Therapeutic potential of curcumin in diabetic complications

Accepted Manuscript Title: Therapeutic potential of curcumin in diabetic complications Authors: Negin Parsamanesh, Maryam Moossavi, Afsane Bahrami, Alexandra E. Butler, Amirhossein Sahebkar PII: DOI: Reference:

S1043-6618(18)30778-3 https://doi.org/10.1016/j.phrs.2018.09.012 YPHRS 3999

To appear in:

Pharmacological Research

Received date: Revised date:

30-5-2018 19-8-2018

Please cite this article as: Parsamanesh N, Moossavi M, Bahrami A, Butler AE, Sahebkar A, Therapeutic potential of curcumin in diabetic complications, Pharmacological Research (2018), https://doi.org/10.1016/j.phrs.2018.09.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Therapeutic potential of curcumin in diabetic complications Negin Parsamanesh1,2, Maryam Moossavi 1,2, Afsane Bahrami2, Alexandra E. Butler,3 Amirhossein Sahebkar4,5,6 1 Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran 2

Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand,

Iran Life Sciences Research Division, Anti-Doping Laboratory Qatar, Sports City Road, Doha,

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Qatar 4

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University

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of Medical Sciences, Mashhad, Iran

Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences,

Mashhad, Iran

School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

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Running title: Curcumin's effects against diabetic complications

Corresponding author:

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Amirhossein Sahebkar, PharmD, PhD, Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, P.O. Box: 91779-48564, Iran. Tel: 985138002288; Fax: 985138002287; E-mail: [email protected]; [email protected]

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Conflict of interest: The authors declare no conflict of interest

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Graphical Abstract

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Abstract

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Diabetes mellitus is an extremely prevalent endocrine disease and a major global public health concern. Diabetic complications, such as retinopathy, nephropathy, neuropathy and

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cardiovascular disease, are common and majorly impact a patient’s quality of life. Curcumin,

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the major active component of turmeric, possesses extensive known pharmacological properties, including anti-inflammatory, antioxidant, and antitumor effects.

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Increasing evidence suggests that curcumin may offer protection against diabetic complications. The current review focuses on the possible molecular targets and pathways involved in diabetic complications and, in particular, the multi-target approach of curcumin in attenuating diabetic nephropathy, retinopathy, and neuropathy. Abbreviations: angiotensin II (AngII); angiotensin-converting enzyme (ACE); adipose differentiation-related protein(ADRP); aspartate aminotransferase (AST); 5' adenosine monophosphate-activated protein kinase (AMPK); blood urea nitrogen (BUN);

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caveolin-1(cav-1), CREB-binding protein (CBP); connective tissue growth factor (CTGF); Diabetic nephropathy (DN); extracellular matrix (ECM); endothelial nitric oxide (eNOS); Endothelin-1 (ET-1); fibronectin (FN); c-Jun N-terminal kinase (JNK); heat shock protein (HSP); Interleukin(IL); lactate dehydrogenase (LDH); mitogen-activated protein kinase (MAPK); monocyte chemoattractant protein-1 (MCP-1); Malondialdehyde(MDA); N-acetyl-β-glucosaminidase (NAG); NOD like receptor pyrin domain-containing 3 (NLRP3); NF-E2-related factor (Nrf2); protein kinase-c (PKC); superoxide dismutase (SOD); sterol regulatory element-binding proteins (SREBP); Streptozotocin (STZ); Toll-like receptors (TLR); tumor necrosis factor (TNF-α); vascular cell adhesion molecule1 (VCAM-1); vascular epithelial growth factor (VEGF).

Keywords: Diabetic nephropathy; diabetic retinopathy; diabetic neuropathy; diabetic

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cardiomyopathy

1. Introduction 1.1. Diabetes and curcumin

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Diabetes is a chronic metabolic disorder that has reached pandemic proportions, and which is

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a major cause of morbidity and mortality worldwide. By 2030, predictions suggest the

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worldwide prevalence of diabetes to reach to 592 million in the world [1]. The well recognized

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signs and symptoms include hyperglycemia, glycosuria, polyuria, polyphagia, polydipsia,

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negative nitrogen balance and ketonemia [2]. Type 1 diabetes is an autoimmune disorder resulting in almost complete destruction (98%) of insulin secreting beta cells in the pancreas,

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while type 2 diabetes is considered to be a disease of protein misfolding where, in addition to the average 65% loss of beta cell mass, insulin resistance occurs in target organs. Type 1

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diabetes, accounting for 5-10% of all cases, is a disease with absolute insulin deficiency, and therefore requires insulin replacement therapy. Type 2 diabetes is the more prevalent form,

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accounting for 90-95% of all cases, and combines a relative insulin deficiency with insulin resistance [3]. The persistent hyperglycemia of diabetes underlies the progression of both the macro- and microvascular complications in the neurons, eyes, kidneys, heart, liver, and other key organs through several proposed mechanisms: inflammation, oxidative stress, endoplasmic reticulum 3

stress and apoptosis (Figure1) [4]. Oxidative stress, inflammatory cytokines, transcription factors and enzymes, activation of protein kinase-c (PKC), intracellular sorbitol and tissue advanced glycation end products (AGEs) accumulation, polyol pathway and mitochondrial superoxide production all play a role in the development of diabetic complications [5, 6].

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Curcumin is the yellowish polyphenolic component of the dietary spice turmeric, which is the rhizomes of Curcuma longa, a herb in the ginger family (Zingiberaceae) [7]. Turmeric consists

of 2–5% curcuminoids, depending upon geographical region [8]. Turmeric extract is comprised

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of four curcuminoids: curcumin (71%), demethoxycurcumin (18%), bisdemethoxycurcumin

(3%) and cyclocurcumin (8%). The curcuminoid content of turmeric has been reported to range

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between 2 and 9% (Figure 2) [9-13].

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Several studies have indicated that curcumin has pleiotropic effects and a wide spectrum of

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molecular targets that regulate several pathways, intracellular elements, and key enzymes [14].

