Thuốc thảo dược Trung Quốc để điều trị bệnh võng mạc tiểu đường

Thuốc thảo dược Trung Quốc để điều trị bệnh võng mạc tiểu đường Tapan Behl và Anita Kotwani Khoa Dược học, Viện ngực Vallabhbhai Patel, Đại học Delhi, Delhi, Ấn ĐộKeywordsAstragalus Membranaceus; Ginkgo biloba; Lycium barbarum; Panax notoginseng; SalviamiltiorrhizaCorrespondenceTapan Behl, Thành viên nghiên cứu cấp cao, Khoa Dược, Viện ngực VallabhbhaiPatel, Đại học Delhi, Delhi-110007, Ấn Độ.E-mail: tapanbehl31@gmail.comNhận ngày 16 tháng 6 năm 2016 Chấp nhận ngày 26 tháng 11 năm 2016doi: 10.1111 / jphp.12683Abstract các hoạt động dược lý khác nhau và các cơ cấu phân tử đằng sau chúng mà các loại thảo mộc Trung Quốc có xu hướng làm giảm nguy cơ mắc các biến chứng tiểu đường do vi mạch máu phát triển ở võng mạc và ngăn chặn sự phát triển thêm của nó. , chống tạo mạch, chống apoptotic, chất gây tăng sinh peroxisome-kích hoạt thụ thể gamma, đối kháng yếu tố kích hoạt tiểu cầu, ức chế aldosereductase và nhiều hoạt động dược lý có lợi khác, cần thiết để chống lại các tình trạng bệnh lý phổ biến ở võng mạc trong quá trình dia-betes. có thể được sử dụng để điều trị / phòng ngừa bệnh Bệnh võng mạc etic do có nhiều đặc tính giúp làm giảm một số trường hợp bệnh lý do tăng đường huyết gây ra ở võng mạc. Điều này sẽ cung cấp một liệu pháp tự nhiên và an toàn cho bệnh võng mạc do tiểu đường, bệnh mà lâm sàng hạn chế đối với các kỹ thuật phá hủy như quang đông bằng laser và cắt dịch kính

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/312961775 Chinese herbal drugs for the treatment of diabetic retinopathy Article  in  Journal of Pharmacy and Pharmacology · January 2017 DOI: 10.1111/jphp.12683 CITATIONS READS 18 126 authors, including: Tapan Behl Chitkara University 90 PUBLICATIONS   359 CITATIONS    SEE PROFILE Some of the authors of this publication are also working on these related projects: book chapter View project Oncology and Public Health View project All content following this page was uploaded by Tapan Behl on 17 June 2020 The user has requested enhancement of the downloaded file Review Chinese herbal drugs for the treatment of diabetic retinopathy Tapan Behl and Anita Kotwani Department of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India Keywords Astragalus membranaceus; Ginkgo biloba; Lycium barbarum; Panax notoginseng; Salvia miltiorrhiza Correspondence Tapan Behl, Senior Research Fellow, Department of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi-110007, India E-mail: tapanbehl31@gmail.com Received June 16, 2016 Accepted November 26, 2016 doi: 10.1111/jphp.12683 Abstract Objectives To explore the various pharmacological actions and the molecular mechanisms behind them by which Chinese herbs tend to lower the risk of developing microvascular diabetic complications in retina and prevent its further progression Key findings Several Chinese herbs, indeed, elicit potent anti-inflammatory, antioxidant, anti-angiogenic, anti-apoptotic, peroxisome proliferator-activated receptor-gamma receptor agonistic, platelet-activating factor antagonistic, aldose reductase inhibitory and various other beneficial pharmacological activities, required to counteract the pathological conditions prevalent in retina during diabetes Summary Chinese herbs can potentially be used for the treatment/prevention of diabetic retinopathy owing to the virtue of numerous properties by which they alleviate several hyperglycaemia-induced pathological occurrences in retina This would provide a natural and safe therapy for diabetic retinopathy, which currently is clinically limited to destructive techniques like laser photocoagulation and vitrectomy Introduction Diabetic retinopathy is a neuromicrovascular complication associated with diabetes mellitus, characterized by damage and dysfunction of the retinal blood vessels and neurons caused by hyperglycaemia-induced several pathological events It is among the common causes of disease-induced blindness in the world According to a recent epidemiological study, one-third of the total diabetic population of the world is present with variant stages of diabetic retinopathy The countries with the top most prevalence of this diabetic complication include the United States, the United Kingdom and other European countries, Saudi Arabia and Singapore Besides, its incidence in developing countries, like India and China, is on a rise The duration of diabetes directly correlates with the increased risk of the developing this complication, with patients of type diabetes being more susceptible than type diabetic patients.[1] The present clinical treatments of diabetic retinopathy are limited to laser photocoagulation and vitrectomy.[2,3] Although in the last two decades, researchers have targeted a number of preventive agents such as anti-vascular endothelial growth factor (VEGF) agents, anti-TNF-alpha agents, peroxisome proliferator-activated receptor (PPAR)-gamma receptor agonists, all these agents are still on preclinical or clinical testing stages One of the successful agents clinically established now are the anti-VEGF agents which primarily act by restricting/inhibiting angiogenesis The most commonly used anti-VEGF agent is bevacizumab Due to the limitation of its mechanism of action, however, it can only be used for the treatment/prevention of proliferative diabetic retinopathy and not for non-proliferative diabetic retinopathy Also, since all these agents are also of chemical origin, there is a need to develop medicines of natural origin which could elicit all the pharmacological actions (such as antioxidant, anti-inflammatory and anti-angiogenic) demonstrated by these chemical agents Chinese herbs offer one such beneficial exploitable option These herbs have been used since centuries for the treatment and prevention of various disorders This review mentions a detailed account of some of the Chinese herbs which have been demonstrated to elicit the requisite properties during various research studies for the prevention/ treatment of diabetic retinopathy The potential of these © 2017 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2017), pp **–** Chinese herbs in diabetic retinopathy Tapan Behl and Anita Kotwani Chinese herbs may be utilized to overcome the limitations of the present as well as newly developing therapies for diabetic retinopathy Correct utilization of these herbs may prove to be a turning point for decreasing the incidence and progression of this sight-threatening complication among diabetic patients Various pathological events involved in diabetic retinopathy Although extensive research