topiramate and Hyperglycemia

Wound healing is severely affected in hyperglycemia and other metabolic conditions. Finding new therapeutic approaches that accelerate wound healing and improve the quality of the scar may reduce the morbidity commonly associated with skin lesions in diabetes. This study evaluated the effect of topical topiramate (TPM) on wound healing in C57 mice. Streptozotocin-induced hyperglycemic mice were subjected to a wound on the back and randomly allocated for treatment with either vehicle or topical TPM cream (2%) once a day for 14 days. Polymerase chain reaction, Western blotting, and microscopy were performed for the analysis. TPM improved wound healing (complete resolution at Day 10, 98% ± 5 for TPM vs. 81% ± 28 for vehicle), increased organization and deposition of collagen Type I, and enhanced the quality of the scars as determined by microscopy. In addition, TPM modulated the expression of cytokines and proteins of the insulin-signaling pathway: In early wound-healing stages, expression of interleukin-10, an anti-inflammatory marker, increased, whereas at the late phase, the pro-inflammatory markers tumor necrosis factor-α and monocyte chemoattractant protein-1 increased and there was increased expression of a vascular endothelial growth factor. Proteins of the insulin-signaling pathway were stimulated in the late wound-healing phase. Topical TPM improves the quality of wound healing in an animal model of hyperglycemia. The effect of TPM is accompanied by modulation of inflammatory and growth factors and proteins of the insulin-signaling pathway. Therefore, topical TPM presents as a potential therapeutic agent in skin wounds in patients with hyperglycemia.

Topics: Animals; Disease Models, Animal; Hyperglycemia; Hypoglycemic Agents; Mice; Random Allocation; Skin; Topiramate; Wound Healing

Hyperglycemia-induced oxidative stress leads to diabetes-associated damage to the microvasculature of the brain. Pericytes in close proximity to endothelial cells in the brain microvessels are vital to the integrity of the blood-brain barrier and are especially susceptible to oxidative stress. According to our recently published results, streptozotocin-diabetic mouse brain exhibits oxidative stress and loose pericytes by twelve weeks of diabetes, and cerebral pericytes cultured in high glucose media suffer intracellular oxidative stress and apoptosis. Oxidative stress in diabetes is hypothesized to be caused by reactive oxygen species (ROS) produced during hyperglycemia-induced enhanced oxidative metabolism of glucose (respiration). To test this hypothesis, we investigated the effect of high glucose on respiration rate and ROS production in mouse cerebral pericytes. Previously, we showed that pharmacological inhibition of mitochondrial carbonic anhydrases protects the brain from oxidative stress and pericyte loss. The high glucose-induced intracellular oxidative stress and apoptosis of pericytes in culture were also reversed by inhibition of mitochondrial carbonic anhydrases. Therefore, we extended our current study to determine the effect of these inhibitors on high glucose-induced increases in pericyte respiration and ROS. We now report that both the respiration and ROS are significantly increased in pericytes challenged with high glucose. Furthermore, inhibition of mitochondrial carbonic anhydrases significantly slowed down both the rate of respiration and ROS production. These data provide new evidence that pharmacological inhibitors of mitochondrial carbonic anhydrases, already in clinical use, may prove beneficial in protecting the brain from oxidative stress caused by ROS produced as a consequence of hyperglycemia-induced enhanced respiration.

Topics: Animals; Blood-Brain Barrier; Carbonic Anhydrase Inhibitors; Cell Respiration; Cells, Cultured; Diabetes Mellitus, Experimental; Ethoxzolamide; Fructose; Glucose; Hyperglycemia; Mice; Mitochondria; Oxidative Stress; Pericytes; Reactive Oxygen Species; Topiramate

