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Depression: From Molecular Basis to Therapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (20 September 2024) | Viewed by 15870

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Dr. Terezia Kiskova

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Institute of Pathology, Faculty of Medicine, Pavol Jozef Safarik University, 040 01 Kosice, Slovakia
Interests: brain cancer; molecular mechanism; natural compounds
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Special Issue Information

Dear Colleagues,

Depression, often described as the “silent epidemic” of the 21st century, stands as a complex and pervasive mental health challenge that affects millions of individuals worldwide. While its clinical manifestations are readily observable in the form of persistent sadness, hopelessness, and loss of interest in daily life, the true depths of this condition lie hidden within the intricate web of the human brain. Understanding the molecular basis of depression has become a crucial endeavor in contemporary neuroscience and psychology, as it holds the potential to unravel the mysteries behind this debilitating disorder and, ultimately, pave the way for more effective therapeutic interventions.

This Special Issue welcomes original research and review papers demonstrating the molecular mechanisms of depression—from its molecular basis to therapy.

Dr. Terézia Kisková
Guest Editor

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Keywords

depression
neurobiology
molecular basis
neurotransmitters
genetic factors
psychopharmacology
psychotherapy
genetic markers

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Published Papers (9 papers)

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Research

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15 pages, 1493 KiB

Open AccessArticle

Gyrophoric Acid, a Secondary Metabolite of Lichens, Exhibits Antidepressant and Anxiolytic Activity In Vivo in Wistar Rats

by Nicol Urbanska, Martina Karasova, Zuzana Jendzelovska, Martin Majerník, Mariana Kolesarova, Dajana Kecsey, Rastislav Jendzelovsky, Peter Bohus and Terezia Kiskova

Int. J. Mol. Sci. 2024, 25(21), 11840; https://doi.org/10.3390/ijms252111840 - 4 Nov 2024

Viewed by 706

Abstract

Gyrophoric acid (GA) is a secondary metabolite of various lichens. It exhibits various biological activities in vitro, but only one study has been carried out in vivo. Because our previous study showed that GA stimulates neurogenesis in healthy rats, the current study aimed to explore the potential of GA during stress-induced depressive-like states in male Wistar rats. In the experiment, pregnant females were used. In the last week of pregnancy, females were subjected to restraint stress. After birth, progeny aged 60 days were stressed repeatedly. The males were divided into three groups: control animals (CTR; n = 10), males with a depression-like state (DEP; n = 10), and GA-treated animals (GA; n = 10). GA males were treated with GA (per os 10 mg/kg) daily for one month, starting from the 60th postnatal day. Our results indicate that GA acts as an antioxidant, as shown by a lowered ROS level in leukocytes (p < 0.01). Moreover, it prolonged the time spent in open arms in the elevated plus maze (p < 0.001). Concomitantly, the stimulation of proliferative activity in hippocampal regions was seen (hilus p < 0.01; subgranular zone p < 0.001) when compared with DEP males. Additionally, the number of mature neurons in the CA1 region of the hippocampus increased markedly (p < 0.01), indicating the role of GA in the maturation process of neurons. Thus, our study points to the potential anxiolytic/antidepressant activity of GA. However, future studies are needed in this complex area. Full article

(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy)

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13 pages, 1566 KiB

Open AccessArticle

Are Methylation Patterns in the KALRN Gene Associated with Cognitive and Depressive Symptoms? Findings from the Moli-sani Cohort

by Miriam Shasa Quiccione, Alfonsina Tirozzi, Giulia Cassioli, Martina Morelli, Simona Costanzo, Antonietta Pepe, Francesca Bracone, Sara Magnacca, Chiara Cerletti, Danilo Licastro, Augusto Di Castelnuovo, Maria Benedetta Donati, Giovanni de Gaetano, Licia Iacoviello and Alessandro Gialluisi

Int. J. Mol. Sci. 2024, 25(19), 10317; https://doi.org/10.3390/ijms251910317 - 25 Sep 2024

