possible adverse effects of herbal therapy are also discussed.
Methods
Search strategy
PubMed, Scopus and Google Scholar were searched for articles published from 1995 up
to the present. Search terms included “herbal products and psoriasis”, “herbal treatments
for psoriasis”, “topical herbal medication for psoriasis”, and “herbal drug delivery
systems in psoriasis treatment”. References from reviews about herbal products and
psoriasis were examined for additional articles and case reports. A manual search
was also conducted, based on citations in scientific literature.
Inclusion and exclusion criteria
Selection criteria included articles which are examining herbal products used for
the topical treatment of psoriasis by means of animal studies and clinical trials,
and are comparing herbal products treatment vs. control treatments (placebo or active
therapy). Other forms of psoriasis treatment than topical administration of herbal
products (e.g. oral, systemic) were excluded from the study. Also publications in
languages other than English were excluded.
Pathology of Psoriasis
The pathophysiology of psoriasis involves both skin cells and immune cells. Psoriasis
is typically characterized as inflamed skin with surface scales, thickening of the
epidermis (acanthosis; granular layer is reduced or absent) caused by parakeratosis,
which is a consequence of nuclei retention in SC keratinocytes caused by abnormal
differentiation and hyperproliferation of epidermal keratinocytes [1], [7]. Some scientific reports consider nitric oxide (NO), released from keratinocytes
at high concentrations, as a key inhibitor of cellular proliferation and inducer of
cell differentiation in vitro. Although a high-output NO synthesis is suggested by the expression of inducible
NO synthase (iNOS), mRNA, and proteins in psoriasis lesions, the pronounced hyperproliferation
of psoriatic keratinocytes may indicate that iNOS activity is too low to effectively
deliver antiproliferative NO concentrations [8]. As a consequence, the impairment of corneocyte differentiation, including an impaired
formation and secretion of lamellar body contents and the processing of lamellar body
contents into lamellar bilayers, causes a reduction in the psoriatic skin barrier
function [9]. Moreover, skin barrier problems in psoriasis are not only the excessive growth
and aberrant differentiation of corneocytes but also almost absent normal moisturizing
factors (NMFs) like water, an imbalance of skin lipids (rise in the levels of cholesterol
and fall in the levels of ceramides), and dry and sensitive skin [10].
The role of the immune system and its interactive network of leukocytes and cytokines
in disease pathogenesis was also described [11], [12]. Psoriatic lesions are highly infiltrated with immune cells, most notably CD3+ T cells and CD11c+ dendritic cells [13], [14]. Proinflammatory cytokines produced by these cells, including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-17 (IL-17), IL-20, IL-22, IL-23, IL-12, and IL-1b, have been linked
to the pathogenesis of psoriasis through causing keratinocytes hyperproliferation
[7]. Moreover, IFN-γ and IL-15 seem to increase the apoptotic resistance of the keratinocytes [15], [16]. Also growth factors and genetic factors like transforming growth factor (TGF)-β, toll-like receptor (TLR)-2, signal transducer and activator of transcription (STAT-3),
coiled-coil alpha-helical rod protein 1 (CCHCR1), steroidogenic acute regulatory protein
(StAR), and vitamin D receptor (VDR) are suggested to be the most critical factors
governing the exacerbation of psoriasis [17], [18]. The essential transcription factor in psoriasis, nuclear factor kappa B (NF-κB), has been shown to be a key regulatory element occurring in a variety of immune
and inflammatory pathways, in cellular proliferation and differentiation, and in apoptosis
[19]. An imbalance between the proapoptotic and antiapoptotic activities of NF-κB proteins has been demonstrated to cause differentiation and hyperproliferation in
psoriatic lesions rather than in normal cells [20].
Topically Used Herbal Products for the Treatment of Psoriasis
Many herbal topical formulations have been marketed worldwide to prevent psoriasis
[21]. There are many advantages of using natural drugs, including patient compliance,
less side-effects, easy availability, low-costs, and more than one mode of biochemical
action for psoriasis treatment. Therefore, researchers are searching for new herbal
products, which have the potential to be an alternative for synthetic drugs in psoriasis
therapy.
