INTRODUCTION:

Berberine (5, 6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolo[5,6-a] quinolizinium) {Fig.1} is a quaternary benzylisoquinoline alkaloid. It is a very important natural alkaloid for the synthesis of several bioactive derivatives by means of modification, condensation and substitution of functional groups in strategic positions for the design of new, selective, and powerful drugs.¹

HCL

Figure: 1. Structure of Berberine

Traditional Use of Berberine containing Species:

In the Berberidaceae family, the genus Berberis comprises of 450–500 species, which represent the main natural source of berberine. Plants of this genus are used against the inflammation, diabetes, infectious disease, constipation, and other pathologies.² In Ayurveda, Berberis species have been used for the treatment of a wide range of infections of the ear, eye, and mouth, for quick healing of wounds, treatment of uterine and vaginal disorders. Berberine has also been used to reduce obesity, and as an antidote for the treatment of scorpion sting or snakebite.³

In Yunani medicine, Berberis asiatica has multiple uses, such as for the treatment of asthma, eye sores, jaundice, skin pigmentation, and toothache, as well as for favoring the elimination/removal of inflammation and swelling, and for drying ulcers.⁴ Nowadays, a significant number of dietary supplements based on plants containing berberine⁵ are used for minimizing fever, common cold, respiratory infections, and influenza.⁶

Botanical Sources of Berberine:

Berberine has been isolated, and quantified from various plant families and genera including Annonaceae (Annickia, Coelocline, Rollinia, and Xylopia), Berberidaceae (Berberis, Caulophyllum, Jeffersonia, Mahonia, Nandina, and Sinopodophyllum), Menispermaceae (Tinospora), Papaveraceae (Argemone, Bocconia, Chelidonium, Corydalis, Eschscholzia, Glaucium, Hunnemannia, Macleaya, Papaver, and Sanguinaria), Ranunculaceae (Coptis, Hydrastis, and Xanthorhiza), and Rutaceae (Evodia, Phellodendron, and Zanthoxyllum).

Berberine is also widely present in barks, leaves, twigs, rhizomes, roots, and stems of several medicinal plants species, including Argemone mexicana (Etminan et al., 2005), Berberis aristata, B. aquifolium, B. heterophylla, B. beaniana, Coscinium fenestratum.⁷

Several experiments found that berberine is widely distributed in the barks, roots, and stems of plants, nevertheless, bark and roots are richer in berberine compared to other plant parts.^8,9 In the Papaveraceae family, Chelidonium majus is important herbal source of berberine.¹⁰ Different researches have reported that maximum berberine concentration accumulates in root (1.6–4.3%) and in most of the berberis species, plants that grow at low altitude contain more berberine compared to higher altitude plants.^11,12,8

Extraction Methods:

Berberine, a quaternary protoberberine alkaloid (QPA) is one of the most widely distributed alkaloid of its class. Current studies suggest that isolation of the quaternary protoberberine alkaloids from their matrix can be done using several methods. The principle behind this consists of inter-conversion reaction between the protoberberine salt and the base. The salts are soluble in water, stable in acidic and neutral media, while the base is soluble in organic solvents. Thus during the extraction, the protoberberine salts are converted into their specific bases and further extracted in the organic solvents.^13,14

Pharmacological Applications of Berberine:

Antioxidant Effect:

Under normal conditions, the body maintains a balance between the antioxidant and pro-oxidant agents (reactive oxygen species—ROS and reactive nitrogen species—RNS.)¹⁵ An experimental study confirmed the effect of berberine on lipid peroxidation after inducing chemical carcinogenesis in small animals (rats). An increase in LPO (lipid peroxidation) was observed after carcinogenesis induction, but also its significant reversal after berberine administration (30 mg/kg). Berberine shows therefore at least fractional antioxidant properties, due to its effect on lipid peroxidation.¹⁶

Effect on Cardiac Contractility:

The beneficial effect of berberine in cardiac failure was confirmed in a study on 51 patients diagnosed with NYHA (New York Heart Association) III/IV cardiac failure with low left ventricular ejection fraction (LVEF) and premature ventricular contractions and/or ventricular tachycardia.