Viewed by 588

Abstract

The KALRN gene (encoding kalirin) has been implicated in several neuropsychiatric and neurodegenerative disorders. However, genetic evidence supporting this implication is limited and targeted epigenetic analyses are lacking. Here, we tested associations between epigenetic variation in KALRN and interindividual variation in depressive symptoms (PHQ9) and cognitive (MoCA) performance, in an Italian population cohort (N = 2409; mean (SD) age: 67 (9) years; 55% women). First, we analyzed the candidate region chr3:124584826–124584886 (hg38), within the KALRN promoter, through pyrosequencing of 1385 samples. Then, we widened the investigated region by analyzing 137 CpGs annotated to the whole gene, rescued from epigenome-wide (Illumina EPIC) data from 1024 independent samples from the same cohort. These were tested through stepwise regression models adjusted for age, sex, circulating leukocytes fractions, education, prevalent health conditions and lifestyles. We observed no statistically significant associations with methylation levels in the three CpGs tested through pyrosequencing, or in the gene-wide association analysis with MoCA score. However, we observed a statistically significant association between PHQ9 and cg13549966 (chr3:124106738; β (Standard Error) = 0.28 (0.08), Bonferroni-corrected p = 0.025), located close to the transcription start site of the gene. This association was driven by a polychoric factor tagging somatic depressive symptoms (β (SE) = 0.127 (0.064), p = 0.048). This evidence underscores the importance of studying epigenetic variation within the KALRN gene and the role that it may play in brain diseases, particularly in atypical depression, which is often characterized by somatic symptoms. Full article

(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy)

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14 pages, 1649 KiB

Open AccessArticle

Evaluation of New Approaches to Depression Treatment Using an Animal Model of Pharmacoresistant Depression

by Alexandra Zvozilova, Stanislava Bukatova, Romana Koprdova and Mojmir Mach

Int. J. Mol. Sci. 2024, 25(10), 5265; https://doi.org/10.3390/ijms25105265 - 12 May 2024

Viewed by 1280

Abstract

Depression is emerging as the predominant psychiatric disorder globally. Despite the wide availability of antidepressants, up to 30% of patients exhibit poor response to treatment, falling into the category of treatment-resistant depression (TRD). This underscores the need for the exploration of novel therapeutic options. Our work aims to study the effect of chronic administration of the pyridoindole derivative SMe1EC2M3, a triple reuptake inhibitor, and the combination of zoletil and venlafaxine under conditions of stress induced by a 4-week chronic mild stress (CMS) procedure in Wistar-Kyoto male rats as an animal model of TRD. Therefore, we investigated the possible effect of the selected compounds in four experimental groups, i.e., stress + vehicle, stress + venlafaxine, stress + zoletil + venlafaxine and stress + SMe1EC2M3. The following variables were assessed: anhedonia in sucrose preference test (SPT), spontaneous locomotion and exploration in open field test (OF), anxiety-like behavior in elevated plus maze test (EPM), motivation and depressive-like behavior in forced swim test (FST) and nociception in tail flick test. We also evaluated cognition, particularly recognition memory, in the novel object recognition test (NOR). Sucrose preference was significantly increased in the SMe1EC2M3 group (p < 0.05) in comparison with the venlafaxine animals. In the OF, we observed a significantly higher number of entries into both the central and peripheral zones in the venlafaxine (p < 0.05 central zone; p ≤ 0.05 periphery zone) and SMe1EC2M3 (p < 0.05 central zone; p < 0.05 periphery zone) groups compared to the venlafaxine + zoletil group. SMe1EC2M3 was able to significantly increase the time of climbing in FST (p < 0.05) in comparison with the venlafaxine and control groups. The NOR test revealed a significantly higher discrimination ratio in the SMe1EC2M3 group (p < 0.05) compared to the control and venlafaxine groups. Analyses of the tail flick test showed a significant increase in reaction time to painful stimuli in the SMe1EC2M3 group (p < 0.05) in comparison to both the control and venlafaxine groups. Our findings suggest that SMe1EC2M3 has the potential to ameliorate some behavioral changes associated with TRD, and the venlafaxine + zoletil combination treatment was not a promising treatment alternative in the animal model of TRD. Full article

(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy)

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15 pages, 1066 KiB

Open AccessCommunication

Higher Seasonal Variation of Systemic Inflammation in Bipolar Disorder

by Sara Dallaspezia, Vincenzo Cardaci, Mario Gennaro Mazza, Rebecca De Lorenzo, Patrizia Rovere Querini, Cristina Colombo and Francesco Benedetti

Int. J. Mol. Sci. 2024, 25(8), 4310; https://doi.org/10.3390/ijms25084310 - 13 Apr 2024

Viewed by 1371

Abstract

Seasonal rhythms affect the immune system. Evidence supports the involvement of immuno-inflammatory mechanisms in bipolar disorder (BD), with the neutrophil to lymphocyte ratio (NLR), and the systemic immune-inflammatory index (SII; platelets × neutrophils/lymphocytes) consistently reported to be higher in patients with BD than in HC, but seasonal rhythms of innate and adaptive immunity have never been studied. We retrospectively studied NLR and SII in 824 participants divided into three groups: 321 consecutively admitted inpatients affected by a major depressive episode in course of BD, and 255 consecutively admitted inpatients affected by obsessive–compulsive disorder (OCD; positive psychiatric control), and 248 healthy controls (HC). Patients with BD showed markedly higher markers of systemic inflammation in autumn and winter, but not in spring and summer, in respect to both HC and patients with OCD, thus suggesting a specific effect of season on inflammatory markers in BD, independent of a shared hospital setting and drug treatment. Given that systemic inflammation is emerging as a new marker and as target for treatment in depressive disorders, we suggest that seasonal rhythms should be considered for tailoring antidepressant immuno-modulatory treatments in a precision medicine approach. Full article

