Topiramate Normalizes Hippocampal NPY-LI in Flinders Sensitive Line ‘Depressed’ Rats and Upregulates NPY, Galanin, and CRH-LI in the Hypothalamus: Implications for Mood-Stabilizing and Weight Loss-Inducing Effects

Husum, Henriette; Kammen, Daniel van; Termeer, Evelien; Bolwig, Tom G.; Mathé, Aleksander A.

doi:10.1038/sj.npp.1300178

Cited by 81 publications

(45 citation statements)

References 64 publications

(84 reference statements)

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“…Topiramate has been shown to have hypothalamic effects, which could explain the reduction in appetite also recently shown in other clinical trials including diabetic patients. 19,20 The weight loss seen in the topiramate-treated group can, at least partly, explain the improved blood glucose control in these patients, although the magnitude of improvement seems considerably greater than expected for a 6.6% reduction in body weight. Animal studies indicate that the anti-hyperglycaemic effect of topiramate is independent of its effect on energy intake and/or body weight loss.…”

Section: Discussionmentioning

confidence: 90%

Weight loss and metabolic effects of topiramate in overweight and obese type 2 diabetic patients: randomized double-blind placebo-controlled trial

et al. 2007

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Objective: To examine the metabolic effects and body composition changes after topiramate treatment of obese type 2 diabetic patients (DM2) for 11 months. Design and subjects: Thirty-eight DM2 on diet or sulfonylurea treatment participated in this randomized double-blind placebocontrolled trial. Thirteen placebo-treated and nine topiramate-treated patients completed the trial. Patients were randomized to treatment with topiramate 96 mg b.i.d. or placebo (6-week run-in phase, 2-months titration phase, 9-months maintenance phase). Measurements: Insulin sensitivity was measured with euglycaemic hyperinsulinemic clamps. Weight, HbA1c, fasting glucose, blood lipids and safety variables were measured at regular intervals. Body composition was determined with computerized tomography. Meal tests were performed to evaluate postprandial glucose and insulin levels. Three-day diet recalls were carried out to evaluate energy ingestion. Results: The mean age was 58.677.1 years, body weight 98.1716.1 kg, BMI 33.074.5 kg/m 2 , and glycosylated hemoglobin (HbA1c) 7.370.9%. In topiramate-treated patients, there were significant reductions in HbA1c (1.170.9%), fasting plasma glucose, body weight (À6.673.3%), as well as body fat, lean body mass, postprandial glucose and free fatty acid levels but there were no significant changes in insulin sensitivity. The daily average energy intake decreased more in the topiramate group than in the placebo group. Paresthesia and central nervous system-related side effects were the main causes for the dropout rate. Conclusions: Topiramate treatment of overweight DM2 reduced body weight and body fat, and was associated with a marked improvement in glycaemic control whereas no significant improvement in insulin-stimulated glucose uptake was demonstrated. Further studies are required to clarify whether this effect might occur through changes in insulin sensitivity in the liver and/or pancreatic insulin secretion.

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Section: Discussionmentioning

confidence: 90%

Weight loss and metabolic effects of topiramate in overweight and obese type 2 diabetic patients: randomized double-blind placebo-controlled trial

et al. 2007

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“…Animal studies suggest that central action may potentially reduce appetite and/or food intake (17,18). Studies in rodent models suggest that topiramate may also affect energy utilization, possibly due to stimulation of lipoprotein lipase in adipose tissue and skeletal muscle (19).…”

Section: Topiramate In Obese Diabetic Patientsmentioning

confidence: 99%

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Assess the Efficacy and Safety of Topiramate Controlled Release in the Treatment of Obese Type 2 Diabetic Patients

Rosenstock

Hollander²,

Gadde³

et al. 2007

Diabetes Care

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FOR THE OBD-202 STUDY GROUPOBJECTIVE -This is a randomized, placebo-controlled study of the weight-loss efficacy and safety of a controlled-release (CR) formulation of topiramate in overweight and obese patients with type 2 diabetes treated with diet and exercise alone or in combination with metformin.RESEARCH DESIGN AND METHODS -Patients with type 2 diabetes, BMI Ն27 kg/m 2 , A1C Ͼ6.5 and Ͻ11.0%, treated with diet and exercise alone or in combination with metformin monotherapy were enrolled. Patients were randomized to placebo or topiramate CR titrated up to 175 mg/day. Treatment consisted of a 7-week titration phase followed by a 9-week maintenance phase.RESULTS -A total of 111 subjects were randomized and analyzed. By the end of week 16, patients in the placebo and topiramate groups lost 2.5 and 6.0 kg, which represented 2.3 and 5.8%, respectively, of their baseline body weight (P Ͻ 0.001 vs. placebo). A1C improved from a baseline of 7.4% in the placebo and 7.6% in the topiramate groups to 7.1 and 6.7%, respectively, representing a 0.4 and 0.9% reduction from baseline, respectively (P Ͻ 0.001 vs. placebo). Topiramate also significantly reduced blood pressure and urinary albumin excretion. Adverse events were predominantly neuropsychiatric or central and peripheral nervous system related.CONCLUSIONS -Topiramate CR treatment produced significant weight loss and meaningful improvements in A1C and blood pressure in obese patients with type 2 diabetes treated with diet and exercise or in combination with metformin. However, the central nervous system and psychiatric adverse event profile of topiramate CR makes it unsuitable for the treatment of obesity and diabetes.