Animal-based studies
Herbal products with an anti-psoriasis potential tested in animal-based studies are
summarized in [Table 1]. Most of the in vivo studies performed in animals are based on a mouse tail model of psoriasis, introduced
by Jarrett and Spearman [22]. The model is based on the induction of orthokeratosis in those parts of the adult
mouse tail, which have normally a parakeratotic differentiation. Antipsoriatic drug
activity is defined by the percentage increase of orthokeratotic regions after topical
drug treatment of a mouse tail. Ethanolic extract of Aloe vera leaf gel [23], ethanolic extract of Nigella sativa [24], ethanolic extract of Rubia cordifolia [25], methanol extract of Smilax china and the isolated flavonoid quercetin [26], Thespesia populne extract [27], hydro alcoholic extract of Wrightia tinctoria [28], and baicalin isolated from Scutellaria baicalensis [29] were assessed for their antipsoriatic activity using the mouse tail model. All of
them exhibited a significant percentage reduction of relative epidermal thickness,
promoted epidermal differentiation and normal keratization of keratinocyte, produced
significant orthokeratosis, and exhibited a higher antipsoriatic activity as the positive
control (tretinoin 0.05 %, tazarotene 0.1 %, dithranol 1 %, tacrolimus 0.03 %, retinoic
acid). A topically administered ointment containing methanol extract of Kigelia africana induced a significant and dose-dependent increase in orthokeratosis in parakeratotic
areas of albino mouse tails, with significant effects on the epidermal thickness compared
to the vehicle control [30].
Table 1 Herbal products used for the topical treatment of psoriasis – animal studies.
|
Plant
|
Animal
|
Model of the study
|
Pharmacological data
|
Effect
|
Ref.
|
|
Cassia tora
|
albino mice
|
UVB-induced psoriasis
|
methanolic C. tora extract (0.05 %, 0.1 %, 0.2 %) in O/W creams;
positive control: tretinoin (0.05 %) in base cream;
treatment: single dose of creams with different concentrations of extract/tretinoin/cream
base/crude extract
|
O/W creams with extracts exhibited a significant reduction in percentage of relative
epidermal thickness as compared to tretinoin
|
[31]
|
|
Kigelia africana (sausage tree)
|
albino mice
|
mouse tail model of psoriasis
|
ointments containing 200, 100 and 50 mg/ml of methanol extracts from stem, leaves,
and fruit of K. africana;
control: vehicle and placebo;
treatment: 0.1 ml of the ointment, contact time of 2–3 h, once daily for 2 weeks
|
stem methanol extracts induced orthokeratosis in parakeratotic areas of mouse tail
with significant effects on epidermal thickness
|
[30]
|
|
Nigella sativa
|
albino mice
|
mouse tail model of psoriasis
|
95 % ethanolic extract of N. sativa desolved in water; ratio 1 : 2;
control: placebo;
positive control: tazarotene gel (0.1 %);
treatment: once daily for 14 days, contact with the skin for 2 h
|
extract produced equivalent epidermal differentiation in degree of orthokeratosis
as tazarotene
|
[24]
|
|
Rubia cordifolia
|
BALB/c mice
|
mouse tail model of psoriasis
|
ethanolic extract was fractioned sequentially with hexane, ethyl acetate (EA), n-butanol,
and water;
1 %, 2 % and 5 % EA fraction of extract was formulated into gel;
control: placebo;
positive control: 1 % w/w dithranol in gel;
treatment: twice a day, 7 times a week for 4 consecutive weeks
|
EA fraction dose-dependently increased granular layer and epidermal thickness;
potency of keratinocyte differentiation 5 % EA fraction is similar to that of dithranol
gel
|
[25]
|
|
Scutellaria baicalensis
|
BALB/c mice
|
mouse tail model of psoriasis
|
creams with 1 %, 3 % and 5 % baicalin isolated from S. baicalensis;
control: placebo;
negative control: 2,4-dinitrofluorobenzene-induced contact hypersensitivity (CHS);
positive control 1: 0.1 % tazarotene cream;
positive control 2: 0.03 % tacrolimus ointment;
treatment: twice daily for 4 weeks
|
creams with baicalin inhibit CHS reaction at a less significant magnitude than that
