Neuroactive Peptides as Putative Mediators of Antiepileptic Ketogenic Diets

Giordano, Carmela; Marchiò, Maddalena; Timofeeva, Elena; Biagini, Giuseppe

doi:10.3389/fneur.2014.00063

Cited by 102 publications

(74 citation statements)

References 220 publications

(209 reference statements)

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“…Clinical evidence supporting efficacy of the KD in refractory epilepsy is undeniable (Li et al 2013; Giordano et al 2014; Reid et al 2014). However, establishing efficacy of the KD under experimental conditions in animals has repeatedly proven to be a challenge (Hartman et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Proconvulsant effects of the ketogenic diet in electroshock-induced seizures in mice

et al. 2016

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Among non-pharmacological treatments, the ketogenic diet (KD) has the strongest demonstrated evidence of clinical success in drug resistant epilepsy. In an attempt to model the anticonvulsant effects of the KD pre-clinically, the present study assessed the effects of the KD against electroshock-induced convulsions in mice. After confirming that exposure to the KD for 2 weeks resulted in stable ketosis and hypoglycemia, mice were exposed to electroshocks of various intensities to establish general seizure susceptibility. When compared to mice fed the standard rodent chow diet (SRCD), we found that mice fed the KD were more sensitive to electroconvulsions as reflected by a significant decrease in seizure threshold (3.86 mA in mice on the KD vs 7.29 mA in mice on the SRCD; P < 0.05) in the maximal electroshock seizure threshold (MEST) test. To examine if this increased seizure sensitivity to electroconvulsions produced by the KD would affect anticonvulsant effects of antiepileptic drugs (AEDs), anticonvulsant potencies of carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA) against maximal electroshock (MES)-induced convulsions were compared in mice fed the KD and SRCD. We found that potencies of all AEDs studied were decreased in mice fed the KD in comparison to those on the SRCD, with decreases in the anticonvulsant potencies ranging from 1.4 fold (PB) to 1.7 fold (PHT). Finally, the lack of differences in brain exposures of the AEDs studied in mice fed the KD and SRCD ruled out a pharmacokinetic nature of the observed findings. Taken together, exposure to the KD in the present study had an overall pro-convulsant effect. Since electroconvulsions require large metabolic reserves to support their rapid spread throughout the brain and consequent generalized tonic-clonic convulsions, this effect may be explained by a high energy state produced by the KD in regards to increased energy storage and utilization.

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Section: Discussionmentioning

confidence: 99%

Proconvulsant effects of the ketogenic diet in electroshock-induced seizures in mice

et al. 2016

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“…have inhibited its application (22). Therefore, exogenous BHB preparations may be preferable to KD to treat epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Anticonvulsant effect of exogenous β-hydroxybutyrate on kainic acid-induced epilepsy

Wang

Liu

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. The present study aimed to investigate the anticonvulsant effects of β-hydroxybutyrate (BHB) in a kainic acid (KA)-induced rat seizure model. The concentrations of BHB and glucose were detected in the blood prior to exogenous BHB administration. Three different doses of BHB (2, 4 and 8 mmol/kg) were then injected into male Wistar rats intraperitoneally, and the concentrations of BHB and glucose in the blood were detected. Rats received 0.9% normal saline intraperitoneally at a dose of 4 ml/kg as a control. Subsequently, a KA-induced rat seizure model was established and the anticonvulsant effects of BHB were investigated. The onset time of seizure and the degree of seizure behavior were recorded. Nissl and Timm staining were used to evaluate neuronal loss and mossy fiber sprouting, respectively. The present study demonstrated that exogenous BHB administration could significantly increase BHB concentration in the blood and this concentration was maintained for 90 min without affecting blood glucose levels. Furthermore, it was determined that a dose of 4 mmol/kg BHB is optimal for exogenous administration. The onset time of seizure was significantly prolonged in BHB-pretreated rats (63.31±4.050 min) compared with the control group (37.08±1.958 min; P=0.039). In addition, neuronal loss and mossy fiber sprouting were both alleviated in the BHB-pretreated model group. Exogenous BHB administration at a dose of 4 mmol/kg may be an alternative to a ketogenic diet to exert a protective effect in the epileptic model induced by KA. The results of the present study may allow novel therapeutic strategies to be developed to treat epilepsy.

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“…There is no convincing evidence that increased effects of ghrelin, the only peripheral orexigenic peptide known to date [85,86] , is a proximate cause of diet-induced obesity. DIO rats showed significantly lower levels of plasma ghrelin at dark onset and similar levels 6 h later compared to the DR rats [87] .…”

Section: Dysfunction In the Integration Of Peripheral Signals In Diomentioning

confidence: 99%

The role of relaxin-3 and its receptor RXFP3 in defense of elevated body weight in diet-induced obesity

Lenglos

Calvez

Timofeeva

2014

Receptor Clin Invest

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Incidence of overweight and obesity has dramatically increased during the past three decades. Treatment of this serious clinical problem is hindered by the fact that once obesity has developed, the elevated body weight is defended against weight-decreasing treatment strategies by mechanisms that are not yet fully understood. This review focuses on the neuronal mechanisms that contribute to the maintenance of obesity after it development in the DIO rat model. Among the neuronal factors regulating energy intake, orexigenic neuropeptide relaxin-3 and its cognate receptor RXFP3 may play an important role in the defense of elevated body weight in DIO. The levels of expression of relaxin-3 mRNA in the brainstem nucleus incertus (NI) were significantly increased in thead libitum feeding state in DIO rats compared to DR rats. However, the effects of relaxin-3 in the DIO ad libitumfed rats may be compensated by a significant decrease in the levels of expression of RXFP3 mRNA in the food intake-regulating brain regions of DIO rats including the paraventricular hypothalamic nucleus (PVN), central amygdala (CeA), NI, and nucleus of the solitary tract (NTS). Remarkably, the DIO rats showed an immediate rebound in food intake at refeeding and regained all body weight lost during starvation. This significant increase in food intake during refeeding was accompanied by an increase in the levels of expression of RXFP3 in the parvocellular PVN, CeA, NI, and NTS in the DIO rats to the levels of the DR rats. Moreover, the expression of RXFP3 in the paraventricular thalamic nucleus was significantly higher in the refed DIO rats compared to the DR counterparts. A constitutive increase in the expression of relaxin-3 accompanied by a relative increase in the expression of RXFP3 in food intake-regulating brain regions during refeeding after food deprivation may contribute to the mechanisms of defense of elevated body weight in the DIO phenotype.

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Neuroactive Peptides as Putative Mediators of Antiepileptic Ketogenic Diets

Cited by 102 publications

References 220 publications

Proconvulsant effects of the ketogenic diet in electroshock-induced seizures in mice

Proconvulsant effects of the ketogenic diet in electroshock-induced seizures in mice

Anticonvulsant effect of exogenous β-hydroxybutyrate on kainic acid-induced epilepsy

The role of relaxin-3 and its receptor RXFP3 in defense of elevated body weight in diet-induced obesity

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