These patients received tablets containing 1.2g berberine/day, together with conventional therapy (diuretics, ACEI- Angiotensin-Converting Enzyme Inhibitors, digoxin, nitrates) for 2 weeks. The increase in LVEF was observed in all patients after this period, but also a decrease in the frequency and complexity of premature ventricular contractions. The magnitude of the beneficial effect was found to be direct proportion with the plasma concentration of berberine.¹⁷

The Role of Berberine in Atherosclerosis:

Atherogenesis is a consequence of high blood lipid levels and deals with inflammatory changes in the vascular wall. Berberine interferes with this process by up-regulating the expression of SIRT1 (silent information regulator T1) and inhibits the expression of PPARγ (peroxisome proliferatoractivated receptor-γ). SIRT1 is a NAD-dependent deacetylase. The SIRT1 enzyme has many targets (PPARγ, p53), all playing different roles in atherogenesis.¹⁸

The Role of Berberine in Lipid Metabolism:

The effects of berberine on lipid metabolism are also the consequence of its effects on LDL cholesterol receptors. On one hand, these receptors are stabilized by an extracellular signal regulated kinase (ERK)-dependent pathway, and on the other, berberine increases the activity of LDL receptors through the JNK pathway.¹⁹Moreover, berberine has an effect on ACAT (cholesterol acyltransferases), a class of enzymes that transform cholesterol into esters, thus playing an essential role in maintaining cholesterol homeostasis in different tissues. There are two types of ACAT enzymes, ACAT1, and ACAT2. ACAT1 is a ubiquitous enzyme, while ACAT2 can be found only in hepatic cells and enterocytes. Berberine influences the activity of ACAT2 without an effect on ACAT1, therefore reducing the intestinal absorption of cholesterol and decreasing its plasmatic level.^20,21

The Role of Berberine in Glucose Metabolism:

Many studies demonstrated that berberine lowers blood sugar, through the following mechanisms: - Inhibition of mitochondrial glucose oxidation and stimulation of glycolysis, and subsequently increased glucose metabolization²² followed by decrease in ATP level through the inhibition of mitochondrial function in the liver, which may be the probable explanation of gluconeogenesis inhibition by berberine.²³ Berberine has a beneficial effect in improving insulin resistance and glucose utilization in tissues by lowering the lipid (especially triglyceride) and plasma free fatty acids levels.²⁴

Nephroprotective effect of Berberine:

The chronic kidney damage occurring in time in patients with HT (hypertension) and DM (diabetes mellitus) is well known; it is mainly due to the atherosclerosis of the renal artery, caused by inflammation and oxidative stress. The protective effect of berberine on kidneys was studied on 69 patients suffering from both HT and DM, with blood pressure and blood sugar levels controlled with conventional medication. The patients received 300 mg berberine/day for 24 months, with 2-week interruptions every 5 months. The authors recorded lower CRP (C-reactive protein), MDA and SOD levels after treatment, but without significant changes in creatinine, arterial pressure, or glycaemia levels. These results support the renal protective effect of berberine through its anti-inflammatory and antioxidant effects.²⁵

Hepatoprotective effect of Berberine:

The hepatoprotective effect of berberine was demonstrated on lab animals (mice), in which hepatotoxicity was induced by doxorubicin. Pretreatment with berberine significantly reduced both functional hepatic tests and histological damage (inflammatory cellular infiltrate, hepatocyte necrosis.²⁶ Berberine prevents the decrease in SOD activity and the increase in lipid peroxidation and contributes to the reduction in TNF-α, COX-2, and iNOS (inducible nitric oxide synthase) levels. The decrease in transaminase levels supports the hypothesis according to which berberine helps maintain the integrity of the hepatocellular membrane.²⁷

Berbrine in the Management of Skin Diseases:

Kim and Chung (2008) had reviewed that Berberine is anti skin aging agent due to its inhibitory effect on basal and UV induced matrix metalloproteinase-1 and metalloproteinase-9 expressions in human dermal fibroblasts and normal human keratinocytes respectively.²⁸

Yashiki et al. (2010) had reviewed that berberine has inhibitory effects on subcutaneous preadipocytes differentiation and facilitates lipolysis in adipocytes and useful for slimming and skin related problems such as skin swelling and cellulite.²⁹