of tacrolimus ointment;
5 % baicalin cream promotes epidermal differentiation and normal keratization of keratinocyte
in mouse similar to that of tazarotene cream
|
[29]
|
|
Smilax china
|
Swiss albino mice
|
mouse tail model of psoriasis
|
methanol extract and isolated flavonoid quercetin;
positive control: retinoic acid
|
flavonoid quercetin shows significant orthokeratosis, anti-inflammatory, and maximum
antiproliferant activities
|
[26]
|
|
Thespesia populne
|
Wistar rats
|
mouse tail model of psoriasis
|
cream with 100 mg of each extract (ethanolic, pet-ether, butanolic, ethyl acetate)
and 50 mg of each isolated compound (TpF-1 and TpF-2 as flavonoids, TpS-2 as sterole);
positive control: 0.05 % tretinoin cream;
treatment: once daily, 5 times a week for 2 weeks
|
pet-ether extract and TpF-2 increased orthokeratotic region
|
[27]
|
|
Wrightia tinctoria
|
albino mice
|
mouse tail model of psoriasis
|
hydro alcoholic extract of W. tinctoria leaves;
control: vehicle;
positive control: isoretinoic acid;
treatment: once daily for 14 days
|
extract produced significant degree of orthokeratosis compared to isoretinoic acid
and increased the epidermal thickness compared to control
|
[28]
|
Only two studies were based on an UVB-induced model of psoriasis. UVB-induced photodermatitis
in rats has been proposed as an experimental model for Psoriasis vulgaris by Nagakuma et al. [32]. The model is based on the induction of dark-brown scale on the erythematous lesion
after UVB irradiation. Singhal and Kansara [31] showed antipsoriatic activities of O/W creams containing methanolic extract of Cassia tora leaves as well as of the crude extract, by using UVB-induced psoriasis in rats. Both
of them exhibited a significant percentage reduction of relative epidermal thickness
and spleen index as compared to 0.05 % tretinoin as positive control. Also irradiated
rat skin treated with SUEX GEL containing aqueous extract of the bark of Pongamia pinnata showed a significant reduction in the total epidermal thickness and retention of
the Stratum granulosum compared to ointment base and placebo group [33]. However, there is no animal model that could replace clinical studies. Moreover,
positive results of animal-based studies are not always proved in clinical trials.
They can only help in the initial determination of new herbal products, which may
proceed to further stages of clinical trials and become useful drugs for the treatment
of psoriasis in the future.
Clinical studies
Herbal products with anti-psoriasis potential tested in clinical studies are listed
in [Table 2]. Topical application of cream with 10 % Mahonia aquifolium extract [34], 0.03 % Camptotheca acuminata nut [35], Aloe vera extract [36], oleoresin from Copeifera langsdorffii (5 %) ointment [37], and cream with Persea americana oil [38] showed significantly greater improvements in psoriatic treatment compared with calcipotriol
and fluticasone propionate mixture, hydrocortisone, triamcinolone acetonide, and calcipotriol
ointment, respectively. In turn, Aloe vera cream [39], Baphicacanthus cusia ointment [40], Camptotheca acuminata nut extract in tincture/gel/ointment [41], Curcuma longa microemulgel [42], Hypericum perforatum ointment [43], Indigo naturalis ointment [44], Indigo naturalis extract in oil [45], Mahonia aquifolium cream [46], Mahonia aquifolium bark extract ointment [47], Strobilanthes formosanus ointment [48], and cream with capsaicin from Capsicum frutescens [49] were found to be significantly more effective than the vehicle control group. There
are also literature data showing no significant difference between herbal products
and drug/placebo treatment. The effect of Mahonia aquifolium ointment appears to be less potent than that of dithranol [50]. Aleurites moluccana (Kukui nut) oil [51], Aloe vera gel [52], as well as ointment and lotion containing 20 % kunzea oil [53] showed no significant difference compared to a placebo psoriasis treatment.
