PPARα modulation of mesolimbic dopamine transmission rescues depression-related behaviors

Scheggi, Simona; Melis, Miriam; Felice, Marta De; Aroni, Sonia; Muntoni, Anna Lisa; Pelliccia, Teresa; Gambarana, Carla; Montis, Maria Graziella De; Pistis, Marco

doi:10.1016/j.neuropharm.2016.07.024

Cited by 43 publications

(39 citation statements)

References 56 publications

(74 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Nevertheless, the finding that such an effect does not correlate with seizure control, and the significant mood amelioration reported on the questionnaires, in addition to the patient determination to continue the therapy even after the completion of the study, support the preclinical findings suggestive of an independent role of fenofibrate on mood regulation. 39,40 Taken together, our results, although preliminary, call for a double-blind placebo trial and suggest that fenofibrate is an effective and well-tolerated adjunctive therapy in NFLE due to its effects as a disease-modifying drug, and point out the role of PPARa in the regulation of neuronal functions.…”

Section: Discussionmentioning

confidence: 64%

“…Thus, caution has to be taken when interpreting these results, as the improvement in quality of life scores might be related to a placebo effect or to the subjective feeling of well‐being due the amelioration of pathology and of the quality of sleep. Nevertheless, the finding that such an effect does not correlate with seizure control, and the significant mood amelioration reported on the questionnaires, in addition to the patient determination to continue the therapy even after the completion of the study, support the preclinical findings suggestive of an independent role of fenofibrate on mood regulation …”

Section: Discussionmentioning

confidence: 66%

See 1 more Smart Citation

Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 66%

Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…It may also reduce athero-thrombotic risks in DM (Treweeke et al, 2012). Fenofibrate, a lipid-lowering agent, was reported to have antidepressant-like effects in animal models (Scheggi et al, 2016). Fenofibrate, a lipid-lowering agent, was reported to have antidepressant-like effects in animal models (Scheggi et al, 2016).…”

Section: Drug Enrichment Analysesmentioning

confidence: 99%

“…Allopurinol is a urate-lowering agent which was shown antidepressant-like effects in mouse models (Gurbuz Ozgur, Aksu, Birincioglu, & Dost, 2015), and may also improve cardiovascular outcomes in hyperuricemic patients (Larsen, Pottegard, Lindegaard, & Hallas, 2016). Fenofibrate, a lipid-lowering agent, was reported to have antidepressant-like effects in animal models (Scheggi et al, 2016). Verapamil is a calcium channel blocker (CCB) that may also have broader effects on ameliorating obesity-related complications (Park et al, 2014) and depression-like symptoms in animal models (Sharma, 2015), although the clinical evidence of CCB on mood disorders is mixed (Huffman & Stern, 2007).…”

Section: Drug Enrichment Analysesmentioning

confidence: 99%

Differential associations of depression‐related phenotypes with cardiometabolic risks: Polygenic analyses and exploring shared genetic variants and pathways

Wong

Chau

et al. 2018

Depress Anxiety

View full text Add to dashboard Cite

Background: Numerous studies have suggested associations between depression and cardiometabolic (CM) diseases. However, little is known about the mechanism underlying this comorbidity, and whether the relationship differs by depression subtypes.Methods: Using polygenic risk scores (PRS) and linkage disequilibrium (LD) score regression, we investigated the genetic overlap of various depression-related phenotypes with a comprehensive panel of 20 CM traits. GWAS results for major depressive disorder (MDD) were taken from the PGC and CONVERGE studies, with the latter focusing on severe melancholic depression. GWAS results on general depressive symptoms (DS) and neuroticism were also included. We identified the shared genetic variants and inferred enriched pathways. We also looked for drugs overrepresented among the top-shared genes, with an aim to finding repositioning opportunities for comorbidities. Results:We found significant genetic overlap between MDD, DS, and neuroticism with cardiometabolic traits. In general, positive polygenic associations with CM abnormalities were observed except for MDD-CONVERGE. Counterintuitively, PRS representing severe melancholic depression was associated with reduced CM risks. Enrichment analyses of shared SNPs revealed many interesting pathways such as those related to inflammation that underlie the comorbidity of depressive and CM traits. Using a gene-set analysis approach, we also revealed several repositioning candidates with literature support (e.g., bupropion). Conclusions:Our study highlights shared genetic bases of depression with CM traits, and suggests the associations vary by depression subtypes, which may have implications in targeted prevention of cardiovascular events for patients. Identification of shared genetic factors may also guide drug discovery for the comorbidities. K E Y W O R D Sbiological markers, cardiovascular/cardiac/heart disease, depression, epidemiology, genetics 330

show abstract

“…Fenofibrate is a well-known lipid-lowering agent. However, an animal study also revealed antidepressant-like effects of fenofibrate by PPARα stimulation in the mesolimbic dopamine system 68 . Verapamil is a calcium channel blocker mainly used for hypertension, angina and arrhythmias.…”

Section: Drug Enrichment Analysesmentioning

confidence: 99%

Differential associations of various depression-related phenotypes with cardiometabolic risks: Identification of shared genetic factors and implications for drug repositioning

Wong

Chau

et al. 2017

Preprint

View full text Add to dashboard Cite

Depression and cardiometabolic diseases, such as coronary artery disease (CAD) and type 2 diabetes (DM), are commonly considered as risk factors to each other. However, little is known about the mechanism underlying the relationship between depression and cardiometabolic traits. Using a polygenic risk score approach, we investigated the genetic overlap of major depressive disorder (MDD) with various cardiometabolic traits based on summary statistics from large-scale meta-analyses of genome-wide association studies (GWAS). GWAS results for MDD were taken from MDD-CONVERGE which represents a relatively homogenous sample of severe depression. We also identified shared genetic variants and inferred the enriched pathways. In addition, we looked for drugs over-represented among the top shared genes, with an aim to finding repositioning opportunities for both kinds of disorders.We found significant polygenic sharing between MDD and cardiometabolic traits, including positive associations with CAD, fat percentage, LDL, triglyceride, body mass index (BMI), waist-hip ratio (WHR) and WHR adjusted for BMI, and an inverse association with HDL. We also observed a modest association of MDD with DM but no significant associations with other glycemic traits or leptin. Some of the shared pathways include lipoprotein metabolism, neurotrophin and oxytocin pathways. Using a gene-set analysis approach, we revealed drugs that may be repositioned for both types of disorders, many of which are supported by previous studies, such as statins, bupropion, verapamil and s-adenosylmethionine. Our study highlights shared genetic bases of MDD with cardiometabolic traits, and implicates the potential of repurposing drugs for comorbidities based on overlapping genetic factors.

show abstract

PPARα modulation of mesolimbic dopamine transmission rescues depression-related behaviors

Cited by 43 publications

References 56 publications

Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy

Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy

Differential associations of depression‐related phenotypes with cardiometabolic risks: Polygenic analyses and exploring shared genetic variants and pathways

Differential associations of various depression-related phenotypes with cardiometabolic risks: Identification of shared genetic factors and implications for drug repositioning

Contact Info

Product

Resources

About