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Diabetic Complications: a Natural Product Perspective

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Diabetic Complications: a Natural Product Perspective Send Orders for Reprints to [email protected] Pharmaceutical Crops, 2014, 5, (Suppl 1: M4) 39-60 39 Open Access Diabetic Complications: A Natural Product Perspective S. N. C. Sridhar, Sushma Kumari and Atish T. Paul* Laboratory of Natural Drugs, Department of Pharmacy, Birla Institute of Technology and Science (BITS Pilani), Pilani campus, Pilani-333031 (Rajasthan), India Abstract: Diabetes is a chronic disease that affects over 400 million people globally. With 5.5% increase in diabetes re- lated deaths in 2010, as compared to the 2007 and World Health Organisation's projection of diabetes as the 7th leading cause of death by 2030, has dazed the current drug discovery fraternity. The major focus of drug discovery has been to- wards the control of hyperglycemia while the severe complications arising due to it have been overlooked. Plant based natural products (pure phytochemicals or in the form of crude extracts) have been the mainstay of drug discovery program for treatment of numerous human diseases. In addition, indigenous systems of medicines like Ayurveda and Traditional Chinese Medicine (TCM) possess a rich plethora of knowledge about clinically used medicinal plants for controlling the diabetic complications. With India becoming the capital of diabetes and its associated complications, the present natural products perspective is more evident and highlights the current natural products based research that has been done for the last five years in tackling diabetic complications. Keywords: Cardiovascular disease, diabetes, diabetic complications, natural products, nephropathy, neuropathy, retinopathy. INTRODUCTION in the form of pure phytochemicals (e.g. taxol, artemisinin etc.) or crude extracts (single or combinations) for the treat- Diabetes is defined as “a chronic disease that occurs ei- ment of various diseases. Also there has been an increasing ther when the pancreas does not produce enough insulin or importance in the utilization of plant based natural products, when the body cannot effectively use the insulin it produces” commercially due to their lower side effects as compared to [1]. Hyperglycaemia, or raised blood sugar, is a common the synthetic drugs. The contribution of plant based thera- effect of uncontrolled diabetes and with time, this leads to peutics for treatment of diabetes has been very valuable and serious damage to many of the body systems, especially the the vast plethora of research articles being published makes nerves and blood vessels. Globally, 382 million people were it more evident. With India becoming the diabetic capital of detected with diabetes in 2013, and the number is expected the world and with still a lot of uncertainty over the other to project to 592 million by 2035. The severity of diabetes is subclass of diabetes like Type 1.5 (Latent Autoimmune Dia- more in low and middle income countries with 80% of the betes in Adults, LADA), it became imperative to discover population contributing to the global statistics [2]. Close to and develop newer, safer and effective antidiabetic therapeu- four million deaths in the age group of 20-79 were recorded tics which will not only control diabetes but also its associ- due to diabetes in 2010, accounting for 6.8% of global all- ated complications. The present review discusses about the cause mortality in this age group. There has been a 5.5% various natural products that have been investigated for their increase in diabetic deaths in 2010, as compared to the 2007 potential to prevent or ameliorate various diabetic complica- statistics [3]. Another problem associated with diabetes is tions during the last five years. This review is an attempt to that the increase in blood glucose level may lead to severe channelize the available research data to add value to natural complications that affect various systems of the body. These products in the area of diabetic complications. complications are divided into two types. Microvascular complications include eye disease or “retinopathy”, kidney disease termed “nephropathy”, and neural damage or “neu- DIABETIC EYE DISEASES ropathy”. The major macrovascular complication includes Diabetic eye diseases include cataract (where the eye lens accelerated cardiovascular disease resulting in myocardial is clouded), glaucoma (where the fluid pressure inside the infarction and cerebrovascular disease manifesting as strokes eye increases leading to optic nerve damage) and diabetic [4]. Diabetic retinopathy and cardiovascular disease are one retinopathy (where the blood vessels of the retina are dam- among the leading causes of blindness and deaths, respec- aged) [5]. Diabetic retinopathy is the most common disease tively. among all the diabetic complications and is characterized by Medicinal plants have been an integral part of human a spectrum of lesions within the retina. The first stage (Mild healthcare systems for centuries. They have been used either Nonproliferative Retinopathy) starts with the occurrence of microaneurysms, small