Diabetes mellitus causes cerebral microvasculature deterioration and cognitive decline. The specialized endothelial cells of cerebral microvasculature comprise the blood-brain barrier, and the pericytes (PC) that are in immediate contact with these endothelial cells are vital for blood-brain barrier integrity. In diabetes, increased mitochondrial oxidative stress is implicated as a mechanism for hyperglycemia-induced PC loss as a prerequisite leading to blood-brain barrier disruption. Mitochondrial carbonic anhydrases (CA) regulate the oxidative metabolism of glucose and thus play an important role in the generation of reactive oxygen species and oxidative stress. We hypothesize that the inhibition of mitochondrial CA would reduce mitochondrial oxidative stress, rescue cerebral PC loss caused by diabetes-induced oxidative stress, and preserve blood-brain barrier integrity. We studied the effects of pharmacological inhibition of mitochondrial CA activity on streptozotocin-diabetes-induced oxidative stress and PC loss in the mouse brain. At 3 wk of diabetes, there was significant oxidative stress; the levels of reduced glutathione were lower and those of 3-nitrotyrosine, 4-hydroxy-2-trans-nonenal, and superoxide dismutase were higher. Treatment of diabetic mice with topiramate, a potent mitochondrial CA inhibitor, prevented the oxidative stress caused by 3 wk of diabetes. A significant decline in cerebral PC numbers, at 12 wk of diabetes, was also rescued by topiramate treatment. These results provide the first evidence that inhibition of mitochondrial CA activity reduces diabetes-induced oxidative stress in the mouse brain and rescues cerebral PC dropout. Thus, mitochondrial CA may provide a new therapeutic target for oxidative stress related illnesses of the central nervous system.

Topics: Animals; Blood-Brain Barrier; Brain; Carbonic Anhydrase Inhibitors; Carbonic Anhydrase V; Cells, Cultured; Diabetes Mellitus, Experimental; Endothelial Cells; Fructose; Hyperglycemia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Oxidative Stress; Pericytes; Topiramate

Topiramate (TPM) is a novel neurotherapeutic agent. Clinical studies reported that TPM treatment reduced body weight and decreased fasting blood glucose levels in obese patients with or without type 2 diabetes. It is unclear whether the blood glucose-normalizing phenomenon observed during TPM treatment is a primary effect or the consequence of reduced food intake and weight loss. In the present studies, we chronically treated female Zucker diabetic fatty (ZDF) rats (fed with a diabetogenic diet) and db/db mice with TPM (30-300 mg/kg/day) to examine the effect of TPM on hyperglycaemia and its relationship with food intake and body weight gain. Our data showed that TPM treatment markedly reduced blood glucose levels in both ZDF rats and db/db mice without a significant reduction in body weight gain. Pair-fed db/db mice treated with the vehicle alone did not exhibit a significant decrease in blood glucose levels compared with mice fed ad libitum. TPM treatment increased glucose-stimulated insulin release by 2-3-fold during an oral glucose tolerance test in both ZDF rats and db/db mice. We also observed a 1.4-fold increase of pancreatic insulin content and heightened insulin immunostaining in pancreatic beta cells in db/db mice treated with TPM. Our data suggest that the antidiabetic effect of TPM is independent of the changes in body weight gain and food intake. Improved glucose-induced insulin release may, in part, underlie the mechanisms by which TPM ameliorates the hyperglycaemia.

Topics: Abdomen; Adipose Tissue; Animals; Blood Glucose; Eating; Female; Fructose; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Insulin; Islets of Langerhans; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Pancreas; Rats; Rats, Zucker; Topiramate; Triglycerides; Weight Gain

Topiramate is an antiepileptic agent, which is being investigated as a mood-stabilizer. Three obese individuals with DSM-IV bipolar I disorder and type II diabetes mellitus received topiramate treatment in combination with antipsychotics and valproate or carbamazepine. In addition to improved mood stability, these individuals lost between 16 to 20.5% of their pre-topiramate body weight and also achieved significant glycemic control.

Topics: Adult; Anticonvulsants; Bipolar Disorder; Body Mass Index; Diabetes Mellitus, Type 2; Female; Fructose; Humans; Hyperglycemia; Male; Middle Aged; Obesity; Time; Topiramate; Weight Loss