has been conducted in the last two decades to explore the molecular pathways involved in the pathogenesis of diabetic retinopathy and several hypothetical mechanisms are proposed which indeed explain its aetiology to a great extent, no single pathway among them can be pinpointed as the sole reason behind the evolvement of this complication The pathophysiology of diabetic retinopathy is a complex interplay between several interconnected hyperglycaemia-induced pathological occurrences which damage retinal endothelial and neuronal cells, causing anatomical destruction as well as physiological impairment of retina leading to vision loss These events are discussed as follows: Oxidative stress An imbalance in the normal physiological concentrations of the free radicals produced and antioxidant species present in the body which ultimately leads to overexpression of the former is called oxidative stress The prime sources of hyperglycaemia-induced oxidative stress are the upregulated glucose-metabolizing pathways – glycolysis and citric acid cycle, leading to the overproduction of NADH and FADH2 Overflux of NADH through the mitochondrial electron transport chain is the source of oxidative stress, which is based on establishments that more NADH recycling by mitochondrial complex I leads to more electron leakage and thus more partial reduction of oxygen and superoxide production.[4,5] Since the initial substrate (glucose) of these metabolic cycles is present in excess amount during diabetes, the resulting products (superoxide radicals) of the above-described pathway are also produced in a higher amount than their normal physiological concentration and hence lead to oxidative stress This process is termed as hyperglycaemia-induced mitochondrial dysfunction Also, increased NADH production takes place from another glucose-metabolizing pathway, polyol pathway, which gets activated during hyperglycaemia due to saturation of hexokinase (the enzyme responsible for catalysing the first step of glycolysis) In polyol pathway, glucose gets converted into sorbitol by the action of enzyme aldose reductase in the first step Second step of this reaction involves the conversion of sorbitol to fructose, which is also accompanied by the production of NADH NADH produced during this reaction again participates in the ATP production producing more superoxide radicals Besides, some proportion of sorbitol produced in the first step does not undergo the second step of the reaction, and since cellular membranes are impermeable to sorbitol, it starts accumulating in the cells This causes osmotic imbalance in the cell, which starts drawing water towards itself This generates osmotic stress in the cell ultimately leading to cell death Besides, NADH overproduction also inhibits the enzyme glyceraldehyde 3-phosphate dehydrogenase, leading to accumulation of triose phosphate Both triose phosphate and fructose (end product of polyol pathway) lead to the formation of methylglyoxal and diacylglycerol (DAG), which react with various amino acids and proteins to produce advanced glycation end products (AGEs) These AGEs interact with their receptors (RAGE) to upregulate oxidative stress and inflammatory responses The DAG produced during this process also activates PKC which leads to the production of reactive oxygen species via upregulating the expression of NADPH oxidases.[6,7] Reactive oxygen species also induce activation of retinal microglia which further downregulate the expressions of various antioxidant enzymes, thus upregulating oxidative stress.[8] Also PKC overactivation increases the transcription of endothelial nitric oxide synthase (eNOS), leading to overproduction of nitric oxide which reacts with superoxide radical to produce peroxynitrite, a highly reactive oxygen species, which further upregulates oxidative stress Since retina is a highly lipoidal and an oxygen demanding tissue, it is greatly affected by the overproduction of reactive oxygen species The retinal photoreceptors biochemically comprise of longchain unsaturated fatty acids which are easily prone to undergo lipid peroxidation upon getting exposed to free radicals Besides, oxidative stress-induced DNA damage leads to apoptosis of the neuronal layer of retina which comprises of the Muller glial cells adjoining the posterior chamber of eye.[6,7] These structural damages induce inflammatory responses which further aggravate the conditions during hyperglycaemia Angiogenesis The de-novo formation of blood vessels on the pre-existing vasculature is termed as angiogenesis It is usually maintained to a physiological level by a balance between pro-angiogenic and anti-angiogenic factors.[9] However, hyperglycaemia increases the expression of several proangiogenic agents, such as VEGF, in retina leading to upregulation of retinal neovascularization VEGF is a highly potent pro-angiogenic agent which induces retinal angiogenesis mainly by upregulating the circulation of endothelial progenitor cells (via nitric oxide–cGMP pathway) and © 2017 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2017), pp **–** Tapan Behl and Anita Kotwani induction of matrix metalloproteinases (MMPs), thus stimulating endothelial cellular proliferation, migration and tube formation.[9] MMPs are extracellular matrix-degrading enzymes which cause degeneration of collagen, elastins, gelatin and other proteins and also destroy the integrity of blood–retinal barrier (BRB), leading to its breakdown.[9] Matrix degradation acts as a trigger for angiogenesis as well as inflammation Several mechanisms have been proposed to explain the hyperglycaemia-induced activation of VEGF which include overactivation of PKC, upregulated RAGE expression and induction of hypoxia-inducible factor-1alpha (HIF-1a).[9] Besides, hyperglycaemia overactivates renin–angiotensin–aldosterone system by various pathways (such as overactivated PKA-induced[10] and succinateinduced renin release,[11] and overexpression of pro-renin receptor[12]) and leads to upregulation of angiotensin II (Ang-II), which is highly pro-angiogenic and pro-inflammatory Ang-II increases both transcriptional and translational expressions of VEGF (via inducing nuclear factorkappa B (NF-jB) signalling)[13] and also causes loss of retinal pericytes, which induces vascular remodelling.[14] Also, Ang-II has been speculated to increase the production of certain reactive oxygen species which activate Src kinase, subsequently leading to phosphorylation of Akt (protein kinase B) The activated Akt critically promotes cellular proliferation and migration.