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“…It is worth noting that drug withdrawal often precipitates symptoms of depression, and depression is a commonly observed withdrawal symptom in humans (17,18). In addition, decreased galanin expression in DRN, hippocampus, and hypothalamus have been observed in rat models of depression (19)(20)(21), and a recent clinical study reported preliminary evidence for an acute antidepressant effect of galanin (i.v.) in depressed patients (22), whereas a few early microdialysis and behavioral studies in rodents suggested depressive actions of galanin (6,8,23,24).…”

mentioning

confidence: 99%

A role for galanin in antidepressant actions with a focus on the dorsal raphe nucleus

Lü

Barr²,

Kinney³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

120

131

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Selective serotonin reuptake inhibitors, such as fluoxetine (FLX), are the most commonly used drugs in the treatment of major depression. However, there is a limited understanding of their molecular mechanism of action. Although the acute effect of selective serotonin reuptake inhibitors in elevating synaptic serotonin concentrations is well known, the clinical amelioration of depressive symptoms requires 14 -21 days of treatment, suggesting that numerous other rearrangements of function in the CNS must take place. In the present study, we demonstrated that 14 days of FLX treatment up-regulated galanin mRNA levels by 100% and GalR2-binding sites by 50%, in the rat dorsal raphe nucleus, where galanin coexists with serotonin. Furthermore, a galanin receptor antagonist, M40, attenuated the antidepressant-like effect of FLX in the forced swim test, a rodent preclinical screen commonly used to evaluate antidepressant-like efficacy. Direct activation of galanin receptors by a galanin receptor agonist, galnon, was found to produce an antidepressant-like effect in the same task. Two other antidepressant treatments also affected the galaninergic system in the monoaminergic nuclei: Electroconvulsive shock elevated galanin mRNA levels in dorsal raphe nucleus, whereas sleep deprivation increased galanin mRNA levels in the locus coeruleus, further underlining the connection between activation of the galaninergic system and antidepressant action of various clinically proven treatments. O ur understanding of the molecular mechanism of action of fluoxetine (FLX), beyond its effect of elevating synaptic serotonin [5-hydroxytryptamine (5-HT)] concentration, is limited. The delay in the onset of clinical antidepressant effect suggests that transcriptional and translational events, leading to functional changes in signaling within the major serotoninergic nucleus dorsal raphe nucleus (DRN) and in its projection areas, may be required for these therapeutic effects (1-3). One potential player in mediating the long-term effects of FLX, besides 5-HT, is the neuropeptide galanin. Galanin, through its three G-protein-coupled receptors, GalR1, GalR2, and GalR3 (4), regulates homeostatic and motivated behaviors including pain perception, sleep, food intake, sexual activity, learning, and memory (5). Galaninergic transmission modulates the activity of monoaminergic neurons in the ventral tegmental area, DRN, and locus coeruleus (LC) (6-10). Galanin receptor subtypes GalR1 (7) and GalR2 are expressed in DRN neurons (11) that can be activated by galanin dendritically released from the dorsal raphe 5-HT neurons (9, 12) or from surrounding galanin immunoreactive terminals (7). In the noradrenergic nucleus LC, an area that is closely connected both structurally and functionally to DRN (13,14), GalR1 expression is induced by morphine withdrawal (15), and the galanin receptor agonist, galnon, was shown to attenuate several withdrawal signs (16). It is worth noting that drug withdrawal often precipitates symptoms of depression, and depression is a ...

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Topiramate Normalizes Hippocampal NPY-LI in Flinders Sensitive Line ‘Depressed’ Rats and Upregulates NPY, Galanin, and CRH-LI in the Hypothalamus: Implications for Mood-Stabilizing and Weight Loss-Inducing Effects

Cited by 81 publications

References 64 publications

Weight loss and metabolic effects of topiramate in overweight and obese type 2 diabetic patients: randomized double-blind placebo-controlled trial

Weight loss and metabolic effects of topiramate in overweight and obese type 2 diabetic patients: randomized double-blind placebo-controlled trial

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Assess the Efficacy and Safety of Topiramate Controlled Release in the Treatment of Obese Type 2 Diabetic Patients

A role for galanin in antidepressant actions with a focus on the dorsal raphe nucleus

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