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Major molecular targets are transcription factors (e.g., nuclear factor [NF]-kB, activator protein

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[AP]-1, early growth response gene [Egr]-1, NF-E2-related factor [Nrf2] and β-catenin), transcriptional coactivators (e.g.p300), growth factors and their receptors (e.g., transforming

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growth factor [TGF]-β, connective tissue growth factor [CTGF], vascular epithelial growth factor [VEGF], epidermal growth factor receptor [EGFR] and human epidermal growth factor

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receptor2 [HER2]), cytokines and chemokines (e.g. tumor necrosis factor [TNF]-α, interleukin [IL]-6), adhesion molecules (e.g. endothelin-1, intracellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM1]), enzymes (e.g. cyclooxygenase 2 [COX2],

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malondialdehyde [MDA], 5-lipoxygenase [LOX]), and apoptotic proteins as well as protein kinases (e.g. phosphorylase kinase [PhK], PKC and protamine kinase) [15-20]. In the past decades, natural compounds have received increasing attention for the control of diabetes and its consequences [21]. Curcumin has anti-tumor [22-24], anti-inflammatory [25],

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antioxidant [26-28], immunomodulatory [29], anti-ischemic [30], anti-thrombotic [31], hepatoprotective [32], lipid-lowering [33-36] and analgesic [37] activities via its inhibitory effects on the production of pro-inflammatory cytokines, macrophage inflammatory protein1α, signal transducer and activator of transcription (STAT), TNF-α, superoxide anion and lipid peroxidase [38-40]. Curcumin has been shown to play a therapeutic role in treatment of human

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malignancies (e.g. gastrointestinal cancer), heart disease (e.g. atherosclerosis), inflammatory

disease (e.g. bronchitis), infectious disease (e.g. AIDS), cognitive impairment (e.g. Alzheimer

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disease), skin disease (e.g. eczema), and endocrine disorders (e.g. diabetes) (Figure 3) [41-43]. In diabetes, curcumin exerts hypocholesterolemic and hypoglycemic effects and increases

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insulin sensitivity [44, 45]. This has been shown to occur through suppression of blood glucose

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and systolic blood pressure, maintenance of pancreatic β cell volume, and normalization of

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triglyceride, cholesterol, phospholipids levels, total oxidative status, lipid peroxidation, TNF-

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α, free fatty acids (FFA), C-reactive protein (CRP), leptin, and adiponectin in both streptozotocin (STZ)-induced diabetes rats [46-50], and ob/ob, db/db and KK-A(y) mice [40,

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51-55]. Curcumin impeded phosphorylation of the inhibitor of kappa B alpha (IkBa), plateletderived growth factor (PDGF)-induced proliferation, PDGF-BB-induced cyclin D1 expression

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and activation of extracellular signal-regulated kinase (ERK) [56]. In addition, curcumin

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induced hemeoxygenase 1 (HO-1) gene action, glucose uptake of cells, GLUT2, GLUT3, GLUT4 gene expression, and also activated PPAR-γ, nuclear factor erythroid-2-related factor2 (Nrf2), 5' adenosine monophosphate-activated protein kinase (AMPK) and free-radical

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scavengers in animal models of diabetes [57, 58]. Recently, in a randomized controlled trial, 118 patients with type 2 diabetes received curcuminoids (1000 mg/day plus piperine 10 mg/day) or placebo for two months. The curcuminoid group had significantly higher total antioxidant capacity and superoxide dismutase (SOD,a superoxide radical scavenger enzyme) in serum; by contrast, serum 5

malondialdehyde (MDA,an index of lipid peroxidation) was markedly decreased in comparison to the placebo group. These findings favor the concept of curcumin as an antioxidant in type 2 diabetic patients [21]. By inference, curcumin possibly exerts beneficial effects on both hyperglycemia and insulin resistance (Figure 3). In this review, we aimed to

decipher the possible mechanisms by which curcumin affords this protection.

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1.2. Methodology

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investigate the therapeutic capacity of curcumin to counteract diabetes complications, and to

To prepare this narrative review, all the available literature regarding to this topic was gathered through electronic databases including Pubmed, Web of Science, Medline, Embase,

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Sciencedirect, Scopus, Cochrane Library, and Google Scholar. All basic and clinical studies

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selected for further evaluation in detail were selected using the following search terms in titles

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and abstracts (Diabetes OR diabetic patients OR hyperglycemia OR diabetic complications)

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AND (nephropathy OR kidney disease OR neuropathy OR retinopathy OR eye disease) AND

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(Curcumin OR turmeric OR Curcuma longa). All papers which cited studies enrolled in this review were also hand checked in order to find additional relevant papers. Moreover,

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clinicaltrials.gov website was searched to find all clinical trials concerning the effect of different curcumin regimens on diabetic complications. Only English language studies

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published from inception to May 30, 2018 were included in this review. 2. Curcumin and complications associated with diabetes

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2.1. Nephropathy

Diabetic nephropathy (DN) is the most common cause of end stage renal failure requiring dialysis, and is a catastrophic consequence of diabetes mellitus. DN affects about 15–25% of patients with type 1and 30–40% of patients with type II diabetes [59, 60]. In the initial stages of diabetes, the blood glucose is elevated above the renal threshold, therefore glucose is 6

excreted in the urine and its osmotic pressure causes an increase in urine volume. Clinically, the diagnosis of DN is based on the amount of urinary albumin protein (proteinuria). The cut off values for proteinuria in a 24-hour urine collection are <30 mg, 30–300 mg and > 300 mg which reflect normal state, microalbuminuria and macroalbuminuria [61].

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The pathological features in the early phase of DN are glomerular and tubular hypertrophy, hyper-filtration, persistent albuminuria, raised arterial blood pressure and accumulation of

extracellular matrix (ECM) components such as collagen, laminin and fibronectin (FN). Later,

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upon triggering of TGF-β1, of the glomerular basement membranes (BM) thicken and there is

expansion of the tubulointerstitial and mesangial matrix, eventually culminating in proteinuria,

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glomerulosclerosis and renal fibrosis [62]. Numerous mechanisms have been suggested to play

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a role in the development and progression of DN, such as mitochondrial overproduction of

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reactive oxygen species (ROS), oxidative stress, lipid disorders, glomerular hemodynamic and

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structural alterations, glycosylation of non-enzymatic proteins, generation of pro-fibrotic and fibrotic cytokines (e.g. CTGF, PAI-1, and FN-1) and a switch to the polyol pathway and Ras-

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mitogen-activated protein kinase (MAPK) signaling cascade [63-66].

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The beneficial effects of curcumin have been demonstrated in STZ-induced diabetes in both rats and db/db mice, models of type 1 and type 2 diabetic mellitus, respectively (Table 1).