(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy)

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14 pages, 1013 KiB

Open AccessArticle

Long-Term Immunomodulatory Impact of VNS on Peripheral Cytokine Profiles and Its Relationship with Clinical Response in Difficult-to-Treat Depression (DTD)

by Erhan Kavakbasi, Evelien Van Assche, Kathrin Schwarte, Christa Hohoff and Bernhard T. Baune

Int. J. Mol. Sci. 2024, 25(8), 4196; https://doi.org/10.3390/ijms25084196 - 10 Apr 2024

Viewed by 1164

Abstract

Vagus nerve stimulation (VNS) represents a long-term adjunctive treatment option in patients with difficult-to-treat depression (DTD). Anti-inflammatory effects have been discussed as a key mechanism of action of VNS. However, long-term investigations in real-world patients are sparse. In this naturalistic observational study, we collected data on cytokines in peripheral blood in n = 6 patients (mean age 47.8) with DTD and VNS treatment at baseline and at 6 months follow-up. We have identified clusters of peripheral cytokines with a similar dynamic over the course of these 6 months using hierarchical clustering. We have investigated cytokine changes from baseline to 6 months as well as the relationship between the cytokine profile at 6 months and long-term response at 12 months. After 6 months of VNS, we observed significant correlations between cytokines (p < 0.05) within the identified three cytokine-pairs which were not present at baseline: IL(interleukin)-6 and IL-8; IL-1β and TNF-α; IFN-α2 and IL-33. At 6 months, the levels of all the cytokines of interest had decreased (increased in non-responders) and were lower (5–534 fold) in responders to VNS than in non-responders: however, these results were not statistically significant. VNS-associated immunomodulation might play a role in long-term clinical response to VNS. Full article

(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy)

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18 pages, 3724 KiB

Open AccessArticle

Melatonin Ameliorates Neuropsychiatric Behaviors, Gut Microbiome, and Microbiota-Derived Metabolites in Rats with Chronic Sleep Deprivation

by Bingcong Li, Yin-Ru Hsieh, Wen-De Lai, Te-Hsuan Tung, Yu-Xuan Chen, Chia-Hui Yang, Yu-Chiao Fang and Shih-Yi Huang

Int. J. Mol. Sci. 2023, 24(23), 16820; https://doi.org/10.3390/ijms242316820 - 27 Nov 2023

Cited by 5 | Viewed by 2301

Abstract

With the increasing prevalence of sleep deprivation (SD)-related disorders, the effective treatment of sleep disorders has become a critical health research topic. Thus, we hypothesized and investigated the effectiveness of a 3-week melatonin intervention on neuropsychiatric behavioral responses mediated throughout melatonin receptors, gut microbiota, and lipid metabolites in rats with chronic SD. Eighteen 6-week-old Wistar rats were used and divided into the control grup (C, n = 6), SD group (n = 6), and melatonin-supplemented group (SDM, n = 6). During weeks 0 to 6, animals were provided with the AIN-93M diet and free access to water. Four-week chronic SD was conducted from weeks 7 to 10. Exogenous melatonin administration (10 mg/kg BW) was injected intraperitoneally 1 h before the daily administration of SD for 3 weeks in the SDM group. SD rats exhibited anxiety-like behavior, depression-like behavior, and cognitive impairment. Exogenous melatonin administration ameliorated neuropsychiatric behaviors induced by chronic SD. Analysis of fecal metabolites indicated that melatonin may influence brain messaging through the microbiota–gut–brain axis by increasing the production of short-chain fatty acids (SCFA) and decreasing the production of secondary bile acids (SBA). Four-week SD reduced the cerebral cortex expression of MT1, but not in the colon. Chronic SD led to anxiety and depression-like behaviors and cognitive decline, as well as the reduced intestinal level of SCFAs and the enhanced intestinal level of SBAs in rats. In this work, we confirmed our hypothesis that a 3-week melatonin intervention on neuropsychiatric behavioral response mediated throughout melatonin receptors, gut microbiota, and lipid metabolites in rats with chronic SD. Full article

(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy)