Table 2 Herbal products used for the topical treatment of psoriasis – clinical studies.
|
Plant
|
Type of clinical study
|
Participants
|
Treatments
|
Effect
|
Ref.
|
|
PASI – Psoriasis Area and Severity Index; QLI – Quality of Life Index; NAPSI – Nail
Psoriasis Severity Index
|
|
Aloe vera
|
placebo-controlled, double-blind clinical trial
|
60 patients (18–50 years) with slight to moderate chronic plaque psoriasis and PASI
scores between 4.8–16.7
|
3 times daily (without occlusion) for 5 consecutive days per week for 16 weeks
|
A. vera cream had cured 25/30 patients compared to the placebo cure rate of 2/30 resulting
in significant clearing of the psoriatic plaques and decreased PASI score to a mean
of 2.2
|
[39]
|
|
Aloe vera
|
randomized, comparative, double-blind clinical trial
|
80 patients with mild to moderate plaque psoriasis
|
twice daily for 8 weeks
|
A. vera cream was found to be more effective than triamcinolone acetonide cream
|
[36]
|
|
Baphicacanthus cusia
|
vehicle-controlled clinical trial
|
14 patients with chronic plaque psoriasis
|
once daily for 8 weeks
|
significant reduction of psoriasis compared to control
|
[40]
|
|
Capsicum frutescens
|
comparative, vehicle-controlled, double-blind clinical trial
|
44 patients with moderate to severe psoriasis
|
once a day for 6 weeks
|
capsaicin cream was found to be significantly more effective than control
|
[49]
|
|
Curcuma longa
|
randomized, prospective intra-individual, right–left comparative, placebo-controlled,
double blind clinical trial
|
40 patients (18–60 years) with mild to moderate plaque psoriasis
|
twice a day for 9 weeks
|
progressive reduction of thickness, followed by decrease erythema, pruritus, resulting
in moderate to acceptable improvement;
in some cases, significant resolution of psoriatic lesions
|
[42]
|
|
Hypericum perforatum
|
right–left comparative, vehicle- controlled, single blinded (only patients were blinded)
clinical trial
|
10 patients (20–55 years) with mild plaque psoriasis
|
twice daily for 4 weeks
|
improvement in clinical scores was reported with H. perforatum ointment compared with placebo group
|
[43]
|
|
Indigo naturalis
|
randomized, vehicle-controlled, observer-blind clinical trial
|
31 patients with symmetrically comparable psoriatic nails
|
twice daily for the first 24 weeks
|
reduction of NAPSI scores for the Lindioil group was superior to the reduction in
the control group
|
[45]
|
|
Mahonia aquifolium
|
placebo-controlled, double-blind clinical trial
|
200 patients with mild to moderate psoriasis
|
twice a day for 12 weeks
|
significant improvements in PASI and QLI in the Mahonia-treated group compared with the control group
|
[46]
|
|
Strobilanthes formosanus
|
randomized, vehicle-controlled, observer-blind clinical trial
|
42 patients with chronic plaque psoriasis
|
once a day for 12 weeks
|
31 of 42 patients experienced clearance or near clearance of psoriasis after herbs
ointment treatment
|
[48]
|
|
Persea americana (Avocado)
|
randomized, prospective, right–left comparative clinical trial
|
13 patients (10 men and 3 women) with chronic plaque psoriasis
|
twice daily for 12 weeks
|
cream with vitamin B12 and avocado oil was effective as calcipotriol cream with regard
to PASI score
|
[38]
|
The clinical studies presented in [Table 2] contain some shortcomings, which ultimately do not diminish the value of these limited
research works. [Table 2] reports 10 clinical trials, which were carried out on groups consisting of 10–20
patients (3/10), 30–50 patients (4/10), 60–80 patients (2/10), and more than 100 patients