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Inflammation is involved in the development and progression of DN. Curcumin affects renal inflammation though the amelioration of renal macrophage infiltration and modulation of

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multiple critical molecular targets, such as transcription factors [i.e. activator protein (AP-1)], and profibrotic cytokines (i.e. IL-1, IL-6 and chemokines) [67, 68]. Soetikno et al reported that oral curcumin supplementation (100 mg/kg/day p.o. for 8 weeks) counteracted the formation of DN in STZ-induced diabetic rats by diminishing macrophage infiltration via the suppression of NF-κB and IκBα action, and reducing the regulation of TGF7

β1, ICAM-1, and monocyte chemoattractant protein-1 (MCP-1) at the nuclear level. Macrophage permeation into glomeruli leads to progressive glomerular injury and subsequently glomerular and tubular damage [69]. Curcumin derivatives B06 and C66 have also been reported to improve renal fibrosis, histological abnormalities and kidney dysfunction in STZ-induced diabetic mice by causing a reduction in plasma levels of TNF-α, as well

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decreasing TGF-β and MCP-1 gene expression [67, 68]. Curcumin and its analogue downregulate the expression of p300/CREB-binding protein (CBP) of histone acetyl transferase

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(HAT) and whole HAT activation through inhibition of c-Jun N-terminal kinase (JNK) activation [67, 68, 70, 71]. The JNK pathway regulates the main intracellular processes in

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eukaryotes, such as growth, differentiation, and apoptosis [72]. JNK proteins are members of

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the MAPK family, which are phosphorylated and activated by MAPK kinases during

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conditions of cellular stress [73]. JNK activation can also stimulate p300 and CBP activity,

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and histone acetylation and, thus, can contribute to the onset of diabetes and the progression of renal complications of diabetes [74]. So, targeting of the JNK pathway, p300 activity and

of diabetic nephropathy.

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histone acetylation offer potential novel therapeutic approaches for prevention and treatment

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Toll-like receptors (TLRs) are endogenous ligands which serve as initiators of the innate

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immune response [75]. Previous studies demonstrated that caveolin-1(cav-1) exerts its antiinflammatory function by direct interaction with TLR4, and therefore blocks the ability of TLR4 to engage in MyD88/TRIF pathway, and effect the downstream activators of the NF-

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κB cascade [76]. Results from in vivo and in vitro experimentst show that curcumin is a potent natural anti-inflammatory compound for the treatment of DN progression, possibly via reversing cav-1 phosphorylation and, thereby, inhibiting TLR4 activation [77]. Curcumin is able to moderate ROS, is which is one of the main contributors to the pathological process of DN, responsible for oxidative stress-related structural and functional tubular damage 8

[78, 79]. Curcumin has been found to have a cytoprotective role against oxidative stress via enhancing heme oxygenase-1 activity in vascular endothelial cells, and inducing the generation of antioxidants, SOD, COX-2, LOX, catalases (CAT), glutathione (GSH), peroxiredoxins (PRDX), and inducible nitric oxide synthase inhibitor (iNOS) [80, 81]. Furthermore, curcumin protects tubular and glomerular epithelial cells from the cytotoxicity of hydrogen peroxide via

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a reduction in lipid peroxidation [82]. Dietary curcumin can improve kidney function by normalization of GSH, glucose-6-phosphate dehydrogenase (G6PD), lactate dehydrogenase

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(LDH), aldose reductase (AR), sorbitol dehydrogenase (SDH), transaminases (TAs), ATPases, and the membrane PUFA/SFA ratio[83].

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Moreover, curcumin (100mg/kg/day, p.o. 8 week) treatment down-regulates the nicotinamide

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adenine dinucleotide phosphate (NADPH) oxidase subunits, NOX4 and p67phox, which are

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an underlying mechanism for boosting ROS production [79]. Zhang and coworkers showed

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that curcumin elevated urinary SOD and, simultaneously, reduced urinary MDA. Extensive research has revealed that the regulation of SOD, MDA and CAT are coordinated by the

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transcription factor, Nrf2, which contributes to oxidative stress inhibition and ectopic lipid accumulation in DN. AMPK, as a master signaling intermediary, regulates several intracellular

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systems, such as energy metabolism and metabolic homeostasis in skeletal muscle, heart and

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brain [84, 85]. A decrease in AMPK activation results in renal hypertrophy [86]. Activation of AMPK by natural products is a potent strategy to reverse the metabolic abnormalities associated with diabetes [87]. Curcumin treatment (100 mg/kg/day for 200 week) was shown

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to enhance anti-oxidative and hypo-lipidemic defense mechanisms in a diabetic rat model via the AMPK and Nrf2 pathways [88]. Long term hyperglycemia has been found to trigger the expression of endogenous stress proteins, such as heat shock proteins (HSPs) [89, 90]. HSPs have cytoprotective properties, combating oxidative stress, apoptosis and unsustainable cellular condition [91]. Elevated blood 9

glucose stimulates the activation of the proapoptotic protein, MAPK p38, which is involved in a set of downstream inflammatory cascades connected with renal glomerular and tubulointerstitial injuries in the diabetic milieu [92, 93]. P38 also phosphorylates histone H3, which leads to immature chromatin condensation, altered chromatin structure and, eventually, cell death [94]. Several studies have shown upregulation of HSPs and MAPK p38 in diabetic

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kidney. Curcumin can inhibit phosphorylation of histone H3 and over-expression of HSP-27

and p38 in an animal model of diabetes [95, 96]. However, conflicting results were reported by

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Ma et al. after assessment of the effects of curcumin treatment on cultured podocytes under

hyperglycemic conditions; here, curcumin promoted p38 phosphorylation and downstream

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HSP25, inhibited COX-2 and caspase-3, and reduced the conversion of F-actin to G-actin

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monomers. In STZ-induced diabetes in the DBA2J mouse, curcumin ameliorated the HSP25

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response, enhanced urinary 12-hydroxytetraenoic acid secretion, and failed to decrease the

explain these negative results.

