Effect of topiramate on body weight and body composition of osborne-mendel rats fed a high-fat diet: alterations in hormones, neuropeptide, and uncoupling-protein mRNAs

York, David A.; Singer, Lori; Thomas, S; Bray, George A.

doi:10.1016/s0899-9007(00)00451-2

Cited by 92 publications

(62 citation statements)

References 17 publications

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“…Interestingly, topiramate further increased CRH-LI and NPY-LI in the hypothalamus of both FSL and FRL animals. These findings are in agreement with a previous study in which hypothalamic NPY and CRH mRNA levels were increased by topiramate (York et al, 2000). Consistently with these findings, we have shown that early life stressinduced increase in hypothalamic NPY-LI levels is potentiated by lithium which however did not affect elevated CRH-LI levels in adult rats .…”

Section: Discussionsupporting

confidence: 93%

“…Single but not repeated injections of topiramate reduced leptin in FRL rats, which became similar to levels in FSL, while topiramate had no effect on leptin levels in FSL rats. This is perhaps not surprising given the observation that topiramate affects food intake selectively in obesity-prone rats and only during the first 1-4 days of treatment (York et al, 2000). As also shown in the present study, a feature of the FSL rats is that they weigh less than FRL rats, likely reflecting a lower body fat mass, which could account for the lower leptin levels that were found in FSL rats.…”

Section: Discussionsupporting

confidence: 81%

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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

Husum

Kammen

Termeer

et al. 2003

Neuropsychopharmacol

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Topiramate is currently used in the treatment of epilepsy, but this anticonvulsant drug has also been reported to exert mood-stabilizing effects and induce weight loss in patients. Neuropeptide Y (NPY) is abundantly and widely distributed in the mammalian central nervous system and centrally administered NPY markedly reduces pharmacologically induced seizures and induces antidepressant-like activity as well as feeding behavior. Two other peptides, galanin and corticotropin-releasing hormone (CRH), have also been proposed to play a modulatory role in mood, appetite, and seizure regulation. Consequently, we investigated the effects of single and repeated topiramate (10 days, once daily: 40 mg/kg i.p.) or vehicle treatment in 'depressed' flinders sensitive line (FSL) and control Flinders resistant line (FRL) rats on brain regional peptide concentrations of NPY, galanin, and CRH. The handling associated with repeated injections reduced hippocampal levels of NPY-and galanin-like immunoreactivities (LI) while NPY-and CRH-LI levels were increased in the hypothalamus, regardless of strain or treatment. In the hippocampus, concentrations of NPY-LI, galanin-LI, and CRH-LI were lower in FSL than FRL animals. Repeated topiramate treatment selectively normalized NPY-LI in this region in the FSL animals. In the hypothalamus, galanin-LI was reduced in FSL compared to FRL animals. Topiramate elevated the hypothalamic concentrations of NPY-LI, CRH-LI, and galanin-LI in both strains. Furthermore, topiramate elevated serum leptin but not corticosterone levels. The present findings show that topiramate has distinct effects on abnormal hippocampal levels of NPY, with possible implications for its anticonvulsant and mood-stabilizing effects. Furthermore, stimulating hypothalamic NPY-LI, CRH-LI and galanin-LI as well as serum leptin levels may be associated with the weight loss-inducing effects of topiramate.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 81%

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

Kammen

Termeer

et al. 2003

Neuropsychopharmacol

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“…Despite achieving a therapeutically relevant plasma topiramate level of 18.1 mM after chronic treatment, and a decrease in body weight and serum leptin as reported by others, 160 topiramate did not alter cPLA 2 expression or any of the measured enzymes in the AA cascade, nor did it alter the turnover of AA or DHA in brain phospholipids of the unanesthetized rat. 161,162 Supporting our negative findings, the results of four recent double-blind placebo-controlled trials demonstrate that topiramate is not an effective antibipolar drug, 163 a finding that was predicted by the AA models.…”

