Chinese Journal of Natural Chinese Journal of Natural Medicines 2012, 10(5): 0388−0340 Medicines doi: 10.3724/SP.J.1009.2012.00388 Pharmacologically tested aldose reductase inhibitors isolated from plant sources—A concise report D. K. Patel, R. Kumar, K. Sairam, S. Hemalatha* Pharmacognosy Research Laboratory, Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Vara- nasi-221005, India Available online Sep. 2012 [ABSTRACT] Aldose reductase (AR), a cytosolic, monomeric oxidoreductase, is a key enzyme in the polyol pathway which controls the conversion of glucose to sorbitol. The accumulation of sorbitol by the activation of AR enzymes in lens, retina, and sciatic nerves leads to the cause of diabetic defects resulting in various secondary complications, viz. retinopathy, neuropathy, nephropathy and Alz- heimer’s disease. Thus, reduction of the polyol pathway flux by AR inhibitors could be a potential therapeutic opening in the treatment and prevention of diabetic complications. At present, the AR inhibitors belong to two different chemical classes. One is the hydantoin derivatives, such as Sorbinil, Dilantin, and Minalrestat, and the other is the carboxylic acid derivatives, such as Epalrestat, Alrestatin, and Tolrestat. However, it is known that most of these synthethic compounds have unacceptable side-effects. Well known medicinal plants like Chrysanthemum indicum, Chrysanthemum morifolium, Prunus mume, Myrcia multiflora, Centella asiatica, and Salacia reticulata, Salacia oblonga, and Salacia chinensis exhibited potent AR inhibitory activity. The present review summarizes the list of plant material, and their isolated phytoconstituents which have been tested for their AR inhibitory activity. This litreature review covers the period to 2011, and a total of 72 plants are listed. [KEY WORDS] Aldose reductase; Cataracts; Enzyme; Human recombinant AR; Medicinal plants; Phytoconstituents; Polyol pathway; Rat lens AR; Rat lens [CLC Number] R96 [Document code] A [Article ID] 1672-3651(2012)05-0388-13 1 Introduction diabetic complications, including retinopathy, neuropathy, nephropathy and Alzheimer’s disease [1-3]. In normal tissue, Aldose reductase (AR) is a key enzyme in the polyol aldose reductase has low substrate affinity for glucose, how- pathway that controls the conversion of glucose to sorbitol. ever, in diabetes mellitus, the increased availability of glu- AR is found in almost all mammalian cells, but organs such cose in insulin-insensitive tissues such as the lens, nerve, and as the lens, retina, and sciatic nerves, which are affected by retina leads to the increased formation of sorbitol through the diabetic complications were found to contain the maximum polyol pathway [4]. Oxidative stress is also another factor accumulation of AR enzymes. Increased polyol pathway flux involved in the development of diabetes related complica- cause accumulation of sorbitol in the lens fiber, which, in tions and disorders [5]. turn, causes an increased influx of water and the generation Natural components like flavonoids have health beneficial of osmotic stress thereby leading to cataract formation which properties due to inhibition of certain enzymes, such as xan- is regarded as the main cause of blindness worldwide. Due to thine oxidase, aldose reductase, and antioxidant activity [6-7]. the poor penetration across membranes and inefficient me- Several flavonoids, such as quercitrin, guaijaverin and des- tabolism, sorbitol and its metabolites accumulate in the manthin have been tested and proven for its inhibitory activ- nerves, retina, and kidneys resulting in the development of ity against aldose reductase [8]. Flavonoids are commonly ingested from fruits and vegetables in the diet, although they have no nutritive value, they are capable of exerting various [Received on] 17-Sep.-2011 pharmacological activities, including antioxidative, supero- [Research funding] This project was supported by University Grants [9] Commission, New Delhi. xide-scavenging, and aldose reductase inhibitory activity . [*Corresponding author] S. Hemalatha: E-mail: shemalatha.phe@ Several well-known, natural occurring medicines, medicinal itbhu.ac.in, Mobile No. +91 9415256481 food stuffs and plant such as Chrysanthemum indicum, These authors have no any conflict of interest to declare. Chrysanthemum morifolium, Prunus mume, Myrcia multi- 388 Chin J Nat Med Sep. 2012 Vol. 10 No. 5 2012 年 9 月 第 10 卷 第 5 期 D. K. Patel, et al. /Chinese Journal of Natural Medicines 2012, 10(5): 388−400 flora, Centella asiatica, Salacia reticulata, Salacia oblonga, and the generation or enhancement of oxidative stress, were and Salacia chinensis exhibited potent inhibitory activity considered as the main culprit which lead to the various dia- against