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albuminuria [97]. The differing effects of curcumin on the HSP25 and LOX pathways may

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Recently, Lu and co-researchers investigated the effects of 16 weeks curcumin therapy (200 mg/kg/day) on diabetic renal injury in db/db mice. Curcumin ameliorated renal hypertrophy,

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decreased expansion of the mesangial matrix, and attenuated albuminuria. In addition,

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curcumin suppressed the expression of collagen IV and FN in the kidney cortex of diabetic mice. Furthermore, curcumin decreased IL-1β, caspase-1, and NOD like receptor pyrin domain-containing 3 (NLRP3) protein levels in both the kidney of diabetic mice and in HK-2

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cells maintained in a high glucose medium [98]. HK-2 is an immortalized human renal proximal tubule epithelial-derived cell line, and can be compared to mesangial cells as tubulointerstitial inflammation is critical in the progression of DN [99] and NLRP3 protein is primarily amplified in tubular epithelial cells [100]. The NLRP3 (also termed NALP3 or cryopyrin) inflammasome is a molecular platform activated to potency against perturbation of 10

the homeostatic intracellular process and therefore stimulates the innate immune system via the induction of proinflammatory cytokines, and might be involved in the progression of DN [101]. Another renoprotective role of curcumin, as an intense antifibrotic compound, is exerted by its inhibitory effect on NLRP3 inflammasome function. Curcumin treatment (100 mg/kg/day, p.o. for 8 wk) diminished protein kinase C (PKC) -α and

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PKC-β1 activation and ERK1/2 phosphorylation in STZ- induced diabetic rats [102].The activation of PKCs is involved in proteinuria development and the pathogenesis of DN. The

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PKC family plays an important role in various signal transduction pathways, such as MAPK

signaling [103, 104]. In DN, PKCα was found to be increased in vitro in high glucose-induced in sections of rat glomeruli [105]. Further

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glomerular mesangial cells (GMCs) and

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experimental studies reported that PKCα-deficient mice have a better outcome post STZ-

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induced diabetes, with less proteinuria and with nephrin expression maintained [106, 107].

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The sphingosine kinase 1-sphingosine 1-phosphate (SphK1-S1P) axis has been proposed as

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being involved in the renal fibrosis and progression of DN [108]. S1P, a polar pleiotropic lipid metabolite, regulates various extracellular and intracellular signaling pathways and biological

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and pathophysiological processes. Continuous hyperglycemia has been found to activate SK1 and promote the production of S1P, resulting in glomerular mesangial cell development, and

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the vascular lesions seen in chronic vascular disorders such as DN [109, 110]. S1P induces TGF-β expression, orchestrates the cellular response to TGF-β, and eventually causes progression of renal fibrosis [111]. Huang et al. demonstrated that curcumin negatively

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mediated the expression and activity of SphK1 and S1P in vitro, thereby affording protection to mesangial cells under diabetic conditions and in vivo, diabetic nephropathy. Moreover, curcumin hampered the DNA-binding activity of AP-1 and reversed the diabetes-induced overexpression of SphK1. Curcumin ameliorated the overproduction of FN and TGF-β1 mediated by SphK1-S1P pathway. The preventative effect of curcumin on SphK1-S1P was, in 11

fact, directly associated with AP-1 activity suppression which decreased renal fibrosis and alleviated DN [112]. The PI3K/AKT pathway is thought to be involved in the renal fibrosis process in diabetes [113, 114]. Recently Chen and colleagues reported that J17, a novel curcumin derivative,

induced diabetic mouse model through disruption of the AKT pathway [96].

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prevents hyperglycemia-associated renal fibrosis in both NRK-52E cell lines and a STZ-

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The renin–angiotensin system (RAS) plays an important role in regulation of systemic blood pressure. Accumulating evidence demonstrates the contribution of RAS to the development of DN [115]. Renin dissociates angiotensinogen to release angiotensin I (AngI), and this is

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converted by angiotensin-converting enzyme (ACE) to angiotensin II (AngII) [116]. A novel

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chemically modified curcumin analogue, B6, a regulatory component of the RAS pathway,

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protects the kidney from pathological damage in STZ-diabetic Wistar rats [117].

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A meta-analysis of fourteen randomized trials assessing the effects of curcumin in rats/mice

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with DN showed that curcumin treatment significantly decreased urinary protein, blood urea nitrogen (BUN) and serum creatinine levels and mesangial/glomerular areas ratio. Further

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analysis demonstrated that these outcomes are possibly due to the regulatory effect of curcumin

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on VEGF and AMPK[118].

A randomized clinical trial is now underway to evaluate the interaction between the rs35652124 polymorphism and curcumin allocation on NFE2L2 gene expression levels,

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antioxidant status and kidney function in patients with early DN (NCT03262363). 2.2. Diabetic retinopathy

Diabetic patients are more susceptible to development of several ocular complications, such as glaucoma and cataracts at an earlier age compared to normal nondiabetic subjects. However,

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one of the most severe ocular sequelae due to chronic hyperglycemia is diabetic retinopathy (DR). DR affects the photoreceptors and blood vessels of the retina, is the leading cause of vision loss, and is considered as one of the most debilitating complications of diabetes. Persistent hyperglycemia and poor metabolic control seem to be the main factors in the evolution of this multifactorial retinal injury [119] which is responsible for 15% of all

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ophthalmic disease burden [120] and which severely impacts a patient’s quality of life. About

90% of newly diagnosed cases could be avoided with appropriate treatment and monitoring, so

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effective therapy is considered a priority [121].

Disturbances in retinal metabolism, including hyperpolyol pathway activity, elevated non-

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enzymatic glycation and AGEs, oxidative stress, and PKC function [120, 122, 123] are thought

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to play a role in the development of DR, but the exact underlying mechanism remains to be

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elucidated. DR can be categorized into two stages: non-proliferative DR (NPDR) and

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proliferative DR (PDR). NPDR is characterized by intra-retinal microvasculature alterations [124] and may be further subdivided into mild, moderate, and severe, stages which correlate

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with long term diabetic macular edema (DME). Permeance and fluid/protein synthesis in two disc diameters of the macular region results in DME, which is one of the main reasons for

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complete visual loss in patients with persistent hyperglycemia [125]. There are three types of

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DME: edematous, ischemic and exudative. NPDR may progress into PDR, where signs of pathological angiogenesis of the retina, vascular permeability, fluid accumulation, vitreous fibrotic responses (gliosis) and hemorrhage are apparent [126-128].

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In the diabetic milieu, continuous generation of free radicals in the retina leads to an increment in oxidative stress. ROS play an integral role in the interrelationship between high glucose and the biochemical abnormalities central to development of diabetic complications [129]. Free radicals lead to high-expression of proinflammatory mediators like VEGF, hypoxia-induced growth factor (HIGF) and TNF-α [130, 131]. These mediators are involved in the over13

expression of the adhesion molecules of endothelial cells (ECs) and leucocytes. Consequently, leukostasis can cause maculopathy, the presence of mural cell ghosts, hyperpermeability, angiogenesis, acellularity, formation of microaneurysms, eosinophilic exudate, vascular occlusion, hemorrhage in the both inner nuclear and outer plexiform layers, retinal ischemia, neovascularization, capillary stasis, occlusion, hypoxia and neuron death in the retina [132,

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133]. The initial histopathological alteration found in human DR is the selective loss of

pericytes. Further changes include degeneration of organelles and higher production and lower

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degradation of the ECM proteins, collagen and FN in the retinal endothelial cells (RECs) which leads to capillary BM thickening [130, 134, 135].