Derosa et al., (2012) had reviewed that Berberine showed antilipogenic effect in the sebaceous glands of hamster.³⁰

Fouladi (2012) reviewed that oral extract of barberry is safe having no side effects and is effective in adolescents with moderate to severe acne vulgaris.³¹ Johnson and Rafikhah (2014) had reviewed that B. vulgaris fruit juice was effective against acne lesions.³²

Journal Name	Year	Author	Outcome
Journal of Drug delivery science and technology	2020	Gupta et al.	Optimization of berberine loaded Transniosomes formulation was carried out by employing Box-Behnken design.³³
International Journal of Pharmaceutics	2018	Torky et al.	A new ion-pair complex of berberine was developed to enhance its skin availability and lipid solubility.³⁴
International Journal of Biological Macromlecules	2020	Vanti et al.	Hydrogels of berberine loaded escinosomes have good skin absorption.³⁵
International Journal of Medicines	2020	Niu et al.	Berberine loaded Thilated Pluronic F127 Polymeric micelle is an effective drug for local skin therapy having good safety profile.³⁶
International Journal of Pharmaceutics	2020	H. Lin et al.	Ethosomes containing combination of berberine chloride and evodiamine is a promising delivery system for the melanoma therapy.³⁷
Pharmaceutics	2019	Vanti et al.	Escinosomes loaded berberine has the ability to expand the activity of loaded drug.³⁸
Journal of Drug delivery science and technology	2020	A.Gull et al.	Cinnamaldehyde and berberine loaded micro emulsion gel is effective for the treatment of Acne vulgaris.³⁹
Pharmaceutics	2020	Amato et al.	Hyaluronan/Poly-L-lysine/Berberine Nanogel were prepared using ionotropic gelation method and have good potential on skin wound healing.⁴⁰
Journal of Applied Pharmaceutical Science	2022	Mayangsari et al.	Transfersomal emulgel was prepared for the delivery of berberine through skin.⁴¹
Asian Journal of Pharmaceutical Research	2020	Awate Pooja S et al.	By using Thin Film Hydration technique and different concentration of non-ionic surfactant Span 60 & Cholesterol, Niosomes of Berberine HCL were prepared.⁴²

Berberine in Management of Psoriasis:

Psoriasis is autoimmune disorder which is characterized by patches of abnormal skin. It is thought to be genetic disease which is influenced by the environmental factors. People with inflammatory Bowel Disease such as ulcerative colitis, are at increased risk of developing psoriasis.⁴³

Pathogenesis of Psoriasis:

It is explained by communing the roles of inflammatory pathway, immune system and genetic factors. It is immune mediated skin disease which involves innate and acquired immune system and activation of inflammatory pathway.⁴⁴

Treatment:

There are many methods which are available for the treatment of psoriasis like systemic agents, topical agents, natural therapies, biological agents, phototherapy and combination therapy are also available for the treatment of psoriasis.⁴⁵

Many treatments are available in market but herbal treatment has less toxic effects and side effects, as they have good potency as compare to synthetic system of medicine.⁴⁶

The herbal medicines plays important role in treatment of psoriasis. For the treatment of psoriasis by use of herbal therapy involves various challenges like establishment of anti-inflammatory activity of action of crude drugs, evaluation of anti-proliferative activity of plant, development of suitable dosage form containing herbs and challenge of safety and efficacy of drug.⁴⁷

Development of Topical Herbal gel of berberine for treatment of Psoriasis:

The hydro gel was prepared using Carbopol 934and was evaluated for physical appearance, drug content, viscosity, pH, homogeneity, grittiness and in-vitro release. From the result, it was concluded that berberine Hydrochloride release was enhanced by using Transcutol P in two concentrations (0.1% and 0.2%).⁴⁸

Evaluation of Synergistic Analgesic activity of Berberine and Asiatic Acid:

Mice were divided into seven groups and analgesic activity was evaluated using heat conduction and hot plate reaction method. The mice was treated with standard drug (Tramadol Hcl) and test drug (Berberine Hcl) and in combination drugs at different concentrations to demonstrate the analgesic effect. The study showed that combination of berberine and asiatic acid have high analgesic activity as compared to the individual drug.⁴⁹

Barbaloin for Treatment of Psoriasis:

