Metformin attenuated histopathological ocular deteriorations in a streptozotocin-induced hyperglycemic rat model

Nahar, Nazmun; Mohamed, Suhaila; Noordin, M. M.; Lau, Seng Fong; Ishak, Nur Iliyani Mohd; Umran, Norshahira Solehah

doi:10.1007/s00210-020-01989-w

Cited by 19 publications

(16 citation statements)

References 33 publications

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“…S4 F), which was inconsistent with other studies. 42 , 43 After 2-month metformin gavage, the morphology of the MG was relatively well-maintained ( Figs. 6 E, 6 F), and the acini of rats applied Met for 2 months (the Met4M group) displayed normal structure as the normal control (NT4M) group ( Fig.…”

Section: Resultsmentioning

confidence: 97%

Hyperglycemia Induces Meibomian Gland Dysfunction

Guo

Zhang

Zhao

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose Patients diagnosed with diabetes are inclined to have abnormalities on stability of tear film and disorder of meibomian gland (MG). This study aims to explore the pathological change of MG induced by diabetes in a rat model. Methods Sprague-Dawley (SD) rats were intraperitoneally injected with streptozotocin (STZ) to establish a diabetic animal model. Lipid accumulation in MG was detected by Oil Red O staining and LipidTox staining. Cell proliferation status was determined by Ki67 and P63 immunostaining, whereas cell apoptosis was confirmed by TUNEL assay. Gene expression of inflammatory cytokines and adhesion molecules IL-1α, IL-1β, ELAM1, ICAM1, and VCAM1 were detected by RT-PCR. Activation of ERK, NF-κB, and AMPK signaling pathways was determined by Western Blot analysis. Oxidative stress-related factors NOX4, 4HNE, Nrf2, HO-1, and SOD2 were detected by immunostaining or Western Blot analysis. Tom20 and Tim23 immunostaining and transmission electron microscopy were performed to evaluate the mitochondria functional and structure change. Results Four months after STZ injection, there was acini dropout in MG of diabetic rats. Evident infiltration of inflammatory cells, increased expression of inflammatory factors, and adhesion molecules, as well as activated ERK and NF-κB signaling pathways were identified. Oxidative stress of MG was evident in 4-month diabetic rats. Phospho-AMPK was downregulated in MG of 2-month diabetic rats and more prominent in 4-month rats. After metformin treatment, phospho-AMPK was upregulated and the morphology of MG was well maintained. Moreover, inflammation and oxidative stress of MG were alleviated after metformin intervention. Conclusions Long-term diabetes may lead to Meibomian gland dysfunction (MGD). AMPK may be a therapeutic target of MGD induced by diabetes.

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Section: Resultsmentioning

confidence: 97%

Hyperglycemia Induces Meibomian Gland Dysfunction

Guo

Zhang

Zhao

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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“…LP was given daily through oral gavage, for 10 weeks, beginning 2 weeks after diabetes induction. FBG and BWs were monitored fortnightly via tail prick (Accu Check Performa glucometer, USA) (Nahar et al, 2020).…”

Section: Diabetes Induction With Streptozotocin (Stz) and Treatmentsmentioning

confidence: 99%

“…After 20 min, ophthalmoscopy was performed using the retinal slit-lamp. Diabetic retinopathy (DR) was classified according to the microvascular degeneration level and related ischemic damage (Wilkinson et al, 2003) namely: 0 (no retinopathy); (1) mild non-proliferative diabetic retinopathy (NPDR); microaneurysms in the retina; (2) moderate NPDR; (3) severe NPDR (>20 intraretinal hemorrhages in each quadrant, venous beading in at least two quadrants; (4) intraretinal microvascular abnormalities (IRMA) in one quadrant or more in the absence of proliferative diabetic retinopathy (PDR); (5) PDR, that is, neovascularizations and vitreous/preretinal hemorrhage) (Nahar et al, 2020).…”

Section: Ocular Ophthalmoscopy Observationsmentioning

confidence: 99%

“…Blood was collected and was coagulated for 2 hr at room temperature before centrifuging at 1,000g for 15 min at 4℃ for the serum. Rats' serum MDA, GSH, VEGF, PGE2, TNFα, and claudin-1 levels were measured by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions (Nahar et al, 2020). The TNFα, VEGF, MDA, PGE2, and claudin-1 antibodies from rats were pre-coated on ELISA plates for competitive ELISA testing.…”