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The preventive and therapeutic benefits of curcumin in DR involve a decrease in the structural

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degeneration and ultrastructure modifications of the retina due to diabetes, including

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attenuation of the retina, insolubilization of the lens, cell death from the retinal ganglion and

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inner layer, basement membrane thickening in retinal capillaries and perturbation of photoreceptor cell membranous disks (Table 2) [136, 137]. Steigerwalt et al. demonstrated that

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treatment with Meriva®, a novel curcumin-lecithin delivery form (2 tablets per day containing

patients [138].

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100 mg curcumin for 4 weeks), improved retinal flow, DME and visual acuity in diabetic

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Ample evidence indicates that curcumin exhibits significant hypoglycemic effects through positive modulation of the antioxidant redox system in the diabetic rats. After supplementation, retinal GSH levels and activity of antioxidant enzymes (SOD and CAT) were attenuated [137].

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Curcumin treatment restores retinal antioxidant capacity, and abolishes expression in the retina of proinflammatory cytokines, TNF-α, VEGF and ICAM-1 in diabetic rats [136, 137, 139142]. Curcumin also can inhibit PKC βII translocation, which is induced through VEGF in human RECs [143].

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Activation of NF-κB stimulates the pro-apoptotic process in RECs and its capillary cells, and subsequently induces proinflammatory mediators such as TNF-α and iNOS which are central in the development of DR [144]. Most evidence supports the advantageous effect of curcumin supplementation for DNA damage reduction through suppression of NF-κB activation, and repositioning of oxidatively modified DNA and nitrotyrosine in the diabetic rat retina [145].

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Much evidence supports the antiapoptotic potential of curcumin in the diabetic retina through

high-expression of Bcl-2, down regulation of Bax and glutamine syntheta{Chous, 2016 #22}se

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(GS), mitigation of cell death in Müller cells, and a decrease in glial fibrillary acidic protein

(GFAP) levels [136, 146]. According to these findings, curcumin could delay the onset of

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apoptosis, a predictor of the DR formation, in retinal cells [147].

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EGR-1, a Zn2+ finger-containing transcription factor, is a nuclear phosphoprotein that has been

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implicated in the regulation of gene transcription and cellular response to different factors [148, Curcumin prevented the

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149]. EGR-1 is dysregulated in a variety of human disease.

upregulation of EGR1 in ECs and fibroblasts [150]. Curcumin downregulated the expression

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of EGR1 in vitro in 661W cell lines and in vivo in rat retina with light-injury [151].

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Curcumin inhibits ECM production in DR through decreasing the amount of two major DNA repair enzymes, mammalian excision repair cross-complementing (ERCC) 1 and ERCC4.

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These enzymes are activated in response to high glucose-induced DNA damage and cause high FN production through a p300-dependent pathway with subsequent development of DR [152].

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Recent findings provide evidence for the protective role of curcumin against early retinal vascular leakage, by suppression of Calcium/calmodulin-dependent protein kinase II (CaMKII)/NF-κB signaling in diabetic rat retina [153-155]. CaMKII, as an multifunctional protein kinase is known to be an important regulator of NF-κB, leading to pro-inflammatory reactivity [156]. CaMKII activation has been shown to be 15

selectively upregulated in neuronal cells destruction and the progression of abnormal vascular dysfunction in DR [141, 157]. Curcumin can also prevent cataract formation in STZ or the selenite rat model of diabetes. Notably, curcumin down-regulates Hsp 70, αA-crystalline, and αB-crystallin which are the

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main proteins involved in the preservation of eye lens transparency and are overexpressed in cataracts [158-160].

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Diabetic patients are prone to develop corneal disorders, such as reduced corneal sensitivity,

reduced tear secretion and tear film, degeneration of nerve fibers, corneal neovascularization (CNV), corneal epithelial damage, and corneal ulcers [161, 162]. CNV is historically the most

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common cause of vision loss worldwide [163]. Transparency and avascularity are two

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important properties of the cornea which are disrupted under numerous pathophysiological

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conditions, and which could be associated with CNV development. New-built retinal vessels

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are premature, hyperpermeable and brittle, which causes corneal edema, lipid accumulation

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and the disaggregation of highly vulnerable vessels, leading to stromal intracorneal hemorrhage, corneal scars and swelling and, eventually, vision loss and blindness. Curcumin

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ameliorates CNV formation through suppression of low density lipoprotein receptor-related protein 6 (LRP6) phosphorylation and β-catenin nuclear localization, two markers of the

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activated Wnt/β-catenin pathway [164]. Guo et al. suggested that intranasal nanomicelle delivery of curcumin exerts a beneficial effect on diabetic keratopathy and resulted in the promotion of corneal epithelial or nerve wound healing in STZ-induced diabetic mouse [165].

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Taken together, these mechanisms could explain the protective role of curcumin in DR. Recently, a randomized, single center, double masked, multi-armed trial was initiated to assess the effect of Glauco-Health and Glauco-Select compounds which containing curcumin in DR patients (NCT02984813).

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2.3. Diabetic neuropathy Uncontrolled hyperglycemia has adverse effects on the central nervous system (CNS) [131, 166, 167]. Diabetic neuropathy, a local metabolic and microvascular complication of diabetes involves neurochemical and structural changes in both autonomic and somatic peripheral nerves in diabetic patients. Diabetic peripheral neuropathy (DPN) is closely correlated with

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mortality, high healthcare costs and life threatening outcomes, such as foot ulceration and amputation [120]. The prevalence of clinical DPN in diabetic patients is approximately 30%,

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while up to half of diabetic patients will develop neuropathy over time [168]. There is no FDAapproved agent to treat DPN, the only suggested method for prevention and alleviating

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symptoms being the consistent maintenance of euglycemia[169].

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Signs and symptoms include decreased nerve conduction velocity (NCV), diabetic

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encephalopathy, absence of feeling and tendon reflexes, cognitive impairment, impotence,

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urinary and bowel incontinence, nausea, diarrhea, and indigestion [170-173]. A deficit in performance in global memory, learning, mental flexibility, attention, planning, abstract

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reasoning, decision making, visual-motor practices, and psychomotor slowing are more prevalent in diabetic subjects as a result of direct neuronal damage arising from intracellular

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hyperglycemia [173-176].