Barbaloin is a phytoconstituent which is obtained from aloe vera. Aloe is used as an alternative treatment against skin disease. It shows medicinal and therapeutic activities such as antioxidant, antidiabetic, anti-inflammatory, anticancer and has good effect on CVS system and enzyme/ metabolism availability. It is also used in treatment of Psoriasis, eczema, burns and wounds, dandruff and sunburn.⁵⁰

Development and characterization of Barbaloin gel:

Batches F1 to F10 of hydrogels were formulated using carbopol 934, Xanthan gum, carbopol 934 and carbopol 71G NF as gelling agent. The formulations were evaluated for physical appearance, grittiness, homogeneity, spreadability, pH and viscosity. Formulation F2, F4, F7 and F10 showed good gelling property and further these formulations were selected for in-vitro drug release studies. The in-vitro studies showed that formulations F2 and F10 showed higher release as compare to F4 and F7.⁵¹

CONCLUSION:

This review shows that traditional medical uses of berberine containing plants have been evaluated by modern pharmacological studies. Various species of berberine rich plants have several therapeutic and pharmacological actions, such as immunomodulatory and antioxidant effects, protective action on liver and kidney, cardiovascular system, glucose metabolism regulation which is explained by the presence of berberine and phytoconstituents. Furthermore, berberine, due to its anti-inflammatory and antioxidant effects, it has several clinical applications in many disorders. Instead of this, some traditional uses have not been completely explained and further studies are required.

REFERENCES:

1. Chen Y Y, Chang F R, Wu Y C. Isoquinoline alkaloids and lignans from Rollinia mucosa. Journal of Natural Products. 1996; 59: 904-906.

2. Singh A, Duggal S, Kaur N, Singh J. Berberine: Alkaloid with wide spectrum of pharmacological activities. J. Nat. Prod.2010; 3: 64–75.

3. Dev S. A Selection of Prime Ayurvedic Plants Drugs ancient- Modern Concordance. New Delhi: Anamaya Publishers; 2006.

4. Kirtikar K R, Basu B D. Indian Medicinal Plants. Allahabad : CSIR Publications. 1998;1.

5. Kataoka M, Tokuyama E, Miyananga Y, Uchida T. The taste sensory evaluation of medicinal plants and Chinese medicines. Int. J. Pharm. 2008; 36–44.

6. Fabricant D S, Famsworth N R. The value of plants used in traditional medicine for drug discovery. Journal of Environmental Health Perspectives. 2005; 69.

7. Rosjanga P, Gritsanapan W. Variation of berberine content in the Coscinium fenestratum Stem in Thailand Market. Mahidol University Journal of Pharmaceutical Sciences. 2005;32: 66-70

8. Andola H C, Gaira K S, Rawal M S, Bhatt I D, Purohit V K. Variations of berberine content of Berberis asiatica. Western Himalaya Chem Biodiversity. (2010a) ; 7:415-420.

9. Andola H C, Rawal R S, Rawat M S M, Bhatti I D, Purohit V K. Variations of berberine contents in Berberis pseudumbellata. A High Value Medicinal shrub of West Himalaya. India Medicinal plants Journal of Phytomedicines and related industries. (2010b); 2: 111-115.

10. Tome F, Colombo M L. Distribution of alkaloids in Chelidonium majus and factor affecting their accumulation. Phytochemistry. 1995; 37-39.

11. Chandra P, Purohit A N. Berberine contents and alkaloid profile of Berberis species from different altitudes. Biochemistry systems Ecology. 1980; 379-380.

12. Mikage M, Mouri C. Pharmacognostical studies of Berberis plants from Nepal (1) altitudinal, interspecific and partial variations of berberine content in the barks. Pharmaceutics; 249-254.

13. Marek R, Seckarova P, Hulova D, Marek J, Dostal J, Sklenar V. Palmatine and Berberine isolation artifacts. Journal Of Natural Products. 2003; 66: 481-486.

14. Grycova L, Dostal J, Marek R. Quaternary protoberberine alkaloids. Phytochemistry. 2007; 68: 150-175.

15. Rahal A, Kumar A, Singh V, Yadav B, Tiwari R, Chakrobarty S. The Interplay: Oxidative stress, pro-oxidants and oxidants. Biomedical Research International. 2014.