[15] Hyperglycaemia also induces the expression of plasminogen activator inhibitor-1 (PAI-1) by increasing the glycosylation of Sp1 transcription factor and is mediated by increased flux of glycolysis and mitochondrial superoxide production.[16] PAI-1 induces retinal angiogenesis by promoting the migration of endothelial cells.[17] Under the prevailing hyperglycaemiainduced pathological conditions, the forcefully induced angiogenesis and remodelling lead to the formation of unstable and disfigured vessels The extremely unfavourable conditions (hypoxia, high oxidative stress, osmotic pressure and inflammation) prevalent in retina during diabetes further damage these newly formed immature blood vessels even before they could attain enough strength to become stable As a result, these abnormally grown fragile blood vessels rupture, causing retinal haemorrhage The damaged vessels leak out their contents into the vitreous chamber, causing retinal oedema and further increasing the osmotic pressure on the posterior wall All these events trigger several inflammatory responses which further aggravate the retinal damage.[18,19] Inflammation All the above-mentioned oxidative stress-induced and angiogenesis-induced pathological changes in the retina act as stimuli for the initiation of a robust inflammatory response As already discussed above, Ang-II induces the Chinese herbs in diabetic retinopathy downstream signalling pathways of NF-jB This leads to an upregulation in the transcription of numerous pro-inflammatory mediators, primarily cytokines, such as tumour necrosis factor-alpha (TNF-a) and interleukins (ILs).[20] Besides, the oxidative stress-induced activation of retinal microglia also acts as a source of cytokine production.[8] Among the various inflammatory responses of TNF-a, induction of cellular adhesion molecules, namely intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemotactic protein1 (MCP-1), forms the most critical event as it marks the initiation of endothelial dysfunction by inducing recruitment of leucocytes, causing retinal leukostasis Following leucocyte–endothelial interaction, leucocytes adhere to the endothelium and extravasate across it causing endothelial damage and destruction of BRB This further increases the retinal oedema and osmotic pressure Among interleukins, interleukin-1-beta (IL-1b) plays the most deleterious role in aggravating retinal inflammation It induces the expression of inducible nitric oxide synthase (iNOS) and leads to overproduction of nitric oxide which upregulates oxidative stress (due to the generation of peroxynitrite).[21] TNF-a and IL-1b also produce excitotoxicity-induced retinal neuronal apoptosis by upregulating the production and secretion of glutamate, an excitatory neurotransmitter from the activated retinal microglia by increasing the expression of glutaminase 1, an enzyme responsible for the conversion of glutamine to glutamate.[22] NF-jB also induces the expression of COX-2 which upregulates eicosanoids-mediated pro-inflammatory responses Moreover, VEGF, apart from its angiogenic responses, also produces certain inflammatory responses by inducing the activation of several proinflammatory mediators such as cellular adhesion molecules and COX-2.[9] Ang-II also induces the expression of tissue factor (TF) probably via two pathways which include PKC activation and NF-jB-mediated signalling.[23] The hypercoagulated state maintained by PAI-1 and TF during hyperglycaemia causes hypoxia and ischaemia, and is speculated to play a crucial role in the progression of microvascular diabetic complications including diabetic retinopathy.[24] AGEs also induce TF expression TF mediates inflammation by upregulating IL-1b-mediated responses and vascular dysfunction.[25] The inflammatory response generated by all the above-mentioned mediators causes platelet activation primarily by upregulating the release of platelet-activating factor (PAF) from leucocytes Besides, hyperglycaemia can directly increase platelet reactivity by inducing nonenzymatic protein glycation on platelet surface, via osmotic influence and PKC activation The activated platelets further aggravate inflammation by causing endothelial injury at the site of adhesion.[26] Another characteristic pathological event in the pathophysiology of diabetic retinopathy is the thickening of © 2017 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2017), pp **–** Chinese herbs in diabetic retinopathy Tapan Behl and Anita Kotwani capillary basement membrane which is hypothesized to be caused by several hyperglycaemia-induced alterations such as activation of PKC, induction of various growth factors, inflammation, upregulated endothelin-1 expression, increased flux of polyol pathway and overproduction of AGEs All these alterations ultimately contribute to increased synthesis and accumulation of various components of basement membrane (such as fibronectin, laminin, nidogen/entactin, types I, III, IV and V collagen, and heparan sulfate proteoglycans, chondroitin sulfate proteoglycan) or their reduced degradation, thereby leading to its thickening These changes induce variations in the cell–matrix interactions and stimulate basement membrane remodelling, thus triggering angiogenesis Also the vascular permeability gets altered, causing macular oedema and further aggravating the already existing pathological conditions.[27] Hence, the above-mentioned events critically mediate the progression of diabetic retinopathy and induce increased osmotic pressure, cellular apoptosis and inflammatory responses, thus ultimately leading to the last stage of this complication – the retinal detachment, which is responsible for vision loss Chinese herbs as potential antidiabetic retinopathy therapy Panax notoginseng Panax notoginseng (Family Araliaceae), commonly known by the name San Qi in Chinese traditional medicine, has already been reported to possess antidiabetic activities But very little is known about its antidiabetic retinopathy potential According to the studies concerning its antidiabetic activity, several saponins extracted from the roots of this plant were found to lower fasting blood glucose levels, improve glucose tolerance and produce antihyperlipidemic effects The major saponins eliciting these effects were identified as ginsenoside Re 14, ginsenoside Rd, ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside R1.[28] Recently, it has been found that these saponins also possess antioxidant and anti-inflammatory actions Since both free radical damage and inflammation are critically involved in the pathophysiology of diabetic retinopathy, these beneficial effects of P notoginseng saponins can be utilized in the treatment of this diabetic complication.