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The pathogenesis of DPN is complex and multiple pathways contribute to it. Preclinical investigations have suggested that the pathogenesis of DPN may be due to both hyperglycemia and lack of neurotrophic impact of insulin/C-peptide [177]. Hyperglycemia can cause dramatic

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metabolic and enzymatic alterations; neuropoietic cytokine release (i.e. IL-1, IL-6 and TNF-α) can modify homeostatic plasticity in neuronal networks and is implicated in the development of DPN [43].

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Furthermore, oxidative stress, neuroinflammatory and lipid peroxidation are also considered as important reasons for diabetic membrane and tissue damage [178]. Oxidative damage to nervous tissue was induced experimentally by chronic hyperglycemia in a rat model. ROS induced morphological abnormalities, and damage to both CNS and peripheral nerves, through invasion into sensitive cells, axons and Schwann cells (due to their high level of

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polyunsaturated lipid) [179, 180]. Besides ROS levels, nitric oxide (NO) levels and

mitochondrial NOS expression were also elevated in brain mitochondria, while glutathione

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peroxidase (GPx) performance and manganese superoxide dismutase (MnSOD) concentration were decreased in the diabetic condition [181]. Chronic supplementation with curcumin (60

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mg/kg; p.o.) significantly reduced diabetic encephalopathy, neurodegeneration, cognitive

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impairment, dysfunctional cholinergic activity and neuroinflammation in diabetic rats [182].

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Experimental studies have consistently reported that curcumin administration ameliorated the

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slowing nerve conduction and CNS dysfunction in diabetic rats (Table 3)[183-186]. Supplementation with tetrahydrocurcumin (THC) significantly elevated activities of SOD,

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CAT, GPx and glutathione S-transferase (GST), and returned GSH and hydroperoxides level to normal in rat brains with a remarkable reduction in lipid peroxidation markers and

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carbohydrate and lipid metabolism; thus, liver and kidney damage was alleviated, and the

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functions of major antioxidant enzymes and crucial signaling pathways were returned to normal [187-191].

Diabetic neuropathic pain (DNP) is one important microvascular complication of diabetes

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[192]. It is pain that is difficult to treat that can occur following exposure to light painful stimuli, e.g. hyperalgesia, allodynia and paraesthesia [193]. Several signal transduction pathways are involved in the pathogenesis and progression of DNP, but inflammation the oxidative pathway and oxidative/nitrosative stress are key [195-197].

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Chronic hyperglycemia causes the secretion of major mediators of neuropathic pain in microvascular/neuron-rich tissues, such as TNF-α, SOD, and NO [198] which leads to protein nitration and nitrosylation, lipid peroxidation, oxidative DNA damage, apoptosis, and direct toxicity of neuronal fibers causing DNP[199]. It has been suggested that DNP involves stressed neurons evade death, yet undergo degeneration with pain generation [200].

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A single dose of the curcumin derivative, J147, via suppression of the TNF-α pathway and activation of the AMP kinase pathway, showed great for both rapid attenuation of allodynia

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and motor nerve conduction velocity (MNCV) slowing in a STZ-induced mouse model of type 1 diabetes. Curcumin’s ability to treat both neuropathy and neuropathic pain is promising

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[177].

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Long term consumption of curcumin prevented the mechanical allodynia in experimental

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diabetic rats, probably via activation of delta and mu-opioid receptors [205]. Curcumin also

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showed its antioxidant and anti-inflammatory effects through inhibition of ROS, NO, PKC,

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TNF-α, TNF-α receptor 1, IL-1 β, IL-6, oxidative stress, and NF-κB, and therefore has the potential to ameliorate DNP [183, 206-208]. Alleviation of DNP by curcumin in the spinal

[209].

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cord was likely effected by downregulation of NADPH oxidase-stimulated oxidative stress

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CNS sensory ganglia consist of satellite glial cells (SGCs) and astroglia. A layer of SGCs encircle each soma in the dorsal root ganglia (DRG) [210]. Non-neuronal cells near the DRG

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neurons, such as the SGCs, express purinergic 2 (P2) Y12 receptors [211]. The administration of nanoparticle-encapsulated curcumin blocked the activation of SGCs and reduced the expression of calcitonin gene related peptide (CGRP) in the DRG neurons. Thus, curcumin effectively diminished the over-expression of the P2Y12 receptor on SGCs within the DRG and so, reduced both mechanical and thermal hyperalgesia in STZ-induced diabetic rats [212].

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3. Discussion In the literature, there is only one limited study focused on the effect of curcumin on diabetic complications in the clinical setting. A randomized, placebo-controlled study was performed in Iran, where 40 patients with type 2 DN received either turmeric capsule (500 mg turmeric containing 22.1 mg active component curcumin, 3 per day) or placebo for 60

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days. Serum levels of TGF-β and IL-8 as well as urinary protein excretion was significantly reduced after the trial in the turmeric treated group. Turmeric supplementation was well

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tolerated in treated patients. This findings indicated that short-term curcumin

administration could be a promising therapeutic agent in patients with DN (210). In the

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clinical setting, curcumin supplementation (500 mg/day) for 2-4 weeks significantly

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decreased urinary microalbumin excretion, plasma MDA values and increased the Nrf2

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system specifically regulated protein, NAD(P)H quinone oxidoreductase 1 (NQO-1), and

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other antioxidant enzymes in type 2 diabetic patients. Short-term curcumin administration prevents diabetic kidney disease through activating Nrf2 antioxidative system and

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inhibition of inflammation in patients with type 2 diabetes.

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There is a growing body of clinical evidence highlighting the potential of curcumin therapy in inflammatory eye diseases (211, 212). Results from two investigations demonstrated that

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curcumin-phospholipid complex was clinically beneficial for the treatment of patients with ocular degenerative diseases, such as central serous chorioretinopathy (213, 214) and chronic anterior uveitis (215). This activity of curcumin encouraged the application of it in

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the management of inflammatory and degenerative eye diseases. There are only three clinical trials which assess the effect of curcumin combinations on diabetic complications, although only one of them has been completed to date. The result of a randomized, controlled clinical trial, the Visual Function Supplement Study

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(DiVFuSS) (NCT01646047), demonstrated clinically significant improvements in visual function with a novel, multicomponent nutritional ingredient containing turmeric root extract in diabetic patients with or without non-proliferative diabetic retinopathy (NPDR) (146). Another two trials investigating the effect and safety of curcumin combination in

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DN (NCT03262363) and DR (NCT02984813) are ongoing but not yet recruiting patients. Substantial work is still required to move curcumin from the laboratory to the clinic setting.