16. Thirupurasundari C J, Padmini R, Devaraj S N. Effect of berberine on antioxidant status, ultrastructural modifications and protein bound carbohydrates in azoxymethane- induced colon cancer in rats. Journal of Chemistry Biological Int. 2009; 177: 190-195.

17. Zeng X. Relationship between the clinical effects of berberine on severe congestive heart failure and its concentration in plasma studies by HPLC. Biomedical Chromatogram. 1999; 13: 442-444.

18. Chi L, Peng L, Pan N, Hu X, ZhangY, The anti-atherogenic effects of berberine of foam cell formation mediated through upregulation of sirutin I. International Journal of Molecular Medicines. 2014; 34: 1087-1093.

19. Cicero A, Ertek S. Berberine: Metabolic and cardiovascular effects in preclinical and clinical trials. Journal of Nutraceuticals Diet Supplement. 2009; 1: 1-10.

20. Chang T Y, Li B L, Chang C C, Urano Y. Acyl-coenzyme A: Cholesterol acyltransferases. Journal of Physiology- endocrinology and metabolism. 2009; E1-E9.

21. Wang Y, Yi X, Ghanam K, Zhang S, Zhao T, Zhu X. Berberine decreases cholesterol levels in rats through multiple mechanisms, including inhibition of cholesterol absorption. Mrtabolism 2014; 63: 1167-1177.

22. Yin J, Gao Z, Liu, D, Liu Z, Ye J. Berberine improves glucose metabolism through induction of glycolysis. Journal of Physiology- endocrinology and metabolism. 2008; 148-156.

23. Xia X, Yan J, Shen Y, Tang K, Yin J, Zhang Y. Berberine improves glucose metabolism in diabetic rat by ingibition of hepatic gluconeogenesis. 2011.

24. Chen Y, Wang Y, Lin L, Zhang Y, Sun C, Lopez A. Berberine improves glucose homeostasis in streptozotocin- induced diabetic rats in association with multiple factors of insulin resistance. ISRN Endorinol. 2011; 1-8.

25. Dai P, Wang J, Lin L, Zhang Y, Wang Z. Renoprotective effects of berberine as adjuvant therapy for hypertensive patients with Type-II Diabetes mellitus: Evaluation via biochemical markers and color Doppler ultrasonography. Journal of experimental and therapeutic Medicine. 2015; 10: 869-876.

26. Zhao X, Zhang J, Tong N, Chen Y, Luo Y. Protective effects of berberine on Doxorubicin- induced hepatotoxicity in mice. Journal of Biological and Pharmaceutical Bulletin. 2012; 35: 796-800.

27. Domitrovic R, Jakovac H, Blagojevic G. Hepatoprotective activity of berberine mediated by inhibition of TNF-α, COX-2 expression in CCl4-intoxicated mice. Toxicology. 2011; 33-43.

28. Kim S, Chung J H. Berberine prevents UV-induced MMP-I and reduction of type-I procollagen expression in human dermal fibroblasts. Phytomedicine.2008; 15: 749-753.

29. Yahki K, Kiso A, Zhou Y Y. Abstracts: The effects of Coptis japonica root extract and its key component, berberine on human subcutaneous adipocytes. International Journal of Cosmetic Sciences. 2010; 32: 392-395.

30. Derosa G, Maffioli P, Cicero A F. Berberine on Metabolic and Cardiovascular risk factors: An analysis from preclinical evidences to clinical trials. Expert Opinion Biomolecular Theory. 2012; 12: 1113-1124.

31. Fouladi R F. 2012. Aqueous extract of dried fruit of berberis vulgaris L. in acne vulgaris, a clinical trial. Journal of Dietary Supplement. 2012; 9: 253-261.

32. Johnson M, Rafikhah N. Berberis vulgaris juice and acne vulgaris: a placebo-controlled study. Asian Journal of Clinical Nutrition. 2014; 6: 47-52.

33. Gupta DK, Aqil M, Sultana Y. Tailoring of berberine loaded transniosomes for the management of skin cancer in mice. Journal of Drug Delivery Science and Technology. 2020; 60: 1-13.