(1/10). In practice, the first phase of clinical trials involved usually 100–500 participants,
because only studies carried out with more than 100 patients provide the opportunity
for statistical analyses. Only one of the above described clinical trials was performed
on 200 subjects. The participants in this randomized, double-blind, placebo-controlled
study used either the topical cream Reliéva (a homeopathic product containing a proprietary
M. aquifolium extract) or control (placebo) [46]. Other clinical trials included a nonrepresentative number of participants and therefore
the conclusions of these studies cannot be generalized to the entire population affected
by psoriasis. Moreover, participants (men and women) aged from 18 to 60 years with
mild chronic plaque psoriasis (1/10), mild to moderate chronic plaque psoriasis (4/10),
moderate to severe chronic plaque psoriasis (1/10), and chronic plaque psoriasis without
determining psoriasis area (4/10) were condensed in clinical trials. Plaque psoriasis,
also known as Psoriasis vulgaris, affects about 90 % of all cases of psoriasis, which makes the described research
potentially useful to treat this type of psoriasis. These clinical studies included
randomized trials (5/10), vehicle-controlled (8/10), comparative (5/10), observer-blind
(2/10), single-blind (1/10), and double-blind clinical trials (5/10). It is known
that only well-controlled double-blind clinical trials can prove the efficacy of herbal
products in psoriasis treatment. Moreover, such research is expensive, long lasting
and requires a special permission from the regulatory authorities. Also compared to
multidirectional synthetic drug studies, clinical and toxicological studies to prove
the efficacy and safety of herbal products are rare. Several factors might contribute
to the explanation of such discrepancies, for example a lack of standardization and
quality control of the herbal products used in clinical trials, the use of different
dosages of herbal medicines, inadequate randomization in most studies and an improper
selection of patients, the numbers of patients in most trials are insufficient for
the attainment of statistical significance, wide variations in the duration of treatments
using herbal medicines, and lacking or insufficient results of toxicological studies.
Unfortunately, the most of the above-mentioned factors can be related to the clinical
trials described in [Table 2].
Herbal Products Penetration Through Psoriasis Skin
Novel drug delivery systems such as liposome, niosome, ethosome, microemulsion, nanoemulsion,
solid lipid nanoparticles (SLNs), and nanostructured lipid carrier systems (NLCs)
present desirable attributes for the use in extremely dehydrated and thickened psoriatic
skin that has a lipid imbalance and is sensitive to irritants [54], [55]. They offer an enhanced penetration through skin with less toxic effects compared
to free drugs (liposomes), slow down drug release and reduce systemic toxicity (niosomes),
enable drugs to reach the deep skin layers and/or the systemic circulation (ethosomes),
provide long-term stability and high solubilization capacity for hydrophilic and lipophilic
drugs (microemulsions), prolonge action on the skin and protect the drug from instability
(nanoemulsions), cause only negligible skin irritation, and ensure the compatibility
of the drugs (NLCs) [54]. Moreover, topical drug delivery systems with herbal formulations enhance the therapeutic
effects of herbal drugs and facilitate their penetration through the skin [56], [57].