outpouchings from retinal capillaries, and dot intraretinal haemorrhages. As the disease progresses *Address correspondence to this author at the 3121D, Department of Phar- to the second stage (Moderate Nonproliferative Retinopa- macy, Birla Institute of Technology and Science (BITS Pilani), Pilani cam- pus, Pilani-333031 (Rajasthan), India; Tel: +91 1596 515814; thy), there is an increase in the number and size of intrareti- Fax: +91 1596 244183; E-mail: [email protected] nal haemorrhages. This increase may be accompanied by 2210-2906/14 2014 Bentham Open 40 Pharmaceutical Crops, 2014, Volume 5 Sridhar et al. cotton-wool spots which indicate regional failure of the reti- Protein kinase C (PKC)- activation, Connexion 43 degrada- nal microvascular circulation resulting in ischemia. Further tion and enhanced Gap junction intercellular communication progression of the disease leads to Severe Proliferative Dia- [9]. In another study it was found by Srivastava et al. that betic Retinopathy where the retina sends signals to the brain resveratrol regulated Forkhead box O (FOXO) transcription for the development of new blood vessels. This leads to the factors at concentrations ranging from 10-20 M determined final stage (Proliferative Retinopathy) which involves the through luciferase assay and suggested to be useful in treat- formation of new blood vessels that develop from the retinal ment of diabetic retinopathy [10]. circulation [5, 6]. These new vessels can extend into the vit- Ginsenoside Rb2 (4): It is a steroidal constituent isolated reous cavity of the eye and can lead to haemorrhages into the from genus Panax (Araliaceae). Park et al. found that Ginse- vitreous, resulting in vision loss. Another important change noside Rb2 exhibited its protective effect against diabetic that can occur is the diabetic macular oedema, which in- retinopathy by prevention of high glucose-induced apoptosis volves the breakdown of the blood–retinal barrier, with leak- through decreasing Bcl-2 expression, lipid peroxide (LPO) age of plasma from small blood vessels in the macula, the and COX-2 expression, and increasing Bax expression in central portion of the retina that is responsible for the major ARPE-19 cells at a concentration of 1 g/mL [11]. part of visual function. This causes swelling of the retina [6]. It is the leading cause of blindness among adults aged 20–74 3,5-Di-O-caffeoyl-epi-quinic Acid (5): It is isolated from years. the leaves and stems of Erigeron annuus L. Pers. (Composi- tae). It was found by Jang et al. to inhibit the formation of Hence prevention of diabetic eye diseases by targeting AGEs and rat lens aldose reductase (RLAR) with IC values different pathways and enzymes via strategies like inhibiting 50 of 6.06 μM and 0.44 μM respectively, along with AGEs- the production of Advanced Glycation End products (AGEs), bovine serum albumin cross-linking to collagen and pre- down regulation of inflammatory mediators, Interleukins vented opacification of rat lenses [12]. (ILs), Cyclooxygenase-2 (COX-2), Vascular Endothelial Growth Factor (VEGF), prevention of oxidative stress Puerariafuran (6): It is a 2-arylbenzofuran isolated from through anti-oxidant activity, and inhibition of certain en- the roots of Pueraria lobata Ohwi. (Fabaceae). Kim et al. zymes like Aldose reductase (AR) are needed. Various pure found that Puerariafuran potently inhibited RLAR with an natural products and plant extracts have been reported to IC50 value of 22.34 μM. The xylose induced opacity of prevent or delay the progression of diabetic eye diseases and lenses was significantly improved, and there was a signifi- are summarized below. cant increase in the reduced glutathione (GSH)/oxidized glu- tathione (GSSG) ratio, superoxide dismutase (SOD) and Pure Compounds catalase (CAT) activity in rat lenses on treatment with puer- Various pure phytochemicals have been tested in differ- ariafuran (3 -15 μM) [13]. ent cell cultures, in vitro and in vivo studies for their poten- Scopoletin (7) and Tiliroside (8): Scopoletin is a cou- tial in treatment of diabetic retinopathy (See Fig. 1) and are marin, while Tiliroside is a phenolic compound. Both the described below. compounds were isolated from the flower buds of Magnolia Epigallocatechin-3-gallate (EGCG) (1): EGCG is one of fargesii Cheng. (Magnoliaceae) and investigated for their the major polyphenols isolated from Camellia sinensis (L.) RLAR and AGEs inhibitory activity by Lee et al. Scopoletin Kuntze. (Theaceae). It was found by Ye et al. to exhibit pro- inhibited AGEs formation with IC50 value of 2.93 μM and tective effect against high glucose-induced apoptosis in Hu- showed a significant RLAR inhibition with IC50 value of man lens epithelial B-3 cells by decreasing the expression of 22.5 μM. Scopoletin significantly inhibited cataractogenesis Bcl-2/Bax (B-cell lymphoma 2/Bcl-2 associated X), c-fos (A of rat lenses induced with xylose in ex vivo experiments in murine fos proto-oncogene), c-myc (A cellular homolog dose dependent manner. Tiliroside exhibited potent inhibi- gene of the v-myc oncogene) and p53 (A tumour suppressor tory activity against RLAR with an IC50 of 14.9 μM [14].
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