Richard D, Ferland J, Lalonde J, Samson P, Deshaies Y
Centre de recherche de l'hôpital Laval et Centre de recherche sur le Métabolisme énergétique de l'Université Laval, Faculté de Médecine, Université Laval, Québec, Canada.
Nutrition. 2000 Oct;16(10):961-6. doi: 10.1016/s0899-9007(00)00452-4.
Topiramate (TPM) is a novel neurotherapeutic agent currently indicated for the treatment of epilepsy and undergoing development for other central nervous system indications including neuropathic pain, bipolar disorder, and migraine prophylaxis. TPM is synthesized from D-fructose and contains a sulfamate moiety that is essential for its pharmacologic activity. TPM has been observed to significantly reduce body weight in patients treated for seizure, which has prompted the realization of preclinical studies to characterize the effects of TPM in the regulation of energy balance. Studies carried out in various strains of rats have provided good evidence for the ability of TPM to blunt energy deposition. Body composition analyses from rat trials have demonstrated that TPM inhibits fat deposition while reducing the activity of lipoprotein lipase (LPL) in various white adipose tissue depots. High doses of TPM (likely above the therapeutic dose range) have also been observed to reduce protein gain without catabolic effects. Although TPM cannot be described as a potent anorectic agent, it seems to have the ability to reduce food intake; significant reductions in food intake have been observed in female obese (fa/fa) Zucker rats and in female Wistar rats. TPM can also reduce energy deposition in the absence of alterations in food intake. This effect has been clearly emphasized in female lean (Fa/?) Zucker rats. In female Sprague-Dawley rats, TPM also increased energy expenditure and it has been observed to increase LPL activity in brown adipose tissue, which could indicate that TPM has the ability to enhance regulatory thermogenesis. In addition, TPM stimulates LPL activity in skeletal muscles, further emphasizing its potential to promote substrate oxidation. The mechanisms whereby TPM affects the regulation of energy balance have yet to be understood. TPM represents an antiepileptic drug (AED) with complex biochemical/pharmacologic actions. Its negative effects on energy deposition cannot be readily predicted from these actions, as AEDs are generally expected to stimulate body weight gain. Recent data, obtained from investigations aimed at assessing the effects of TPM on neuropeptidergic systems involved in the regulation of energy balance, have failed to demonstrate any significant effects of TPM on the neuropeptide Y and proopiomelanocortin systems. In conclusion, it is clear that TPM can reduce fat deposition by either reducing food intake or stimulating energy expenditure. The mechanisms whereby an AED such as TPM controls food intake and energy expenditure remains to be delineated. Copyright1999 ASCRS and ESCRS
托吡酯（TPM）是一种新型神经治疗药物，目前被用于治疗癫痫，并且正在针对包括神经性疼痛、双相情感障碍和偏头痛预防在内的其他中枢神经系统适应症进行研发。TPM由D-果糖合成，含有对其药理活性至关重要的氨基磺酸酯部分。据观察，TPM能显著降低接受癫痫治疗患者的体重，这促使人们开展临床前研究以表征TPM在能量平衡调节中的作用。在各种品系大鼠中进行的研究为TPM抑制能量沉积的能力提供了充分证据。大鼠试验的身体成分分析表明，TPM抑制脂肪沉积，同时降低各种白色脂肪组织库中脂蛋白脂肪酶（LPL）的活性。高剂量的TPM（可能高于治疗剂量范围）也被观察到能减少蛋白质增加且无分解代谢作用。虽然TPM不能被描述为一种强效的食欲抑制剂，但它似乎有减少食物摄入的能力；在雌性肥胖（fa/fa） Zucker大鼠和雌性Wistar大鼠中已观察到食物摄入量显著减少。TPM在不改变食物摄入量的情况下也能减少能量沉积。这种作用在雌性瘦型（Fa/?） Zucker大鼠中得到了明确体现。在雌性Sprague-Dawley大鼠中，TPM还增加了能量消耗，并且据观察它能增加棕色脂肪组织中的LPL活性，这可能表明TPM有增强调节性产热的能力。此外，TPM刺激骨骼肌中的LPL活性，进一步强调了其促进底物氧化的潜力。TPM影响能量平衡调节的机制尚待明确。TPM是一种具有复杂生化/药理作用的抗癫痫药物（AED）。其对能量沉积的负面影响无法从这些作用中轻易预测，因为一般认为AED会刺激体重增加。最近从旨在评估TPM对参与能量平衡调节的神经肽能系统影响的研究中获得的数据未能证明TPM对神经肽Y和阿片促黑素皮质素系统有任何显著影响。总之，很明显TPM可以通过减少食物摄入或刺激能量消耗来减少脂肪沉积。像TPM这样的AED控制食物摄入和能量消耗的机制仍有待阐明。版权所有1999年美国白内障与屈光手术学会和欧洲白内障与屈光手术学会