Studies performed on liposomal vesicles (combination of methotrexate and menthol)
incorporated in vesicular gel base [58], elastic liposomal formulation of colchicine isolated from Colchicum autumnale and Gloriosa superb [59], and capsaicin-containing liposomes, niosomes and emulsomes [60] confirmed their potential to enhance skin accumulation, prolong drug release, and
improve the site-specificity of active constituents as effective drugs in the treatment
of psoriasis. Niosomes loaded with ammonium glycyrrhizinate from Glycyrrhiza glabra showed no toxicity, good skin tolerability and improved the drugʼs anti-inflammatory
activity in mice and human [61]. Psoralen from Fructus psoraleae loaded in ethosomes increased the lipid fluidity and cell membrane penetrability,
which made it possible to enhance the skin deposition in vitro and in vivo and can be used to cure psoriasis [62]. Microemulsion gel-based systems of babchi oil (Psoralea corylifolia) and chitosan-coated microemulsions are a potential vehicle for the topical delivery
of psoralen and methoxypsoralen (extracted from Ammi majus) for the treatment of psoriasis [63], [64]. Microemulsion systems of 5 % tea tree oil distilled from Melaleuca alternifolia are promising vehicles for a transdermal drug delivery [65]. Skin delivery of nanoemulsion system loaded turmeric oil (15 %) from Curcuma longa [66], nanoemulsion O/W containing rice bran oil [67], and nanoemulsion with glycyrrhetic acid from Glycyrrhiza glabra [68] significantly increased the transdermal permeability of these compounds, showed
anti-inflammatory activities and a low irritation potential, and so can be used for
psoriasis treatment. NLCs and SLNs showed a good ability to increase the drug accumulation
in various skin layers. NLCs may as well be a more potent carrier for the topical
delivery of capsaicin, to allow for an effective therapy of psoriasis [69].
Mechanisms of Action of Herbal Products Used in Psoriasis Treatment
In general, herbal products used in the treatment of psoriasis work by (1) inhibition
of the keratinocyte hyperproliferation and induction of apoptosis, (2) inhibition
of immune-inflammatory reactions, (3) suppression of phosphorylase kinase (PhK) activity,
(4) inhibition of the hedgehog (Hh) signaling pathway.
A number of studies show that the inhibition of keratinocyte hyperproliferation, induction
of apoptosis, and modulation of keratinocyte differentiation have been considered
as targets of antipsoriatic strategies. Animal-based studies support the efficacy
of the herbal products for the treatment of psoriasis via inhibition of keratinocyte
hyperproliferation. The ethanolic extract of Aloe vera leaf gel showed antipsoriatic activity by a significant differentiation of the epidermis,
seen as orthokeratosis as well as an increase in the relative epidermal thickness
when compared with the control group in mice [23]. The ethanolic extract of Nigella sativa seeds extract produced a significant epidermal differentiation from its degree of
orthokeratosis comparable to tazarotene gel (0.1 %) in albino mice [24]. However, most desired for the treatment of psoriasis are herbal products that inhibit
epidermal hyperplasia and inflammation simultaneously. Tuhuai extract reduced epidermal
hyperplasia and inflammation in normal hairless mice, which makes it a valuable drug
for treatment of psoriasis [70]. Baicalin isolated from Scutellaria baicalensis acts by inhibiting inflammatory reactions and inducing the differentiation of keratinocytes
at the same time [29]. Moreover, baicalin cream (5 %) promotes epidermal differentiation and normal keratization
of keratinocyte in mouse skin similar to tazarotene cream (0.1 %). The flavonoid quercetin
from the rhizome of Smilax china shows significant orthokeratosis, reduction in epidermal thickness, anti-inflammatory,
and maximum antiproliferant activities compared to mice treated with retinoic acid
[26]. The treatment of psoriasis by inhibition of keratinocyte hyperproliferation through
herbal products was also confirmed in clinical studies. Indigo naturalis ointment modulates the proliferation and differentiation of keratinocytes in the
epidermis as well as inflammatory reactions by inhibiting the infiltration of T lymphocytes
in patients with chronic plaque psoriasis [40]. Analysis of biopsies taken from patients after I. naturalis ointment treatment showed that the expressions of proliferating marker Ki-67 and
inflammatory marker CD3 were decreased, while differentiation markers, such as filaggrin,
were increased in the epidermis. Moreover, I. naturalis as well its major active constituent induribin inhibited the proliferation and abnormal
differentiation of epidermal keratinocytes through decreasing proliferating cell nuclear
antigen (PCNA) and increasing involucrin at both mRNA and protein levels in patients
with psoriatic lesions [71].