This is the logical step, because curcumin has revealed effectiveness in in vitro and animal

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studies. Following that, prospective studies comparing the effect of curcumin combinations (as curcumin particles or oral curcumin) are required. Another important aspect that is

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currently unclear is whether curcumin can prevent some of these complications before they

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become established. It is unknown whether curcumin is of benefit in the acute setting in

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humans, as opposed to being more useful when applied as a preventative measure. While

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curcumin has emerged as a promising therapeutic agent for diabetic conditions, more

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research is required before it is established in the clinical setting. 4. Conclusion

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Due to the rapid increase in the global prevalence of diabetes mellitus, finding effective treatments for diabetic complications is of the utmost importance. Current therapy for diabetes

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is mainly based on metabolic control, and available agents in clinical practice cannot completely control the development of complications.

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Research over the past decade has demonstrated the ability of curcumin to regulate multiple biochemical pathways and has revealed its preventive and therapeutic importance in numerous diseases, including diabetes. Data from preclinical and clinical investigations using curcumin have revealed various mechanisms of action that could ameliorate oxidative stress, proinflammatory pathways and reduce glucose production in diabetic patients. 21

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previously been shown that curcumin therapy can ameliorate diabetes with regard to glucose and lipid metabolism, enhance the sensitivity to insulin and reduce the insulin resistance in laboratory animal models of diabetes. Moreover, in vitro, in vivo, and human clinical reports point towards a beneficial effect of curcumin as adjuvant therapy to conventional anti-diabetic agents for the treatment of severe diabetes and its complications. Currently, however, the utility

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of curcumin is limited due to its low aqueous solubility and oral bioavailability. Moreover, the effective doses of the curcumins or their extracts/derivatives should to be determined.

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In the future, it will be essential to design long-term randomized human clinical trials using combinations of curcumin with other available therapeutic options for prevention and treatment

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of nephropathy, retinopathy, neuropathy, cardiomyopathy and other adverse diabetic

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complications, since many experiments have supported the potential value of curcumin for

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treatment of these conditions.

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Figure legends:

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Figure 1. Adverse micro-vascular and macro-vascular complications of diabetes leading to diabetic nephropathy, retinopathy, and neuropathy

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Figure 2. The chemical structures of Curcuminoids.

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Figure 3. The effect of curcumin treatment on diabetic complications in organs and tissues.

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Table 1: List of in vivo studies using curcumin for diabetic nephropathy treatment Dosage Animal model outcomes Curcumin(200 db/db mice -reduce IL-1β, caspase-1, and NLRP3 protein mg/kg/day,PO); 16 weeks -decreased albuminuria Curcumin STZ-induced DN -reduced the renal F4/80 expression (50mg/kg/day,PO); 7 mice -decrease AST and LDH weeks -decrease hyperglycemia through AKT pathway disruption B6(novel curcumin) (1, 3 STZ-diabetic -decrease the AngII and ACE2 levels and 9 mg/kg/day, PO); 8 wistar rats -increased the expression level of ACE2 weeks -decrease creatinine, urea nitrogen, and urine albumen/24 h levels Curcumin (15, 30 STZ-induced DN -elevated antioxidant molecules mg/kg/day, PO); 2 weeks in rats -elevated urea and creatinine clearances -decrease MDA level Curcumin (100 mg/kg/day, STZ-induced DN -decrease proteinuria and BUN PO); 8 weeks in rats -elevated creatinine clearance -down-regulation of NF-κB and IκBα -reduce macrophage infiltration -decrease the TGF-β1, ICAM-1 and MCP-1 expressions at the nuclear level Curcumin (100 mg/kg/day, STZ-induced DN -elevated AMPK phosphorylation PO); 8 weeks in rats

38

ref [98] [96]

[117]

[225]

[69]

[226]

Curcumin (0.5% in diet ); 8 weeks

STZ-induced DN in rats

curcumin(30 mM); 5000 and 7500 ppm in diet;7 days before primary STZ injection; 11weeks Curcumin (150/kg/day); 4 weeks

STZ-induced DN in DBA2J mice

Curcumin (100 mg/kg/day PO); 8 weeks

STZ-induced DN in rats

C66 (new curcumin derivative) (5 mg/kg PO); 60 days

STZ-induced DN in C57 BL/6 male mice

B06 (0.2 mg/kg/day); 6 weeks C66 (0.2, 1, and 5 mg/kg/day); 6 weeks

STZ-induced DN in rats STZ-induced DN in SD rats

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STZ-induced DN in rats

STZ-induced DN in rats

curcumin (100 mg/kg/day); 12 weeks

STZ-induced DN in rats

A

C66(5 mg/kg/day); 3 months

[88]

[112]

[95]

IP T

STZ-induced DN in rats

SC R

Curcumin (50 mg/kg/day); 6 weeks

U

STZ-induced DN in rats

N

Curcumin (150 mg/kg/day, PO); 12 weeks

A

OLETF rats

[83]

[97]

[71]

[102]

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Curcumin (100 mg/kg/day, PO); 45 weeks

-decreased VEGF, TGF-β and ECM proteins including FN and collagen type IV -down-regulation of SREBP-1c and ADRP and acetyl CoA, carboxylase, and fatty acid synthase -hypo-lipidemic and anti-oxidative defense via Nrf2 and AMPK pathways -improves albuminuria, urinary MDA, and urinary SOD linked to Nrf2 signaling -decrease Cr, BUN and albumin levels -suppress of SphK1-S1P-mediated FN and TGF-β1 expression -reduce DNA-binding activity -increased albumin and reduce creatinine and BUN levels -decrease MDA and elevated SOD levels -down-regulation of HSP-27 and p38 histone H3 acetylation enhancement -decrease dephosphorylation -decrease AST, ALT, NAG, and phosphatase levels -up-regulation of ATPases -modulating the glucose-6-phosphatase and lactate dehydrogenase function -improve the HSP25 response -enhanced urinary 12-hydroxy tetraenoic acid overproduction -reduce the albuminuria -decrease of eNOS, TGF-β1, ET-1, and ECM proteins -down-regulation of p300, 8-OHdG, and nitrotyrosine in kidney -reduced NF-kB P65 translocation -decrease the PKC-α and PKC-β1 activation and ERK1/2 phosphorylation -enhance creatinine clearance -decrease proteinuria, BUN, NOX4, and p67 phox levels -down-regulation of CTGF,TGF-β1, p300, and ECM proteins including collagen type IV and FN -decrease VEGF and its receptor -down-regulation of VCAM-1, MCP-1, and ICAM-1 -decrease MAPK activation -decrease expansion of renal adhesion cell, NF-kB activation and macrophage infiltration -inflammatory mediators reduction