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Review

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36 pages, 1484 KiB

Open AccessReview

Human Gut Microbiota for Diagnosis and Treatment of Depression

by Olga V. Averina, Elena U. Poluektova, Yana A. Zorkina, Alexey S. Kovtun and Valery N. Danilenko

Int. J. Mol. Sci. 2024, 25(11), 5782; https://doi.org/10.3390/ijms25115782 - 26 May 2024

Cited by 1 | Viewed by 3078

Abstract

Nowadays, depressive disorder is spreading rapidly all over the world. Therefore, attention to the studies of the pathogenesis of the disease in order to find novel ways of early diagnosis and treatment is increasing among the scientific and medical communities. Special attention is drawn to a biomarker and therapeutic strategy through the microbiota–gut–brain axis. It is known that the symbiotic interactions between the gut microbes and the host can affect mental health. The review analyzes the mechanisms and ways of action of the gut microbiota on the pathophysiology of depression. The possibility of using knowledge about the taxonomic composition and metabolic profile of the microbiota of patients with depression to select gene compositions (metagenomic signature) as biomarkers of the disease is evaluated. The use of in silico technologies (machine learning) for the diagnosis of depression based on the biomarkers of the gut microbiota is given. Alternative approaches to the treatment of depression are being considered by balancing the microbial composition through dietary modifications and the use of additives, namely probiotics, postbiotics (including vesicles) and prebiotics as psychobiotics, and fecal transplantation. The bacterium Faecalibacterium prausnitzii is under consideration as a promising new-generation probiotic and auxiliary diagnostic biomarker of depression. The analysis conducted in this review may be useful for clinical practice and pharmacology. Full article

(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy)

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24 pages, 733 KiB

Open AccessReview

Chronic Stress-Induced Neuroinflammation: Relevance of Rodent Models to Human Disease

by Abigail G. White, Elias Elias, Andrea Orozco, Shivon A. Robinson and Melissa T. Manners

Int. J. Mol. Sci. 2024, 25(10), 5085; https://doi.org/10.3390/ijms25105085 - 7 May 2024

Cited by 3 | Viewed by 2326

Abstract

The brain is the central organ of adaptation to stress because it perceives and determines threats that induce behavioral, physiological, and molecular responses. In humans, chronic stress manifests as an enduring consistent feeling of pressure and being overwhelmed for an extended duration. This can result in a persistent proinflammatory response in the peripheral and central nervous system (CNS), resulting in cellular, physiological, and behavioral effects. Compounding stressors may increase the risk of chronic-stress-induced inflammation, which can yield serious health consequences, including mental health disorders. This review summarizes the current knowledge surrounding the neuroinflammatory response in rodent models of chronic stress—a relationship that is continually being defined. Many studies investigating the effects of chronic stress on neuroinflammation in rodent models have identified significant changes in inflammatory modulators, including nuclear factor-κB (NF-κB) and toll-like receptors (TLRs), and cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6. This suggests that these are key inflammatory factors in the chronic stress response, which may contribute to the establishment of anxiety and depression-like symptoms. The behavioral and neurological effects of modulating inflammatory factors through gene knockdown (KD) and knockout (KO), and conventional and alternative medicine approaches, are discussed. Full article

(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy)

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17 pages, 1543 KiB

Open AccessReview

Mechanisms Involved in the Link between Depression, Antidepressant Treatment, and Associated Weight Change

by Tomas Kukucka, Nikola Ferencova, Zuzana Visnovcova, Igor Ondrejka, Igor Hrtanek, Veronika Kovacova, Andrea Macejova, Zuzana Mlyncekova and Ingrid Tonhajzerova

Int. J. Mol. Sci. 2024, 25(8), 4511; https://doi.org/10.3390/ijms25084511 - 20 Apr 2024

Cited by 1 | Viewed by 1886

Abstract

Major depressive disorder is a severe mood disorder associated with a marked decrease in quality of life and social functioning, accompanied by a risk of suicidal behavior. Therefore, seeking out and adhering to effective treatment is of great personal and society-wide importance. Weight changes associated with antidepressant therapy are often cited as the reason for treatment withdrawal and thus are an important topic of interest. There indeed exists a significant mechanistic overlap between depression, antidepressant treatment, and the regulation of appetite and body weight. The suggested pathomechanisms include the abnormal functioning of the homeostatic (mostly humoral) and hedonic (mostly dopaminergic) circuits of appetite regulation, as well as causing neuromorphological and neurophysiological changes underlying the development of depressive disorder. However, this issue is still extensively discussed. This review aims to summarize mechanisms linked to depression and antidepressant therapy in the context of weight change. Full article

(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy)

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