[29] The antioxidant activity of P notoginseng saponins is attributed to their ability to scavenge hydroxyl and superoxide radicals[30] (thus preventing the free radical-induced apoptosis of retinal pigment epithelium), while its anti-inflammatory property is due to saponininduced downregulation in the mRNA expression of several pro-inflammatory mediators, primarily monocyte chemoattractant protein-1 (MCP-1) and NF-jB.[31] Since MCP-1 is one of the prime cellular adhesion molecules involved in inducing leukostasis and subsequent inflammatory responses (leucocyte transmigration across the endothelium and their migration into the interstitial tissues towards the chemotactic stimulus), its transcriptional inhibition attenuates the retinal leukostasis, an event responsible for increased retinal vascular permeability and subsequent breakdown of BRB Besides, inhibiting the transcription of NF-jB demolishes its downregulatory responses which primarily include induction of transcription of cellular adhesion molecules and other pro-inflammatory mediators such as cytokines, mainly TNF-a and ILs.[21] Apart from antioxidant and anti-inflammatory responses, ginsenoside Rb1 (extracted from the roots of P notoginseng) also elicits anti-angiogenic effects by inhibiting the release of VEGF from the retinal pigment epithelial cells Since VEGF is one of the most potent pro-angiogenic agents involved in inducing proliferation, migration and tube formation of endothelial cells, the inhibition of its release attenuates retinal neovascularization in proliferative diabetic retinopathy.[32] Additionally, treatment of human retina microvascular endothelial cells with another P notoginseng saponin, ginsenoside Rk1, showed significant inhibition in VEGF-induced and AGEinduced retinal endothelial permeability, thereby reducing retinal oedema.[33] Besides inhibiting the pathogenic agents causing increased permeability, ginsenoside Rk1 also produces these antipermeability effects by inducing phosphorylation of myosin light chain and cortactin (critical cytoskeleton restructuring elements), thereby stabilizing the tight junction proteins at the boundary of endothelial barrier.[33] The above discussion clearly indicates that P notoginseng saponins may potentially attenuate various pathological events associated with diabetic retinopathy Salvia miltiorrhiza Salvia miltiorrhiza (Family Lamiaceae), commonly referred to as Chinese sage or red sage root, is a traditional Chinese herb whose dried roots (Danshen) have been used since decades for treating several cardiac, vascular and hematopoietic disorders Intense study on its diverse pharmacological actions has been done and, probably, due to its well-established mechanisms of action and efficiency, its commercial preparation (Danshen dripping pills) has been accepted as a therapy for several blood circulation disorders such as angina, myocardial infarction, ischaemic heart disease, stroke and thrombosis.[34,35] Danshen possesses remarkable antioxidant properties owing to its ability to upregulate endogenous antioxidant enzymes, namely catalase, superoxide dismutase (SOD), eNOS and glutathione © 2017 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2017), pp **–** Tapan Behl and Anita Kotwani peroxidase, and may also directly induce superoxide, hydroxyl, hydrogen peroxide and 1,1-diphenyl-2-picrylhydrazyl free radical scavenging Besides, Danshen also inhibits the production of superoxide anion in microglia By the virtue of these antioxidant activities, Danshen elicits neuroprotective effects.[36] Since oxidative stress-induced retinal neurodegeneration is one of the critical pathological events involved in the pathogenesis of diabetic retinopathy, Danshen may be utilized for preventing retinal neuronal apoptosis.[36] Interestingly, antioxidant properties of another chemical constituent of S miltiorrhiza, salvianolic acid A, have been demonstrated to inhibit Ang-II-induced endothelial cell proliferation.[15] The molecular mechanism behind the same has been described as the inhibition of Ang-II-induced NADPH oxidase-4 (Nox4), which is mainly responsible for producing reactive oxygen species which then further activate a signalling cascade leading to phosphorylation of Src and subsequently Akt Phosphorylated Akt promotes cellular proliferation and migration Besides inhibiting activation of Nox4, salvianolic acid A has been shown to inhibit phosphorylation of Src and Akt directly, thereby preventing endothelial cell proliferation and angiogenesis during proliferative diabetic retinopathy.[15] In fact, Danshen has also been shown to elicit beneficial effects in clinical trials Two separate clinical studies – one conducted as a randomized, double-blind, placebo-controlled multicentre clinical trial and the other as a randomized, double-dummy, double-blind study, established the therapeutic effects and safety of Danshen in patients of diabetic retinopathy and concluded that it can effectively be used for the treatment of this diabetic complication in humans.[37,38] Rosmarinic acid, another phytoconstituent of S miltiorrhiza, inhibits retinal neovascularization by causing cell cycle arrest at G2 and M phase.[39] A recent study done to explore the antidiabetic retinopathy potential of S miltiorrhiza described the effectiveness of this plant extract to remove haemostasis in retina, caused during diabetic retinopathy due to the thickening of capillary basement membrane which alters the membrane permeability and thus reduces the removal of free radicals formed by the dense mitochondrial population of the highly aerobic retinal tissue The inability to remove these free radicals leads to their accumulation in retina and initiate free radical reactions and lipid peroxidation By reducing blood viscosity and improving microcirculation (probably by the virtue of its anticoagulative properties and promoting blood supply towards retinal artery), S miltiorrhiza removes blood stasis and permits the exit of free radicals, thereby preventing structural damage to retina Also, the study revealed lipid lowering, anti-inflammatory and antioxidant properties of this plant as indicated by decreased levels of lipid peroxide and upregulated activity of SOD.