[227]

[67]

-up-regulation of inflammatory mediators -reduce TNF-α plasma levels

[68]

-reduced H3K9/14Ac level and p300/CBP -prevent renal injury and dysfunction -decreased JNK activation - down-regulation of cav-1 phosphorylation at Tyr14 -suppression of the TLR4 activity

[70]

[77]

Table 2: List of in vivo studies using curcumin for diabetic retinopathy treatment Dosage

Animal model

outcomes

39

ref

STZ-induced DR in male SD rats

AIN-93 diet (containing 0.002/ 0.01% curcumin or 0.5% Turmeric); 8 weeks Curcumin ( 80 mg/kg IP ); 3 months

STZ-induced DR in male WNIN rats

Curcumin(100 and 200 mg/kg/day); 16 weeks

STZ-induced DR in rat

nanomicelle curcumin; 12 weeks

STZ-induced diabetic mice

STZ-induced DR in Wistar albino rats

-elevated antioxidant defense -decrease retina expression of proinflammatory cytokines (TNF-α, VEGF and ICAM-1) -enhance in capillary basement membrane thickness -inhibit VEGF expression

[137]

[152]

[142]

-decrease the GFAP positive cells in the retinal Muller cells -decrease retinal glutamine and oxidative stress in diabetic retina -restores retinal antioxidant capacity -decrease retina expression of proinflammatory cytokines(TNF-α, VEGF and ICAM-1) - over-expression of Bcl-2 and down-expression of Bax in the retina -reduce enzymatic free radical scavengers -enhanced ROS -reduce mRNA expressions of neurotrophic factors -enhanced mRNA expressions of pro-inflammatory cytokines in the cornea -inhibited the CaMKII/NF-κB activity induced -reduced the VEGF, iNOS and ICAM-1 expression -reduce retinal vascular leakage

[146]

[136]

[165]

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N

STZ-induced DR in male SD rats

[145]

IP T

ABA (30 mg/kg/day) and curcumin (150 mg/kg/day); 6 weeks Curcumin suspension (1 g/kg body weight of rat); 16 weeks

-reduces DNA damage by a decrease of the NF- κB activation -increased antioxidant capacity -reduced levels of DNA (8-OHdG) -induced up-regulation of ERCC1, FN, ERCC4 and PARP and oxidative stress

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STZ-induced DR in Lewis rats

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Powdered diet and curcumin (0.5 g/kg diet); 6 weeks

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Curcumin(0.5% STZ-induced [154] carboxymethyl cellulose at diabetic mice a concentration of 20 mg/ ml and oral gavage at a total dose of 100 mg/kg/day) ; 12 weeks Calcium/calmodulin-dependent protein kinase II (CaMK); diabetic retinopathy (DR); excision repair cross-complementing (ERCC); fibronectin (FN); glial fibrillary acidic protein (GFAP); intracellular adhesion molecule-1 (ICAM); inducible nitric oxide synthase inhibitor (iNOS); Poly (ADP-ribose) polymerases (PARP); reactive oxygen species (ROS); Streptozotocin (STZ); tumor necrosis factor (TNF); vascular epithelial growth factor (VEGF)

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Table 3: List of in vivo studies using curcumin for diabetic neuropathy treatment Dosage Animal model outcomes Curcumin (60 mg/kg PO) STZ-induced DN -reduce in paw licking and tail-withdrawal and Insulin (10 IU/kg SC in rats reflex daily); 4 weeks -reduce nitrite and TNF-α rate Curcumin (200 mg/kg), STZ-induced DN -enhancement of p47 phox and gp91 phox of apocyanin (2.5 mg/kg IP); in rats NADPH oxidase expression, H2O2, MDA 14 consecutive days -reduce SOD levels Curcumin (15, 30, 60 STZ-induced DN -decrease in tail-withdrawal reflex and paw mg/kg PO); 4 weeks in rats licking - reduce nitrite and TNF-α rate curcumin (50 mg/kg/day, STZ-induced -prevents weight loss PO); 3 weeks diabetic rats -decrease mechanical allodynia

40

ref [183]

[209]

[206]

[228]

STZ-induced DN in rats

Curcumin (60 mg/kg ;PO); 12 weeks

STZ-induced DN in rats

SNEDDS curcumin (30,100, 300 mg/kg; PO) ; 2 weeks curcumin (60 mg/kg; PO); 10 week

STZ-induced DN in rats

Oral tetrahydrocurcumin(THC) (80 mg/kg ); 45 days curcumin derivative, J147 (10 or 50 mg/kg ); 20 weeks Curcumin(5, 15 and 45 mg/kg; PO twice a day); 3 weeks nano-curcumin (16 mg/kg); 10 weeks

STZ-induced DN in rat

STZ-induced DN in rat

-improve sensorimotor deficits -enhance C-peptide levels -reduce lipid peroxides, peroxynitrite and TNFα levels -decrease TNF-α and TNF-α receptor in spinal cord -improve paw-withdrawal threshold and pawwithdrawal latency -decrease MDA, IL-6, and TNF-α levels -reduce phosphorylation of IKKb -down-regulation of p65 subunit of NF-κB -reduce nitric oxide, oxidative stress and TNF-α

STZ-induced diabetic rats

-inhibit the mechanical allodynia by activation of delta and mu-opioid receptors

[112]

[185]

[182]

[187]

[177]

SC R

STZ-induced mouse model

-enhance SOD, CAT, GPx, GST activity, and returned GSH to normal level - reduction in the lipid peroxidation markers -blocked TNF-α pathway -activation of the AMPK pathway

[229]

IP T

Gliclazide (10 mg/kg PO) with curcumin (100 mg/kg ; PO); 5 weeks

-inhibited the SGCs activation [212] -reduced CGRP expression -reduced the expression of the P2Y12 receptor on SGCs in the DRG -decrease thermal and mechanical hyperalgesia adenosine monophosphate kinase(AMPK); catalases (CAT); diabetic neuropathy (DN); dorsal root ganglia (DRG) ; calcitonin gene related peptide (CGRP); glutathione peroxidase (GPx); glutathione (GSH); glutathione S-transferase (GST); intraperoneally (IP); malondialdehyde (MDA); nicotinamide adenine dinucleotide phosphate (NADPH); orally (PO); satellite glial cells (SGC); superoxide dismutase (SOD); Streptozotocin (STZ); tumor necrosis factor (TNF).

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STZ-induced diabetic rats

[205]

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