Anti-depression effects of ketogenic diet are mediated via the restoration of microglial activation and neuronal excitability in the lateral habenula

Guan, Yanfei; Huang, Guobin; Xu, Min-Dong; Gao, Feng; Lin, Song; Huang, Jie; Wang, Jin; Li, Yuanquan; Wu, Chunqing; Yao, Shan; Wáng, Ying; Zhang, Yun-Long; Teoh, Jian-peng; Xuan, Aiguo; Sun, Xiangdong

doi:10.1016/j.bbi.2020.05.032

Cited by 76 publications

(60 citation statements)

References 74 publications

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“…Both green tea, characterized by its high levels of polyphenols, especially epigallocatechin gallate (EGCG), as well as nutrients that increase ketone bodies in the blood, such as coconut oil, show great benefits when treating neurodegenerative diseases, as mitochondrial activity is improved [22,23]. Specifically, in the treatment of depression, both EGCG and ketogenic diets have been shown to be effective [24][25][26][27]. This antidepressant effect could, in turn, be linked to the lipolytic activity that shows (both EGCG and ketogenic diets), especially at an abdominal level [28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

The Impact of Epigallocatechin Gallate and Coconut Oil Treatment on Cortisol Activity and Depression in Multiple Sclerosis Patients

Platero

Cuerda-Ballester

Sancho-Cantus

et al. 2021

Life

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(1) Background: Multiple sclerosis (MS) is pathogenically characterized by high oxidative stress and symptomatically by progressive muscle loss and increased body fat associated with the presence of depression. Epigallocatechin gallate (EGCG) (particularly present in green tea) and ketone bodies (in particular beta-hydroxybutyrate (BHB)), whose main source is coconut oil, have shown emotional benefits and body fat loss. The aim of this study was to assess the impact of EGCG and coconut oil on cortisol activity related to fat loss and depression in MS patients. (2) Methods: The study involved 51 MS patients who were randomly divided into an intervention group or a control group. The intervention group received 800 mg of EGCG and 60 mL of coconut oil, which were included in their daily diet for four months. The control group received placebo and all patients followed an isocaloric diet. A blood sample was collected before and after the four-month period, and levels of cortisol, albumin and BHB were measured in serum. In addition, immediately before and after the intervention, anthropometric variables were measured: waist-to-hip ratio (WHR), body fat mass percentage, fat weight, total weight, and muscle mass percentage. Depression was assessed with the Beck Depression Inventory II (BDI-II). (3) Results: No significant changes were obtained in cortisol levels in any of the groups, and there was a significant increase in albumin in the blood of the intervention group only that could lead to a decrease in serum free cortisol. In addition, it was observed a significant decrease in levels of depression and abdominal fat. (4) Conclusions: EGCG combined with coconut oil increase the concentration of albumin in blood and produce less depression in MS patients.

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Section: Introductionmentioning

confidence: 99%

The Impact of Epigallocatechin Gallate and Coconut Oil Treatment on Cortisol Activity and Depression in Multiple Sclerosis Patients

Platero

Cuerda-Ballester

Sancho-Cantus

et al. 2021

Life

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“…The contents of control diet (CD) and ketogenic diet (KD) (Research Diets) are described previously [34]. Briefly, CD (D10070802) (per-calorie macronutrient) contained: 10% protein, 80% carbohydrates, and 10% fat; KD (D10070801) was constituted by: 10% protein and 90% fat.…”

Section: Diets and Feedingmentioning

confidence: 99%

“…qRT-PCR was performed as described previously [34]. Briefly, total RNA was isolated by using TRIzol reagent (15596-026, Invitrogen).…”

Section: Qrt-pcr Analysismentioning

confidence: 99%

Neuregulin 1/ErbB4 signaling contributes to the anti-epileptic effects of the ketogenic diet

Wang

Huang

et al. 2021

Cell Biosci

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Background The ketogenic diet (KD) has been recognized as a potentially effective therapy to treat neuropsychiatric diseases, including epilepsy. Previous studies have indicated that KD treatment elevates γ-Amino butyric acid (GABA) levels in both human and murine brains, which presumably contributes to the KD’s anti-seizure effects. However, this has not been systematically investigated at the synaptic level, and the underlying molecular mechanisms remain to be elucidated. Methods Kainic acid (KA)-induced acute and chronic seizure models were utilized to examine the effects of KD treatment on seizure threshold and epileptogenesis. Synaptic activities in the hippocampus were recorded with the technique of electrophysiology. The effects of the KD on Neuregulin 1 (Nrg1) expression were assessed via RNA sequencing, real-time PCR and Western blotting. The obligatory role of Nrg1 in KD’s effects on seizures was evaluated through disruption of Nrg1 signaling in mice by genetically deleting its receptor-ErbB4. Results We found that KD treatment suppressed seizures in both acute and chronic seizure models and enhanced presynaptic GABA release probability in the hippocampus. By screening molecular targets linked to GABAergic activity with transcriptome analysis, we identified that KD treatment dramatically increased the Nrg1 gene expression in the hippocampus. Disruption of Nrg1 signaling by genetically deleting its receptor-ErbB4 abolished KD’s effects on GABAergic activity and seizures. Conclusion Our findings suggest a critical role of Nrg1/ErbB4 signaling in mediating KD’s effects on GABAergic activity and seizures, shedding light on developing new therapeutic interventions to seizure control.