Section: Elisa Analysismentioning

confidence: 99%

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Gallic acid and myricetin‐rich Labisia pumila extract mitigated multiple diabetic eye disorders in rats

et al. 2021

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Diabetes affected about a quarter of a billion people globally, and one out of four diabetics has eye or vision problems. This study investigated whether gallic acid and myricetin-rich Labisia pumila extract (LP) consumption would help prevent diabetic eye disorders and some probable biochemistry involved relating to inflammation, vascular leakage, and oxidative tension. Male rats were divided into four groups (n = 6), namely healthy control, diabetic non-treated control, and hyperglycemic rats treated with 150 or 300 mg/kg LP. Intraperitoneal injection of 60 mg/kg streptozotocin was used to induce diabetes. Rats were fed in the morning and evening. Diabetic retinopathy was graded in rats using a dilated retinal digital ophthalmoscopy. Rats were sacrificed at 12 weeks and the retina, optic nerve, cornea, lens, sclera, ciliary bodies, iris, and conjunctiva were examined histologically. The diabetic rats consuming LP for 10 weeks showed dose-dependent, histopathologically-reduced eye abnormalities (keratopathy, cataract, sclera, conjunctiva, ciliary bodies, iris, limbus, corneal edema, epithelial barrier inefficiency, shallow punctate keratitis, lower basal layer cell density, retinopathy, glaucoma, and corneal changes). The LP significantly suppressed inflammation [increased serum tumor necrosis factorα (TNFα), prostaglandin-E2 (PGE2)], vascular leakage [claudin-1], abnormal vascularization [vascular endothelial growth factor (VEGF)], oxidative tension [malondialdehyde/reduced glutathione ratio], and hyperglycemia [fasting blood glucose] of the diabetic rats. The LP consumption was significantly protective against diabetic eye disorders and optic nerve dysfunction which were related to inflammation, vascular leakage, abnormal vascularization, and oxidative tension, which most likely influenced eye hemorrhage and collagen cross-linkage. Practical applicationsThe study shows that gallic acid and myricetin-rich Labisia pumila (LP) leaf consumption may be used as a complementary therapy for managing diabetes (fasting blood glucose) and preventing diabetic eye disorders (keratopathy, cataract, sclera, conjunctiva, ciliary bodies, iris, limbus, corneal edema, epithelial barrier inefficiency, shallow punctate keratitis, lower basal layer cell density, retinopathy, glaucoma, and corneal abnormalities). The LP consumptions reduced the serum biomarkers for inflammation (serum tumor necrosis factorα TNFα; prostaglandin-E2), vascular

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“…In the visual system, metformin exerts inhibitory effects on inflammatory responses [ 7 ] and angiogenesis [ 7 , 8 ], as well as vasodilatory effects on the retinal blood vessels [ 9 ]. Furthermore, metformin protects against retinal neuronal damage in diabetic animals [ 10 , 11 ] and maintains the integrity of the photoreceptors and retinal pigment epithelium, through the activation of AMPK, in animal models of retinitis pigmentosa and age-related macular degeneration [ 12 , 13 ]. Similarly, AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside), an activator of AMPK, attenuates diabetes-induced retinal inflammation [ 7 , 14 ] and dilates retinal blood vessels [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats

Watanabe

Asano

Ushikubo

et al. 2021

IJMS

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Metformin, an anti-hyperglycemic drug of the biguanide class, exerts positive effects in several non-diabetes-related diseases. In this study, we aimed to examine the protective effects of metformin against N-methyl-D-aspartic acid (NMDA)-induced excitotoxic retinal damage in rats and determine the mechanisms of its protective effects. Male Sprague–Dawley rats (7 to 9 weeks old) were used in this study. Following intravitreal injection of NMDA (200 nmol/eye), the number of neuronal cells in the ganglion cell layer and parvalbumin-positive amacrine cells decreased, whereas the number of CD45-positive leukocytes and Iba1-positive microglia increased. Metformin attenuated these NMDA-induced responses. The neuroprotective effect of metformin was abolished by compound C, an inhibitor of AMP-activated protein kinase (AMPK). The AMPK activator, AICAR, exerted a neuroprotective effect in NMDA-induced retinal injury. The MEK1/2 inhibitor, U0126, reduced the neuroprotective effect of metformin. These results suggest that metformin protects against NMDA-induced retinal neurotoxicity through activation of the AMPK and MEK/extracellular signal-regulated kinase (ERK) signaling pathways. This neuroprotective effect could be partially attributable to the inhibitory effects on inflammatory responses.

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Metformin attenuated histopathological ocular deteriorations in a streptozotocin-induced hyperglycemic rat model

Cited by 19 publications

References 33 publications

Hyperglycemia Induces Meibomian Gland Dysfunction

Hyperglycemia Induces Meibomian Gland Dysfunction

Gallic acid and myricetin‐rich Labisia pumila extract mitigated multiple diabetic eye disorders in rats

Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats

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