Section: Observations Related To Aa In Bipolar Disorder Patientsmentioning

confidence: 48%

Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

et al. 2008

Mol Psychiatry

109

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Bipolar disorder is a major medical, social and economic burden worldwide. However, the mechanisms of action of effective antibipolar disorder drugs remain elusive. In this paper, we review studies using a neuropharmacological approach in unanesthetized rats, combined with kinetic, biochemical and molecular biology techniques, showing that chronic administration of three Food and Drug Administration-approved mood stabilizers (lithium, valproate and carbamazepine) at therapeutically relevant doses, selectively target the brain arachidonic acid (AA) cascade. Whereas chronic lithium and carbamazepine decrease the binding activity of activator protein-2 and in turn the transcription, translation and activity of its AA-selective calcium-dependent phospholipase A 2 gene product, valproate appears to be a non-competitive inhibitor of long-chain acyl-CoA synthetase. The net overlapping effects of the three drugs are decreased turnover of AA but not of docosahexaenoic acid in rat brain phospholipids, and decreased brain cyclooxygenase-2 and prostaglandin E 2 . Although these observations support the hypothesis proposed by Rapoport and colleagues that the AA cascade is a common target of mood stabilizers, this hypothesis is not necessarily exclusive of other targets. Targeting the AA cascade with drugs or diet may be a useful therapeutic approach in bipolar disorder, and examining the AA cascade in patients might help in better understanding the disease.

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“…30 The mechanism by which topiramate induces weight loss has not completely been elucidated. In a variety of animal models, [31][32][33] topiramate reduced both appetite and interfered with the efficiency of energy utilization. The effect on efficiency of energy utilization may reflect topiramate's ability to stimulate lipoprotein lipase activity in brown adipose tissue and skeletal muscle, 19,33 thus potentially increasing thermogenesis and substrate oxidation.…”

Section: Discussionmentioning

confidence: 99%

A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects

et al. 2004

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BACKGROUND: Treatment of obese subjects with topiramate has recently been associated with significant weight loss in a 6-month dose-ranging study. OBJECTIVE: To investigate the long-term efficacy and safety of topiramate in obese subjects. DESIGN: Randomised, double-blind, placebo-controlled study investigating three doses of topiramate: 96, 192, and 256 mg/ day. All subjects also participated in a nonpharmacological weight-loss programme. SUBJECTS: The study included 1289 subjects 18-75 y with a body mass index Z30 kg/m 2 and o50 kg/m 2 in the absence of comorbidities, or Z27 kg/m 2 and o50 kg/m 2 in the presence of controlled hypertension and/or dyslipidaemia. DURATION: The original study design was for a 6-week, single-blind, placebo run-in phase followed by an 8-week titration phase and 2 y of maintenance at the assigned dose. Sponsor ended study early in order to develop a new controlled-release formulation with the potential to enhance tolerability and simplify dosing in this patient population. Therefore, none of the subjects completed the full 2 y of treatment. Efficacy results are based on subjects who were enrolled early enough to have had an opportunity to complete 1 y at their assigned dose (modified intent-to-treat population, MITT) before learning of the decision to terminate the study. Safety results are based on all subjects who took at least one dose of study medication. RESULTS: The safety population consisted of 1282 subjects, and the MITT efficacy population was 854 subjects. At 60 weeks, subjects in the placebo group lost 1.7% of their baseline body weight, while subjects in the topiramate 96, 192, and 256 mg/day treatment groups lost 7.0, 9.1, and 9.7%, respectively (Po0.001, MITT, last observation carried forward). Weight loss Z5% of baseline weight was achieved by 18% of subjects in the placebo arm vs 54, 61, and 67% of subjects receiving topiramate 96, 192, and 256 mg/day, respectively; weight loss Z10% was achieved by 6 vs 29, 40, and 44%, respectively (Po0.001). Weight loss was accompanied by significant improvements in blood pressure (systolic/diastolic changes of þ 0.4/ þ 1.0, À3.1/À1.3, À5.7/À3.4, and À4.6/À2.4 mmHg were observed for placebo, topiramate 96 mg/day, 192 mg/day, and 256 mg/day, respectively, Po0.001) and glucose and insulin. The most common adverse events more frequently observed in topiramatetreated subjects occurred mostly during the titration phase and were related to the central or peripheral nervous system and included paresthesia, difficulty with concentration/attention, depression, difficulty with memory, language problems, nervousness, and psychomotor slowing. CONCLUSION: Topiramate treatment of obese subjects over the course of 1 y resulted in clinically significant weight loss. Improvements were also observed in blood pressure and glucose tolerance.

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Effect of topiramate on body weight and body composition of osborne-mendel rats fed a high-fat diet: alterations in hormones, neuropeptide, and uncoupling-protein mRNAs

Cited by 92 publications

References 17 publications

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

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

Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects

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