rat lens aldose reductase [4]. A number of structurally betic-related complications, such as cataracts. Sorbitol is an diverse naturally occurring and synthetic AR and advanced alcohol, polyhydroxylated, and strongly hydrophilic, and glycosylation end product (AGEs) inhibitors have been stud- therefore does not diffuse readily through cell membranes ied in vivo, and were reported to be effective for the preven- and accumulates intracellularly with possible osmotic conse- tion of diabetic complications in experimental animals, as quences particularly leading to osmotic stress and finally [5] well as in clinical trials . Natural antioxidants, which are causes diabetic lesions [13]. The intracellular accumulation of ubiquitous in fruits, tea, vegetables, cereals, and medicinal sorbitol also leads to locally hyperosmotic conditions respon- plants, have their importance for the prevention and treatment sible for the loss of clarity in the lens. The usage of NAD by of various diseases caused by oxidative damage, and for im- sorbitol dehydrogenase leads to an increased ratio of proving the shelf life of food products, and they have re- NADH/NAD+, which has been termed “pseudohypoxia” and ceived great attention [10-11]. Thus, reduction of the hypergly- linked to a multitude of metabolic and signaling changes cemia-induced polyol pathway flux by AR inhibitors could be known to alter cell function [14]. Under hyperglycemic condi- a potential therapeutic opening in the treatment and preven- tion, as much as 30% of the glucose is channeled in to the tion of diabetic complications such as cataract formation. polyol pathway causing a substantial depletion of NADPH This review mainly focuses on the aldose reductase inhibitory and consequently a significant decrease in the glutathione activity of the phytoconstituents isolated from different plant (GSH) level. Thus, during hyperglycemia, AR activity di- source, which were scientifically tested and validated, either [15-16] in vitro or in vivo on animal models. minishes the cellular antioxidant capacity . Oxidation of sorbitol to fructose by sorbitol dehydrogenase (SDH) causes 2 Role of aldose reductase in polyol pathway oxidative stress because its co-factor NAD is converted to leading to various health defects NADH in the process, and NADH is the substrate for NADH oxidase to generate reactive oxygen species (ROS) [17]. Al- The polyol pathway is usually a two-step metabolic though the polyol pathway causes oxidative stress in both the process through which glucose is reduced to sorbitol, which lens and the nerve, its role in the development of diabetic is further converted to fructose (Fig. 1). The polyol pathway lesion in these two tissues seems to be different. Osmotic consists of two enzymes. The first enzyme, aldose reductase stress, from the accumulation of sorbitol, is a more important (AR), reduces glucose to sorbitol with the aid of its co-factor [18] NADPH, and the second enzyme, sorbitol dehydrogenase factor for the development of diabetic cataracts . Thus, it (SDH), with its co-factor NAD+, converts sorbitol to fructose can be seen that the activation of aldose reductase enzyme in [12]. The AR enzyme is also responsible for the reduction of the polyol pathway can lead to the alteration of various glucose to sorbitol, and causes the reduction of various alde- metabolic factors, particularly the generation of reactive hydes. This pathway is interestingly one of the most active oxygen species which cause oxidative stress and which can parameters through which the mechanism of diabetic reti- be regarded as the initial and the main factor that aggravated nopathy and cataractogenesis can be explained. The forma- diabetic induced cataract complications. Thus the treatment tion of sorbitol from glucose, the accumulation of fructose, with AR inhibitors (ARI) was shown to be effective in pre- Fig. 1 The polyol pathway 2012 年 9 月 第 10 卷 第 5 期 Chin J Nat Med Sep. 2012 Vol. 10 No. 5 389 D. K. Patel, et al. /Chinese Journal of Natural Medicines 2012, 10(5): 388−400 venting the development of various diabetic complications, 3.5 Belamcanda chinensis (Iridaceae) including cataract formation, neuropathy, and nephropathy [19]. Twelve phenolic compounds, including tectorigenin, iri- genin and their glucosides, were isolated from the rhizomes 3 Pharmacologically-tested aldose reductase of Belamcanda chinensis (L.) Redouté. All of the compounds inhibitors, isolated from plant sources were found to have significant inhibitory activity against the AR enzyme. Moreover, tectoridin and tectorigenin were ex- Significant research efforts have been going on all over hibited the highest inhibitory potency with IC s of 1.08 and the world on the investigation of naturally-occurring bio-