Some studies show that the inhibition of fibroblast-secreted cytokines could regulate
keratinocyte proliferation and differentiation as well slow down the process of inflammation
in psoriasis [72]. Ethanolic extracts from Alpinia galanga, Curcuma longa and Annona squamosa showed effects on the downregulation of NF-κB signaling molecules in the HaCaT keratinocyte cell line, reflecting their potential
use in treating diseases with inflammation and hyperproliferation such as psoriasis
[73]. Copeifera langsdorffii oleoresin, also known as Copaiba balsam, exhibits an anti-inflammatory activity through
inhibiting NF-κB nuclear translocation and secreting proinflammatory cytokines [37]. Preincubation of LPS-stimulated human THP-1 monocytes with increasing concentrations
of the oleoresin purified fraction reduced the release of proinflammatory cytokines
(IL-1β, IL-6, TNF-α) and counteracts LPS-driven NF-κB nuclear translocation. Water-soluble polysaccharide (GP-I) purified from Gynostemma pentaphyllum showed a significant antiproliferative effect and decreased TNF-α, a vital proinflammatory cytokine in psoriasis [74]. Extracts of Acanthus mollis, Achillea ligustica, Artemisia arborescens, and Inula viscosa inhibited 5-LOX and COX-1 activity as well as NF-κB activation [75]. Moreover, A. ligustica, A. arborescens, and A. mollis increased the biosynthesis of 15(S)-HETE, an anti-inflammatory eicosanoid. Herbal
products treatment of psoriasis through inhibition of cytokines was also confirmed
in animal-based studies. The topical application of a mixture of herbal extracts (Tinospora cordifolia, Curcuma longa, Celastrus paniculatus, Aloe vera) lead to the downregulation of overexpressed cytokines in mice, initially induced
with psoriasis-like dermatitis through topical application of imiquimod [17].
Some research found that phosphorylase kinase (PhK) enzyme is expressed on a significantly
higher level in psoriatic epidermis as in normal epidermis [76]. PhK integrates multiple calcium/calmodulin-dependent signaling pathways including
those involved in cell migration and cell proliferation. Therefore, a modulation of
PhK activity by drugs/herbal products may be an effective treatment of psoriasis.
Curcumin is a selective PhK inhibitor [77]. It was observed that the PhK activity was highest in active untreated psoriasis,
lower in the calcipotriol and curcumin treated group, and lowest in normal skin. A
decreased PhK activity in curcumin and calcipotriol treated psoriasis patients was
associated with corresponding decreases in keratinocyte transferrin receptor expression,
severity of parakeratosis, and density of epidermal CD8+ T cells.
Some reports suggest that the Hh pathway is activated in lesional psoriatic skin,
and that treatment with the Hh pathway antagonist cyclopamine may lead to a rapid
resolution of the disease [78]. Cyclopamine isolated from Veratrum californicum was found to be more effective than topical clobetasol-17 propionate in the treatment
of guttate and plaque type psoriasis [79]. Besides, inflammatory cells including CD4+ lymphocytes were found to disappear
rapidly after the treatment with cyclopamine as well as hedgehog/smoothened signaling was inhibited. On the other hand, some research found that the Hh pathway
is not activated in psoriasis [80]. It was observed that Hh target genes (PTCH1 and GLI1), whose expression is elevated in response to Hh signaling, were downregulated in
lesional skin. Therefore, the proposed use of Hh antagonists as antipsoriatic agents
is very questionable.
