Dysfunction in endocannabinoids, palmitoylethanolamide, and degradation of tryptophan into kynurenine in individuals with depressive symptoms
Abstract Background The endocannabinoid (eCB) system and the serotonin (5-HT) are both implicated in the severity of the depression. 5-HT is synthesized from the amino acid tryptophan (Trp), which is also a precursor for kynurenine (Kyn) whose production is increased at the expense of 5-HT in depres...
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | BMC Medicine |
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| Online Access: | https://doi.org/10.1186/s12916-024-03248-8 |
| _version_ | 1797276483296690176 |
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| author | Stefano Comai Nicolas Nunez Tobias Atkin Maykel F. Ghabrash Rita Zakarian Allan Fielding Marie Saint-Laurent Nancy Low Garrett Sauber Eugenio Ragazzi Cecilia J. Hillard Gabriella Gobbi |
| author_facet | Stefano Comai Nicolas Nunez Tobias Atkin Maykel F. Ghabrash Rita Zakarian Allan Fielding Marie Saint-Laurent Nancy Low Garrett Sauber Eugenio Ragazzi Cecilia J. Hillard Gabriella Gobbi |
| author_sort | Stefano Comai |
| collection | DOAJ |
| description | Abstract Background The endocannabinoid (eCB) system and the serotonin (5-HT) are both implicated in the severity of the depression. 5-HT is synthesized from the amino acid tryptophan (Trp), which is also a precursor for kynurenine (Kyn) whose production is increased at the expense of 5-HT in depressed patients. No clinical studies have investigated the crosstalk between the eCB system and the Trp/5-HT/Kyn pathways. Here, we hypothesized that the eCB system is associated with an enhanced Kyn production in relation to the severity of depressive symptoms. Methods Eighty-two subjects (51 patients with a diagnosis of depressive disorder (DSM-5) and 31 healthy volunteers), were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS), Beck Depression Scale, and Global Clinical Impression. Serum concentrations of eCBs (N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG)); structurally related fatty acyl compounds 2-oleoylglycerol (2-OG), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA); Trp, Kyn, Kyn/Trp ratio (an index of Trp degradation into Kyn) and 5-HT were also determined. Results Following a principal component analysis including the severity of depression, Kyn and the Kyn/Trp ratio appear to be directly associated with 2-AG, AEA, and PEA. Interestingly, these biomarkers also permitted to distinguish the population into two main clusters: one of individuals having mild/severe depressive symptoms and the other with an absence of depressive symptoms. Using parametric analysis, higher serum levels of 2-AG, Kyn, and the ratio Kyn/Trp and lower levels of Trp and 5-HT were found in individuals with mild/severe depressive symptoms than in those without depressive symptoms. While in asymptomatic people, PEA was directly associated to Trp, and OEA indirectly linked to 5-HT, in individuals with depressive symptoms, these correlations were lost, and instead, positive correlations between AEA and 2-AG, PEA and AEA, and PEA vs 2-AG and OEA concentrations were found. Conclusions Parametric and non-parametric analyses suggest a possible association between eCBs, tryptophan/kynurenine biomarkers, and severity of depression, confirming a likely interplay among inflammation, stress, and depression. The enhanced relationships among the biomarkers of the 2-AG and AEA pathways and related lipids seen in individuals with depressive symptoms, but not in asymptomatics, suggest an altered metabolism of the eCB system in depression. |
| first_indexed | 2024-03-07T15:28:49Z |
| format | Article |
| id | doaj.art-7fb56a12fc644014872f5422e0b15c65 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-03-07T15:28:49Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-7fb56a12fc644014872f5422e0b15c652024-03-05T16:32:28ZengBMCBMC Medicine1741-70152024-01-0122111210.1186/s12916-024-03248-8Dysfunction in endocannabinoids, palmitoylethanolamide, and degradation of tryptophan into kynurenine in individuals with depressive symptomsStefano Comai0Nicolas Nunez1Tobias Atkin2Maykel F. Ghabrash3Rita Zakarian4Allan Fielding5Marie Saint-Laurent6Nancy Low7Garrett Sauber8Eugenio Ragazzi9Cecilia J. Hillard10Gabriella Gobbi11Department of Pharmaceutical and Pharmacological Sciences, University of PaduaDepartment of Psychiatry, McGill UniversityDepartment of Psychiatry, McGill UniversityDepartment of Psychiatry, McGill UniversityDepartment of Psychiatry, McGill UniversityDepartment of Psychiatry, McGill University Health CenterDepartment of Psychiatry, McGill University Health CenterDepartment of Psychiatry, McGill UniversityNeuroscience Research Center and Department of Pharmacology and Toxicology, Medical College of WisconsinDepartment of Pharmaceutical and Pharmacological Sciences, University of PaduaNeuroscience Research Center and Department of Pharmacology and Toxicology, Medical College of WisconsinDepartment of Psychiatry, McGill UniversityAbstract Background The endocannabinoid (eCB) system and the serotonin (5-HT) are both implicated in the severity of the depression. 