[40] Hence, Chinese herbs in diabetic retinopathy S miltiorrhiza might act as a potential candidate for natural therapy of diabetic retinopathy (Figure 1) Lycium barbarum Lycium barbarum (Family Solanaceae), commonly known as Goji berry or Wolfberry, is a popular Chinese traditional plant known to possess several medicinal properties, namely antitumour, antioxidant, anti-inflammatory, immunoregulatory, anti-ageing, hepatoprotective, antiglaucoma and neuroprotective The main phytoconstituents responsible for these actions have been identified as polysaccharides, zeaxanthin, carotene, betaine, cerebroside, beta-sitosterol, p-coumaric and various vitamins.[41,42] However, recent studies have reported L barbarum-mediated clinical antidiabetic potential[43] and protective actions against diabetic complications such as antinephritic[41] and antiretinopathic effects in animal models.[44] Mainly, the numerous anti-apoptotic effects elicited by L barbarum are speculated to be responsible for its antidiabetic retinopathy potential First, L barbarum polysaccharides prevent oxidative stress-induced retinal endothelial cell apoptosis by upregulating the expression of anti-apoptotic gene Bcl-2 while relatively downregulating the expression of pro-apoptotic gene Bax, as indicated by the measurement of the mRNA expression of these genes by reverse-transcription polymerase chain reaction in cultured human retinal pigment epithelial cell line, ARPE-19, exposed to hydrogen peroxide This increases the ratio of Bcl-2/Bax which is essential for the cell survival.[45] Second, taurine (2-aminoethanesulfonic acid), a non-essential free amino acid found in L barbarum, attenuates hyperglycaemia-induced retinal pigment epithelial cell apoptosis by dual mechanisms viz., inhibition of caspase-3 (a proteolytic enzyme which cleaves essential cellular proteins causing cell apoptosis) activity and activation of PPAR-c receptor[46] which elicits anti-inflammatory, anti-angiogenic and anti-apoptotic effects against oxidative stress-induced retinal pigment epithelium apoptosis.[47] Besides protecting epithelial cells from apoptosis, taurine also possesses potent neuroprotective activities Several molecular mechanisms have been reported to explain the above-stated effect First, it inhibits the activation of cytochrome c/caspase3-mediated apoptotic pathway by blocking Ca2+-dependent mitochondrial permeability transition pore and preventing mitochondrial dysfunction and subsequent oxidative stress.[48] Second, it increases and decreases the transcriptional expressions of Bcl-2 and Bax, respectively.[49] Third, it prevents glutamate-mediated excitotoxicity-induced retinal neuronal apoptosis by upregulating the expressions of glutamate transporter (leading to rapid removal of glutamate from the extracellular space) and glutamate decarboxylase (catalysing the conversion of glutamate to GABA, © 2017 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2017), pp **–** Chinese herbs in diabetic retinopathy Scavenging action against reactive oxygen species (ROS) Inhibits platelet aggregation and promotes fibrinolysis Tapan Behl and Anita Kotwani Enhances the activity of endogenous oxidative enzymes Danshen dripping pills Promotes blood flow and prevents stasis Enhances the expression of endothelial nitric oxide synthase (eNOS) Contains tanshinones which inhibit the activation of interleukin 12 and NF-kappa B which are involved in the progression of inflammatory responses Figure Possible mechanisms which could be responsible for the preventing action of Danshen dripping pills against diabetic retinopathy gamma-aminobutyric acid, which is an inhibitory neurotransmitter) Also, taurine directly downregulates VEGF mRNA expression and prevents retinal angiogenesis.[50] Since retinal pigment epithelium and neuronal cells form an integral part of the BRB, prevention of their apoptosis helps in maintaining the integrity of this barrier and prevents subsequent inflammation, angiogenesis, retinal tissue damage and vision loss Thus, by keeping a check on apoptosis of these cells, L barbarum may potentially inhibit the progression of diabetic retinopathy Astragalus membranaceus Astragalus membranaceus (Family Fabaceae), commonly addressed as Huang Qi in traditional Chinese medicine, is a herb whose roots have been utilized since decades for their antitumour, immunomodulatory,[51] diuretic, antioxidant, anti-inflammatory, antithrombotic[52] and antidiabetic properties.[53] The major phytoconstituents exhibiting these properties include polysaccharides (astragalans I, II and III), saponins (astragalosides I–VIII and isoastragalosides I and II), flavonoids, isoflavonoids, sterols, amino acids, volatile oils and trace elements.[52,53] A recent study reported multiple protective effects of astragaloside IV in the animal models of diabetic retinopathy which included reduction in retinal ganglion cell apoptosis, decreased phosphorylation of ERK1/2 (thus reducing cellular proliferation and differentiation), inhibition of activation of NFjB and various cytokines (thus eliciting anti-inflammatory effects) and downregulation of the expression of enzyme aldose reductase (the enzyme involved in the polyol pathway).[54] Inhibition of aldose reductase not only prevents the direct downstream pathological events associated with increased flux of polyol pathway such as upregulated production of AGEs, induction of redox imbalance and subsequent oxidative stress due to decreased availability of NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) and osmotically induced cellular apoptosis,[55] but also prevents inflammatory responses in retinal microglia This has been recently reported by a study that aldose reductase plays a crucial role in the activation of retinal microglia which further activate extracellular signalregulated kinase (ERK) and mitogen-activated protein kinase (MAPK) signalling and lead to the production of TNF-a Inhibition of aldose reductase inhibits retinal microglial activation, reduces lipopolysaccharide (LPS)induced cytokine secretion from macrophages and microglia, prevents activation of MMP-9 (a pro-angiogenic agent) and inhibits LPS-induced macrophage and microglial migration Reduction in microglial and macrophages migration greatly reduces the extent of inflammation.[56] Apart from the microglial and NF-jB pathways, a study demonstrated another anti-inflammatory mechanism of A membranaceus extract (AME) This alternative pathway encompasses the direct inhibition of AGE-induced overproduction of pro-inflammatory cytokines, namely IL-1b and TNF-a, in macrophages The molecular mechanism behind this is speculated to be AME-induced downregulation of p38 MAPK signalling pathway, besides simultaneous inhibition of NF-jB-mediated pathway.