34. Torky AS, Maha MA, Abdallah AY. Novel skin penetrating berberine oleate complex capitalizing on hydrophobic ion pairing approach. International Journal of Pharmaceutics. 2018; 76-86.

35. Vanti G, Wang M, Billia AR. Hydroxypropyl methylcellulose hydrogel of berberine chlorideloaded escinosomes: Dermal absorption and biocompatibility. International Journal of Biological Macromolecule. 2020; 1-29.

36. Niu J, Yuan M, Chen C, Wang L, Gan Y. Berberine-Loaded Thiolated Pluronic F127 Polymeric Micelles for Improving Skin Permeation and Retention. International Journal of Nanomedicine.2020; 1-19.

37. Lin H, Lim L, Choi Y. Development and in-vitro evaluation of co-loaded berberine chloride and evodiamine ethosomes for treatment of melanoma. International Journal of Pharmaceutics. 2020; 1-7.

38. Vanti G, Bani D, Salvatici CM, Bergonzi MC, Billia AR. Development and Percutaneous Permeation Study of Escinosomes, Escin-Based Nanovesicles Loaded with Berberine Chloride. Pharmaceutics. 2019; 1-22.

39. Gull A, Ahmed S, Ahmed FS, Chandra. Hydrogel thickened microemulsion; a local cargo for the co- delivery of cinnamaldehyde and berberine to treat acne vulgaris. Journal of Drug Delivery Science and Technology. 2020; 58: 1-10

40. Amato G, Grimaudo MA, Lorenzo CA, Carbone C, Musumeci T. Hyaluronan/Poly-L-lysine/Berberine Nanogels for Impaired Wound Healing. Pharmaceutics. 2020; 1-11.

41. Mayangsari F, Surini S, Iswandana R. Development of transfersomal emulgel to enhance the permeation of berberine chloride for transdermal delivery. Journal of Applied Pharmaceutical Science. 2022; 12(02): 48-55.

42. Awate P S, Pimple T P, Pananchery JF, Jain A S. Formulation and evaluation of berberine hcl as niosomal drug delivery system. Asian Journal of Pharmaceutical Research. 2020; 10(3).

43. Rahamat U, Kumar P M, Gella S. Psoriasis: A comprehensive Review. Asian J. of Res.in Pharma. Sciences. 2019; 9(1): 29-38.

44. Mahajan T, Singh N, Goyal K, Jindal S, Pandit V, Ashawat MS. Recent updates on Psoriasis: A Review. Asian Journal of Pharmaceutical research. 2022; 12(1): 3-76.

45. Singh N, Sondhi S, Jindal S, Pandit V, Ashawat MS. Treatment and Management for patients with mild to severe Psoriasis: A Review. Asian Journal of Pharmaceutical Research. 2020; 10(4):286-292.

46. Sondhi S, Singh N, Jindal S. Natural Remedies used in treatment of Psoriasis: A Short review. Asian Journal of Pharmaceutical Research. 2021; 11(1): 43-45.

47. Sharma S, Sharma R, Goyal K, Jindal S. Potential of herbal treatment of Psoriasis: A Laconic Review. Asian Journal of Research in Pharmaceutical Sciences. 2021; 11(1): 51-57.

48. Sondhi S, Singh N, Goyal K, Jindal S. Development of Topical Herbal gel of Berberine Hydrochloride for the treatment of Psoriasis. 2021; 13(1): 12-18.

49. Verma D, Samal P K. Evaluation of Synergistic analgesic Activity of Berberine and Asiatic Acid in Mice. Research Journal of Pharmacy and Technology. 2020; 13(12): 6081-6085.

50. Singh N, Goyal K, Sondhi S, Jindal S. Traditional and medicinal use of Barbaloin: Potential for the Management of Various Disease. 2020; 8(3): 21-30.

51. Singh N, Goyal K, Sondhi S, Jindal S. Development and characterization of Barbaloin Gel for the safe and effective treatment of Psoriasis. Journal of Drug Delivery and Therapeutics. 2020; 10(5): 188-197.

Received on 08.04.2022 Modified on 05.06.2022

Res. J. Pharma. Dosage Forms and Tech.2022; 14(4):304-308.

DOI: 10.52711/0975-4377.2022.00050