5-HT is synthesized from the amino acid tryptophan (Trp), which is also a precursor for kynurenine (Kyn) whose production is increased at the expense of 5-HT in depressed patients. No clinical studies have investigated the crosstalk between the eCB system and the Trp/5-HT/Kyn pathways. Here, we hypothesized that the eCB system is associated with an enhanced Kyn production in relation to the severity of depressive symptoms. Methods Eighty-two subjects (51 patients with a diagnosis of depressive disorder (DSM-5) and 31 healthy volunteers), were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS), Beck Depression Scale, and Global Clinical Impression. Serum concentrations of eCBs (N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG)); structurally related fatty acyl compounds 2-oleoylglycerol (2-OG), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA); Trp, Kyn, Kyn/Trp ratio (an index of Trp degradation into Kyn) and 5-HT were also determined. Results Following a principal component analysis including the severity of depression, Kyn and the Kyn/Trp ratio appear to be directly associated with 2-AG, AEA, and PEA. Interestingly, these biomarkers also permitted to distinguish the population into two main clusters: one of individuals having mild/severe depressive symptoms and the other with an absence of depressive symptoms. Using parametric analysis, higher serum levels of 2-AG, Kyn, and the ratio Kyn/Trp and lower levels of Trp and 5-HT were found in individuals with mild/severe depressive symptoms than in those without depressive symptoms. While in asymptomatic people, PEA was directly associated to Trp, and OEA indirectly linked to 5-HT, in individuals with depressive symptoms, these correlations were lost, and instead, positive correlations between AEA and 2-AG, PEA and AEA, and PEA vs 2-AG and OEA concentrations were found. Conclusions Parametric and non-parametric analyses suggest a possible association between eCBs, tryptophan/kynurenine biomarkers, and severity of depression, confirming a likely interplay among inflammation, stress, and depression. The enhanced relationships among the biomarkers of the 2-AG and AEA pathways and related lipids seen in individuals with depressive symptoms, but not in asymptomatics, suggest an altered metabolism of the eCB system in depression.https://doi.org/10.1186/s12916-024-03248-8DepressionEndocannabinoidsBiomarkersSerotoninKynurenine pathway |
| spellingShingle | Stefano Comai Nicolas Nunez Tobias Atkin Maykel F. Ghabrash Rita Zakarian Allan Fielding Marie Saint-Laurent Nancy Low Garrett Sauber Eugenio Ragazzi Cecilia J. Hillard Gabriella Gobbi Dysfunction in endocannabinoids, palmitoylethanolamide, and degradation of tryptophan into kynurenine in individuals with depressive symptoms BMC Medicine Depression Endocannabinoids Biomarkers Serotonin Kynurenine pathway |
| title | Dysfunction in endocannabinoids, palmitoylethanolamide, and degradation of tryptophan into kynurenine in individuals with depressive symptoms |
| title_full | Dysfunction in endocannabinoids, palmitoylethanolamide, and degradation of tryptophan into kynurenine in individuals with depressive symptoms |
| title_fullStr | Dysfunction in endocannabinoids, palmitoylethanolamide, and degradation of tryptophan into kynurenine in individuals with depressive symptoms |
| title_full_unstemmed | Dysfunction in endocannabinoids, palmitoylethanolamide, and degradation of tryptophan into kynurenine in individuals with depressive symptoms |
| title_short | Dysfunction in endocannabinoids, palmitoylethanolamide, and degradation of tryptophan into kynurenine in individuals with depressive symptoms |
| title_sort | dysfunction in endocannabinoids palmitoylethanolamide and degradation of tryptophan into kynurenine in individuals with depressive symptoms |
| topic | Depression Endocannabinoids Biomarkers Serotonin Kynurenine pathway |
| url | https://doi.org/10.1186/s12916-024-03248-8 |
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