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“…The adeno-associated virus (AAV) vector was used to genetically over-express D3R (pAAV-CMV-EGFP-2A-Drd3-3FLAG, AAV-D3R), and AAV expressing U6-driven shRNA and CMV-driven mCherry were used to inhibit D3R (pAAV-U6-shDrd3-CMV-EGFP-WPRE-spolyA, AAV-shD3R). Their vectors were both serotyped with AAV2/8 and purchased from Obio Technology, and the viral titer respectively was 1×10 12 and 1×10 13 particles per ml. All viral vectors were aliquoted and stored at −80 °C until used.…”

Section: Pharmacological Treatments and Viral Vectorsmentioning

confidence: 99%

“…In line with this phenomenon, positron emission tomography (PET) observed that levels of translocator protein 18 kD (TSPO), which correlates with activated microglia-related neuroin ammation, were signi cantly enhanced in the prefrontal cortex, anterior cingulate cortex and insula in patients with major depression [9,10]. Furthermore, in both in ammatory (LPS) and non-in ammatory (stress) animal models of depression, the microglia in the brain were activated and trigger pro-in ammatory cytokines production, whereas to delete microglia applied by PLX compounds and use anti-in ammatory drug minocycline both exhibited antidepressant effects in rodent models of depression [11][12][13][14][15]. In this regard, activated microglia and itsderived proin ammatory cytokines might directly contribute to the onset of depression.…”

mentioning

confidence: 99%

Nucleus Accumbens Dopamine D3 Receptor Regulates Microglial M1 Polarization Through Akt Signaling Pathway in the Depressive-Like Behavior

Wang

Lai

et al. 2021

Preprint

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Background: Nucleus accumbens (NAc) inflammation is implicated in the development and progression of depression but the underlying mechanism remains largely unclear. We previously reported that dopamine D3 receptor (D3R) expressed in the NAc strongly correlated with inflammation-related depression. The objective of the present study is to determine the exact mechanism of D3R in the NAc inflammation relevant depression.Methods: Bilateral NAc injection of Lipopolysaccharide (LPS)-induced NAc inflammation mouse model was used to explore the relationship between NAc inflammation and depressive-like behaviors. Either conditional knockout of D3R in the NAc in the adult mice or restoration of D3R expression in the NAc in D3R mutant mice was applied to investigate the effects of D3R in the NAc on depressive disorders. The exact molecular mechanism of D3R in the NAc inflammation-induced depressive-like phenotype was ascertained by in vivo and in vitro studies. Results: NAc inflammation induced by intra-NAc LPS triggered a series of depressive-like disorders, and the interaction of D3R and microglia activation involved in the NAc inflammation-induced depressive-like phenotype. We observed that selective knock-down of D3R in the NAc elicited the depressive-like behaviors, but re-expression of D3R in the NAc alleviated the depressive-like behaviors established by D3R mutation. Finally, D3R in the NAc mediated microglial polarization to M1 phenotype mainly through Akt signaling pathway. Conclusions: These findings provide direct evidence that not only NAc inflammation but also down-regulation of D3R in the NAc has a role in regulation the initiation and development of depression, and indicate that D3R negatively regulated microglial M1 polarization mainly via Akt signaling pathway that may be involved in the NAc inflammation and thereby depressive-like behaviors.

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Anti-depression effects of ketogenic diet are mediated via the restoration of microglial activation and neuronal excitability in the lateral habenula

Cited by 76 publications

References 74 publications

The Impact of Epigallocatechin Gallate and Coconut Oil Treatment on Cortisol Activity and Depression in Multiple Sclerosis Patients

The Impact of Epigallocatechin Gallate and Coconut Oil Treatment on Cortisol Activity and Depression in Multiple Sclerosis Patients

Neuregulin 1/ErbB4 signaling contributes to the anti-epileptic effects of the ketogenic diet

Nucleus Accumbens Dopamine D3 Receptor Regulates Microglial M1 Polarization Through Akt Signaling Pathway in the Depressive-Like Behavior

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