Evaluation of Neonatal Streptozotocin Induced Diabetic Rat Model for the Development of Cataract

Type 2 diabetes (T2D) generally follows prediabetes (PD) conditions such as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). Although studies reported an association of IGT or IFG with cataract, the experimental basis for PD associated cataract is not known. Hence, we evaluated neonatal streptozotocin (nSTZ) induced rat model to study PD associated cataractogenesis by injecting STZ to two-day old rats. While majority (70%) of nSTZ injected pups developed IGT (nSTZ-PD) by two months but not cataract even after seven months, remaining (30%) nSTZ rats developed hyperglycemia (nSTZ-D) by two months and mature cataract by seven months. Lens biochemical analysis indicated increased oxidative stress as indicated by increased SOD activity, lipid peroxidation, and protein carbonyl levels in nSTZ-D cataractous lens. There was also increased polyol pathway as assessed by aldose reductase activity and sorbitol levels. Though nSTZ-PD animals have not shown any signs of lenticular opacity, insolubilization of proteins along with enhanced polyol pathway was observed in the lens. Further there was increased oxidative stress in lens of IGT animals. These results suggest that oxidative stress along with increased polyol pathway might play a role in IGT-associated lens abnormalities. In conclusion, nSTZ-PD rat model could aid to investigate IGT-associated lens abnormalities

Insulin resistance mediated biochemical alterations in eye lens of neonatal streptozotocin-induced diabetic rat

749-755Cataract, the leading cause of blindness worldwide, is associated with many risk factors including diabetes. Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) states are associated with pre-diabetes and insulin resistance. This condition subsequently leads to the development of type-2 diabetes. Epidemiological studies indicated that not only diabetes but IGT/IFG will also lead to the development of microvascular disorders and cataract. However, there are no studies on the mechanism of insulin resistance induced changes in the eye lens. In the present study, IGT/IFG-induced changes in lens using neonatal-streptozotocin (nSTZ) rat model have been investigated. Though, nSTZ rats showed the signs of IGT and insulin resistance starting from two months old, they did not develop cataract even at the age of 8-months. However, biochemical analysis indicates a three-fold increase in sorbitol levels in nSTZ lens upon prolonged (6-months) IGT and insulin resistance. Also there was an increase in lipid peroxidation and alterations in antioxidant enzymes. Results of this study showed that activation of polyol pathway and increased oxidative stress, commonly associated with long-term complications of diabetes, have been observed in eye lens due to prolonged IGT and insulin resistance which may lead to cataract

Efficacy of biodegradable curcumin nanoparticles in delaying cataract in diabetic rat model

Curcumin, the active principle present in the yellow spice turmeric, has been shown to exhibit various pharmacological actions such as antioxidant, anti-inflammatory, antimicrobial, and anti-carcinogenic activities. Previously we have reported that dietary curcumin delays diabetes-induced cataract in rats. However, low peroral bioavailability is a major limiting factor for the success of clinical utilization of curcumin. In this study, we have administered curcumin encapsulated nanoparticles in streptozotocin (STZ) induced diabetic cataract model. Oral administration of 2 mg/day nanocurcumin was significantly more effective than curcumin in delaying diabetic cataracts in rats. The significant delay in progression of diabetic cataract by nanocurcumin is attributed to its ability to intervene the biochemical pathways of disease progression such as protein insolubilization, polyol pathway, protein glycation, crystallin distribution and oxidative stress. The enhanced performance of nanocurcumin can be attributed probably to its improved oral bioavailability. Together, the results of the present study demonstrate the potential of nanocurcumin in managing diabetic cataract

Brain Distribution and Metabolism of Flupirtine, a Nonopioid Analgesic Drug with Antiseizure Effects, in Neonatal Rats

Flupirtine, a nonopioid analgesic drug, is effective in treating neonatal seizures. However, its brain delivery and pharmacokinetics are unknown in neonatal mammals. The purpose of this study was to determine the pharmacokinetics of flupirtine and the formation of its active metabolite D-13223 in various tissues such as brain in neonate animals. On postnatal day 7, rat pups received 25 mg/kg of flupirtine intraperitoneally. Liver; heart; kidney; lung; spleen; retina; serum; and brain regions hippocampus, cortex, and the remaining brain (devoid of cerebellum) were harvested up to 24-h postdosing. An LC-MS/MS assay was developed to quantify flupirtine and D-13223. Flupirtine was delivered to all tissues assessed, with the highest area under the concentration vs. time curve (AUC0⁻24h) in liver (488 µg·h/g tissue) and the lowest in spleen (82 µg·h/g tissue). Flupirtine reached the brain, including the hippocampus and cortex, within 1 h of dosing and persisted at 24 h. Flupirtine AUC in various brain regions was approximately 195 µg·h/g tissue. The half-life of flupirtine in various tissues ranged from 3.1 to 5.2 h. D-13223 was formed in vivo and detected in all tissues assessed, with the concentrations being the highest in the liver. Incubation of isolated neonatal rat liver, heart, kidney, lung, spleen, whole eye, serum, or whole brain with flupirtine for 3 h at 37 °C formed D-13223 in all tissues, except serum. D-13223 formation was the highest in isolated liver tissue. Tissue partition coefficients based on isolated tissue uptake correlated well with in vivo tissue:serum drug exposure ratios. Thus, flupirtine reaches the target brain tissues from the systemic route in neonatal rats, and brain tissue forms the active metabolite D-13223

The effect of curcumin and nanocurcumin on blood glucose (Panel A) and insulin levels (Panel B) in STZ-treated rats.

<p>Data are average of all the animals in a given group. Different superscripts in Panel B indicate data are significantly different from other groups.</p

The effect of curcumin and nanocurcumin on crystallin distribution in the soluble protein fraction of rat lens.

<p>Soluble protein was loaded on TSK-G3000 SWXL gel filtration HPLC column and protein peaks were detected at 280 nm. Peaks representing α-, β- and γ- crystallins are indicated at their respective positions.</p

Particle characteristics measured by Malvern zeta sizer fresh (A) after centrifugation (B) and after freeze drying (C).

<p>The numbers in parenthesis are average particle size in nm.</p

Immunodetection of advanced glycation endproducts, CML (Panel A) and AGE-BSA (Panel B), in the soluble protein fraction of rat lens.

<p>The data in bar diagram are mean ± SD (n=3) and the blot is a representative of three independent analyses. <i>Lane 1</i>: control; lane <i>2</i>: diabetic (D); lane <i>3</i>: D + curcumin; lane <i>4</i>: D + nanocurcumin and lane <i>5</i>: D + blank particles. Different superscripts indicate data are significantly different from other groups.</p