[57] Astragalin, a flavonoid extracted from A membranaceus, prevents retinal angiogenesis by reducing the hyperglycaemia-induced overexpression of VEGF in retinal Muller cells.[58] Utilizing all these anti-inflammatory, anti-angiogenic and anti-apoptotic properties of Astragalus membranaceus, it may potentially reduce the extent of retinal damage during © 2017 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2017), pp **–** Tapan Behl and Anita Kotwani hyperglycaemia and hence prevent the progression of diabetic retinopathy Anisodus tanguticus Anisodus tanguticus (Family Solanaceae), known by the names Shan Langdang and Zang Qie in China, is a widely used anticholinergic agent Main clinical utilizations of this plant in the traditional Chinese medicine are as a spasmolytic, anti-asthmatic, antishock remedy and as an antidote for organophosphate poisoning Besides, its potential to treat microcirculatory disorders is also well-acknowledged The main chemical constituents found in this plant which illustrate the above-mentioned properties are the tropane alkaloids, namely anisodamine, anisodine, hyoscyamine, scopolamine, tropine, apoatropine, trichlorophenyl butyryloxytropane and a non-tropane alkaloid cuscohygrine.[59] Owing to its microcirculation-improving properties, it was speculated that A tanguticus might be beneficial in microcirculatory dysfunction complications such as diabetic retinopathy Indeed, it was found in alloxan-induced diabetic animal models that anisodamine improved haemodynamics of retina by increasing retinal blood flow and oxygen supply to the retinal tissues This is hypothesized to prevent retinal lipid peroxidation and hence might be beneficial in the prevention of diabetic retinopathy.[60] Anisodamine prevents coagulative dysfunction and maintains the blood flow by downregulating the expression of plasminogen activator inhibitor-1 (PAI-1) and TF via blocking NF-jB-mediated signalling transduction pathway.[61] Since overexpressed PAI-1 and TF mediated hypercoagulated state during diabetes contribute to endothelial dysfunction, inflammation, retinal ischaemia, angiogenic and oxidative stress damage, their inhibition by anisodamine prevents all these pathological events Besides, anisodamine shows significant anti-inflammatory and anti-apoptotic actions in neuronal cells by inhibiting the production of TNF-a at the transcriptional level Also, the production of other cytokines such as interleukin-1beta (IL-1b) and interleukin-8 (IL-8) also reduces upon anisodamine treatment.[62] Although the mentioned study was not conducted on retinal neurons, and anisodamine has not yet been tested for suppressing hyperglycaemiainduced overproduction of cytokines, it is expected to produce similar results Nonetheless, research on its exact effects on retina is still needed to validate the same In addition, a novel hypothesis regarding the protective action of anisodamine in diabetic retinopathy might be probably stated as anisodamine-mediated activation of alpha-7 nicotinic acetylcholine receptor (a7nAChR) It has earlier been demonstrated that anisodamine elicits its antishock properties by activating a7nAChR[63]; however, the involvement of these receptors in various other physiologies cannot be Chinese herbs in diabetic retinopathy neglected One such potential utilization includes the antioxidant effects elicited by a7nAChR agonism in endothelial cells It was reported that activation of a7nAChR results in increased cell viability by reducing the amount of reactive oxygen species and preventing oxidative stress-induced damage and cell apoptosis The molecular mechanism behind this was illustrated as the downregulation of vascular peroxidase-1 (VPO-1) protein (an enzyme which catalyses the conversion of hydrogen peroxide to hypochlorous acid, a strong pro-oxidant which aggravates oxidative stress) by inhibiting JNK1/2 phosphorylation.[64] However, on the contrary to its beneficial effects, some studies conducted in the last few years have shown that a7nAChR activation is also involved in several pathological angiogenic events as well, including the ones involved in retinal neovascularization, by probably increasing the expression of VEGF.[65] Owing to these contradictory pharmacological actions which seemingly alleviate as well as aggravate the pathological conditions during diabetic retinopathy, more studies are required to explore the exact cumulative effect of a7nAChR activation on retina during hyperglycaemia (Figure 2) Scrophularia ningpoensis Scrophularia ningpoensis (Family Scrophulariaceae), commonly known as Ningpo figwort or Chinese figwort, is used since centuries as an ingredient of Chinese herbal tea for its antipyretic, anti-inflammatory, antioxidant, anti-angiogenic, neuroprotective, antidepressant, cardiovascular-protective, antidiabetic, immunostimulating, memory enhancing and antineoplastic properties The main active chemical constituents identified to be responsible for these properties include angoroside C, acetoside, sibirioside A, 6O-caffeoyl sucrose and oligosaccharides of raffinose, stachyose and verbascose.[66,67] Although it was recently reported by a study that harpagoside, a chemical constituent of S ningpoensis, along with other Chinese herbs (P notoginseng, S miltiorrhiza and A membranaceus) is responsible for the antidiabetic retinopathy potential of clinically established Chinese capsules Fufang Xueshuantong,[68] certain other constituents of S ningpoensis also posses this potential Acetoside is an aldose reductase inhibitor[69] and thus is liable to elicit similar beneficial effects as astragaloside IV (already discussed above) and helps in attenuating the pathological occurrences during diabetic retinopathy Catalpol, an S ningpoensis-derived iridoid glycoside, demonstrates anti-inflammatory and antioxidant properties It significantly prevents endothelial dysfunction and free radical production during diabetes by downregulating the expression of Nox-4 and its component p22phox, both at transcriptional and translational levels.[70] Besides, catalpol induces antioxidant effects by upregulating the © 2017 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2017), pp **–** Chinese herbs in diabetic retinopathy Tapan Behl and Anita Kotwani Anisodamine Via inhibition of lipopolysaccharide induced plasminogen activator inhibitor1 and tissue factor expression (probably by NF-kappa B pathway) Counteracts endothelial cell activation Inhibits the release of pro-inflammatory cytokines such as TNF-aplha, interleukins 1, and Anti-inflammatory effect Figure Anti-hemorrhagic property The cell protective action of anisodamine in the prevention of diabetic retinopathy activity of SOD Catalpol can also downregulate inflammation by suppressing the expressions of various cytokines.