Adverse Effects of Herbal Therapy
The risk of adverse events increases with the topical administration and the long-term
use of herbal-based formulations. Only few of the animal-based and clinical studies
discussed above included a safety profile of herbal products. No side-effects or adverse
events were reported for the psoriasis treatment with Aleurites moluccana oil [51], Curcuma longa microemulgel [42], Hypericum perforatum ointment [43], Indigo naturalis extract in oil [45], and Strobilanthes formosanus ointment [48] in patients participating in clinical trials. Local adverse events, mainly drying
up, stinging, and itching of the skin on test areas, were observed after the topical
application of Aloe vera gel [36], [52]. The only clinical trial which verified the possibility of acute dermal toxicity
showed that methanolic Cassia tora leaves extract incorporated in O/W creams was safe up to a dose of 2000 mg/kg [31]. Moreover, for human safety reasons the assessment of new substances is still evaluated
for irritant potentials by application to animals followed by observation of visible
changes such as erythema and oedema [81]. Testing for skin irritation in animals is not always predictive for humans, but
is still the most widely used method in toxicity research for herbal extracts applied
topically. It is well known that some herbal remedies may cause allergic reactions,
erythema, and edema and several can be responsible for photosensitization [82], [83]. Some herbal preparations can cause organ toxicity, hitting liver, kidneys, heart,
and other organs [84], [85], [86], or possess cancerogenic properties [87]. Moreover, herbal products are often mislabeled (unknown purity and standardization
of active constituents) and may contain additives or contaminants (heavy metals, pesticides)
that are not listed in formulation [88], [89], [90]. Some herbal products may interact with conventional drugs and some are toxic if
used improperly or at to high doses [91]. Moreover, there are no regulations governing which herbal products can be marketed
for various ailments as well as no authorities register adverse effects [92]. An increasing number of herbal formulation available for sale should prompt governments
to introduce regulations on research which should be carried out before such products
are released to the market.
Challenges and Perspectives for the Treatment of Psoriasis by Herbal Products
The review of the literature shows that a great growth has taken place in the worldwide
interest in the potential of herbal medicines for the treatment of psoriasis over
the last 20 years. Parallel to various synthetic medicines used topically (corticosteroids,
vitamin D analogues, retinoids) and systemic (methotrexate, retinoids, cyclosporin),
or targeted (biological) therapies (e.g. alefacept, efalizumab, etanercept) also herbal
products play an important role as therapeutic agents for psoriasis treatment [93], [94], [95]. The long tradition of herbal products used in the treatment of many diseases is
not sufficient to consider them as effective and safe drugs. To confirm their effectiveness
as new promising alternative agent for the therapy of psoriasis a lot of research
must be performed. Studies showing antiproliferative activity of herbal products and
their ability to modulate cell differentiation in HaCaT cell lines [96], [97], [98], [99], [100], [101] do not provide sufficient evidence that these herbal products will be effective
in the treatment of psoriasis. Also promising results obtained in the studies performed
on animals are not always consistent with the results of clinical trials. Therefore,
only well-controlled double-blind clinical trials and toxicological studies can prove
the efficacy and safety of herbal products in psoriasis treatment. In general, numerous
difficulties associated with the evaluation of the efficacy and safety of herbal medicines,
standardization of plant materials, and quality of herbal products cause that only
a few herbal drugs have been approved for clinical applications so far, and finally
reach the market [102]. Unfortunately, until now there are no approved herbal drugs dedicated for the treatment
of psoriasis. However, in my opinion, the great progress in herbal medicine should
make it possible that the first highly efficient and completely safe herbal product
designed for the therapy of psoriasis will be available on the world market in the
near future. Herbal products can make substantial contributions to drug innovation
by providing novel chemical structures and/or multidirectional mechanisms of action,
which are not commonly seen in synthetic compounds. The development of topical drug
delivery systems facilitates plant extract penetration through the skin and enhances
the therapeutic effects of herbal products in psoriasis treatment. Moreover, the growth
of interest in natural medicine may force pharmaceutical companies to invest in extensive
preclinical and well-controlled randomized clinical trials to prove the safety and
efficacy of herbal medicines. Moreover, new branches of biological sciences, including
pharmacogenomic, metabolomic, and microarray methodology, as well as the techniques
of analytical chemistry, such as HPLC and GC/MS, would likely enable progress in the
assessment of pharmacological qualities and safety of herbal products. These all allow
for creating international guidelines that precisely define the requirements for studies
about the use of herbal medicine. It seems that establishing global regulatory mechanisms
for the introduction of herbal drugs to the world market is desirable and necessary.