[71] Scrophuloside B, another iridoid glycoside obtained from S ningpoensis, is reported to be a more effective antiinflammatory constituent as compared to catalpol It inhibits the activity of COX-2 and downregulates the production of TNF-a, MCP-1 and nitric oxide These effects are speculated to be mediated by blocking NF-jB-mediated signal transduction pathway Besides, scrophuloside B attenuates the mRNA expression of cardiolipin synthetase 1, an enzyme required for the formation of mitochondrial cardiolipin which is essential for inflammasome NLRP3 activity Inflammasome NLRP3 is a component of innate immune system involved in the maturation of pro-inflammatory cytokine IL-1b Scrophuloside B-mediated inhibition of inflammasome NLRP3 expression via discussed pathway hinders IL-1b secretion.[72] Since these mentioned pro-inflammatory mediators are critically involved in the pathophysiology of diabetic retinopathy, their inhibition may potentially prevent the progression of this complication Puerariae lobata Puerariae lobata (Family Fabaceae), popularly addressed as Kudzu root, is one of the most substantially used herbs in the traditional Chinese medicine due to the wide range of pharmacological activities elicited by its active phytochemical constituent puerarin, an isoflavonoid Puerarin, also known as Gegen in China, isolated from the dried root (Puerariae radix) of P lobata, possesses a wide range of beneficial properties such as vasodilatory, cardioprotective, neuroprotective, hepatoprotective, analgesic, antipyretic, antioxidant, anti-angiogenic, anti-inflammatory, antinociceptive, hypoglycaemic, hypocholesterolaemic, antithrombotic and osteoblastic, owing to the virtues of which it has been used both as a dietary supplement for maintenance of general health and as a medicine for the treatment of various disorders including cardiovascular and cerebrovascular diseases, diabetes and its complications, osteonecrosis/osteoporosis, Parkinson’s disease, Alzheimer’s disease, endometriosis, thromboembolism, hyperlipidemia, chronic alcoholism, liver diseases and cancer Apart from puerarin, two other isoflavones present in P lobata, daidzein and genistein, are also responsible for some these pharmacological actions.[73,74] P lobata is one of the few Chinese herbs whose antidiabetic retinopathy potential is well reported and acknowledged Mainly, it protects the retinal epithelial and neuronal cells from apoptosis due to its antioxidant mechanisms It prevents peroxynitrite-induced cellular apoptosis, by primarily reducing mRNA expression of iNOS (thus suppressing nitric oxide production) and enhancing SOD activity (thus scavenging superoxide radical), thereby inhibiting peroxynitrite radical formation Besides, puerarin also attenuates AGE-induced oxidative stress by downregulating RAGE expression.[73] In addition to the inhibition of AGE receptor expression, a study reported that puerarin also directly inhibits the production of AGEs.[75] Puerarin prevents apoptosis of retinal pericytes by suppressing the activation of NADPH oxidase (by inhibiting p47phox and Rac1-mediated signalling) and NF-jB, and preventing free radical production Antiangiogenic properties of puerarin are also crucial in preventing the progression of diabetic retinopathy It inhibits © 2017 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2017), pp **–** Tapan Behl and Anita Kotwani Chinese herbs in diabetic retinopathy retinal angiogenesis by suppressing the mRNA expressions of VEGF and HIF-1a.[73] Anti-inflammatory effects of puerarin are demonstrated by its ability to attenuate IL1b-mediated events such as retinal leukostasis (by inhibiting the induction of ICAM-1 and VCAM-1), cell apoptosis (by downregulating the expression of Bax and caspase-3, while simultaneously upregulating the expression of Bcl-2 in mitochondria) and ultimately preventing BRB breakdown.[76] Apart from puerarin, genistein also elicits antiinflammatory effects in diabetic retina It acts as a tyrosine kinase inhibitor and prevents activation of pro-inflammatory cytokine TNF-a by inhibiting microglial activation The molecular mechanism behind this is demonstrated as genistein-mediated inhibition of ERK and p38 MAPK phosphorylation Since TNF-a is primarily involved in the recruitment of leucocytes by stimulating the expressions of cellular adhesion molecules, its inhibition by genistein greatly prevented leucocyte–endothelial interaction, vascular dysfunction, leakage and breakdown, and subsequent retinal oedema.[77] Additionally, genistein and the third isoflavone present in P lobata, daidzein, are reported to elicit certain anti-inflammatory effects by agonism at PPAR-c receptor The most vasoprotective downstream event of genistein and daidzein-induced PPAR-c activation includes the inhibition of monocyte adhesion to endothelium, which is independent of the isoflavone-induced inhibitory effects on the expressions of cellular adhesion molecules.[78] Owing to all the above-mentioned beneficial effects, P lobata may potentially prevent/treat diabetic retinopathy Ginkgo biloba Ginkgo biloba, also known as maiden hair tree, is probably one of the oldest surviving tree species and is known for its utility in food and medicine since centuries The various pharmacological activities of G biloba include improvement in cerebral blood flow, neuroprotection and antiapoptotic actions against oxidative stress-induced damage, toning of vasculature and inhibition of platelet activation Due to these properties, it has been widely used in the Chinese traditional medicine for the treatment of asthma, tinnitus, vertigo, diabetes and several circulatory disorders such as peripheral vascular diseases, but most importantly dementia-related disorders, such as Alzheimer’s disease Even today, G biloba extracts are being clinically used to improve the learning, cognitive and motor activities in dementia patients and as an adjunctive therapy in schizophrenia The chemical constituents responsible for these activities are identified as biflavones, terpene trilactones (ginkgolides A, B, C, J, P and Q, and bilobalides), flavonol glycosides (quercetin, catechin) and proanthocyanidins.[79,80] Its antioxidant, neuroprotective and blood flow-improving properties make it a potential candidate for its utilization in the prevention of diabetic retinopathy Indeed, some studies have reported beneficial effects of G biloba extract in retina during hyperglycaemia Treatment with G biloba extract in diabetic animal models greatly reduces the nitric oxide-induced oxidative stress by acting as nitric oxide scavenger, besides decreasing its production This attenuates apoptosis of retinal ganglion cells Gingko biloba Contains Ginkgolide A Increases ocular blood flow (due to blood thinning property) Contains flavonoids Inhibits activation of platelets Reduces the adhesion of blood cells to endothelium Inhibit the downregulation of eNOS in capillaries Prevent nitric oxide decrease Possess antioxidant properties Cause Vasorelaxation Prevent inflammatory response in capillaries Reduces oxidative stress Prevents Diabetic Retinopathy Figure Mechanism of action of Ginkgo biloba in the prevention of diabetic retinopathy © 2017 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2017), pp **–** Chinese herbs in diabetic retinopathy Table Tapan Behl and Anita Kotwani Mechanism of action of the major constituents of Chinese herbs Chinese herbs Major constituent Mechanism of action Panax notoginseng Ginsenoside Re 14, ginsenoside Rd, ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside R1 Salvianolic acid A, rosmarinic acid • Scavenge hydroxyl and superoxide radicals • Downregulation in the mRNA expression of MCP-1 and NF-jB Salvia miltiorrhiza Lycium barbarum Polysaccharides, zeaxanthin, carotene, betaine, cerebroside, beta-sitosterol, p-coumaric, and various vitamins Astragalus membranaceus Polysaccharides (astragalans I, II and III), saponins (astragalosides I–VIII and isoastragalosides I and II), flavonoids, isoflavonoids, sterols, amino acids, volatile oils and trace elements Anisodamine, anisodine, hyoscyamine, scopolamine, tropine, apoatropine, trichlorophenyl butyryloxytropane and cuscohygrine Anisodus tanguticus Scrophularia ningpoensis Angoroside C, acetoside, sibirioside A, 6-O-caffeoyl sucrose and oligosaccharides of raffinose, stachyose and verbascose Puerariae lobata Puerarin, genistein and daidzein Ginkgo biloba Biflavones, terpene trilactones (ginkgolides A, B, C, J, P and Q, and bilobalides), flavonol glycosides (quercetin, catechin) and proanthocyanidins and photoreceptor cells G biloba prevents retinal detachment by eliciting anti-inflammatory effects,[81] one of whose hypothesized molecular mechanism is the ability of ginkgolide B to downregulate the expression of PAF Ginkgolide B acts both as a competitive antagonist of PAF and as an activity accelerator of PAF-acetylhydrolase (PAFAH), an enzyme which catalyses the hydrolysis (and subsequent inactivation) of PAF Since PAF is critically involved in increasing leucocyte adhesion to retinal vasculature by either accelerating proteolytic shedding of adhesion molecules, P-selectin glycoprotein ligand-1, from leucocytes or modifying it in certain other ways which affect the rolling velocities of leucocytes on retinal endothelium, inhibition of PAF by ginkgolide B prevents leucocyte–endothelial interaction and its downstream inflammatory responses, thereby reducing retinal endothelial cell damage.[82] G biloba extract can also significantly reduce the 10 • • • • • • • • • • Upregulate endogenous antioxidant enzymes Inhibit Ang-II-induced NADPH oxidase-4 (Nox4) Preventing endothelial cell proliferation and angiogenesis Upregulate the expression of anti-apoptotic gene Bcl-2 Downregulate the expression of pro-apoptotic gene Bax Inhibit the activation of cytochrome c/caspase-3-mediated apoptotic pathway Reduce retinal ganglion cell apoptosis Decrease phosphorylation of ERK1/2 Inhibit activation of NF-jB and various cytokines Downregulate the expression of enzyme aldose reductase • Prevent retinal lipid peroxidation • Downregulating the expression of plasminogen activator inhibitor-1 (PAI-1) and tissue factor • Inhibit the production of TNF-a • Activate a7nAChR • Downregulate VPO-1 • Inhibit aldose reductase • Downregulate the expression of Nox-4 and its component p22phox • Suppress the expressions of various cytokines • Inhibit the activity of COX-2 • Attenuate the mRNA expression of cardiolipin synthetase • Prevent peroxynitrite-induced cellular apoptosis • Attenuate AGE-induced oxidative stress • Suppress the activation of NADPH oxidase, VEGF and HIF-1a • Inhibit tyrosine kinase • Prevent leucocyte–endothelial interaction, vascular dysfunction, leakage and oedema • Downregulate the expression of PAF • Reduce the transcriptional expressions of HIF-1a and VEGF transcriptional expressions of HIF-1a and VEGF in retinal pigment epithelial cells under hypoxic conditions However, the molecular mechanisms behind these actions have not yet been elucidated.[83] Nevertheless, these beneficial effects may be potentially explored further and clinically validated for the exploitation of G biloba as an antidiabetic retinopathy therapy (Figure 3, Table 1) Conclusion Diabetic retinopathy is a vision-jeopardizing complication associated with diabetes mellitus which is a result of several hyperglycaemia-induced pathological changes such as increased oxidative stress-induced apoptosis of retinal endothelial and neuronal cells, angiogenesis and inflammatory responses There is an urgent need to develop a natural herbal therapy which could prevent the progression of this © 2017 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2017), pp **–** Tapan Behl and Anita Kotwani Chinese herbs in diabetic retinopathy complication or cure the already existing pathological states in retina without causing much harm to the retinal tissue and devoid of any major side effects In lieu of finding safer alternative treatments of diabetic retinopathy in plants, Chinese herbal drugs are being currently explored Indeed, many of these herbs have shown positive results Various pharmacological actions including antioxidant, anti-angiogenic, anti-inflammatory, PAF antagonism, aldose reductase inhibition, PPAR-c agonism, among various others have been elicited by these herbs which indicate that they might alleviate all the hyperglycaemia-induced pathological conditions Preclinical and clinical studies performed so far on these herbs need to be acknowledged and the development of these herbs into clinical therapies should be accelerated to provide a safer treatment to the patients of diabetic retinopathy References Lee R et al Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss Eye Vis (Lond) 2015; 2: 17 Singh RS et al Retinal complications associated with pars plana vitrectomy for macular holes or epiretinal membranes in eyes with previous retinal detachment repair JAMA Ophthalmol 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