RESUMEN
Guanosine is a purine nucleoside that has been shown to exhibit antidepressant effects, but the mechanisms underlying its effect are not well established. We investigated if the antidepressant-like effect induced by guanosine in the tail suspension test (TST) in mice involves the modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, voltage-dependent calcium channel (VDCC), and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway. We also evaluated if the antidepressant-like effect of guanosine is accompanied by an acute increase in hippocampal and prefrontocortical BDNF levels. Additionally, we investigated if the ability of guanosine to elicit a fast behavioral response in the novelty suppressed feeding (NSF) test is associated with morphological changes related to hippocampal synaptogenesis. The antidepressant-like effect of guanosine (0.05 mg/kg, p.o.) in the TST was prevented by DNQX (AMPA receptor antagonist), verapamil (VDCC blocker), K-252a (TrkBantagonist), or BDNF antibody. Increased P70S6K phosphorylation and higher synapsin I immunocontent in the hippocampus, but not in the prefrontal cortex, were observed 1 h after guanosine administration. Guanosine exerted an antidepressant-like effect 1, 6, and 24 h after its administration, an effect accompanied by increased hippocampal BDNF level. In the prefrontal cortex, BDNF level was increased only 1 h after guanosine treatment. Finally, guanosine was effective in the NSF test (after 1 h) but caused no alterations in dendritic spine density and remodeling in the ventral dentate gyrus (DG). Altogether, the results indicate that guanosine modulates targets known to be implicated in fast antidepressant behavioral responses (AMPA receptor, VDCC, and TrkB/BDNF pathway).
Asunto(s)
Antidepresivos/farmacología , Factor Neurotrófico Derivado del Encéfalo/efectos de los fármacos , Guanosina/farmacología , Glicoproteínas de Membrana/efectos de los fármacos , Proteínas Tirosina Quinasas/efectos de los fármacos , Receptores AMPA/agonistas , Transducción de Señal/efectos de los fármacos , Animales , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Canales de Calcio/efectos de los fármacos , Espinas Dendríticas/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Femenino , Suspensión Trasera , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Glicoproteínas de Membrana/biosíntesis , Ratones , Neurogénesis/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Proteínas Tirosina Quinasas/biosíntesis , Sinapsis/efectos de los fármacosRESUMEN
A role for microglia in neuropsychiatric diseases, including major depressive disorder (MDD), has been postulated. Regulation of microglial phenotype by immune receptors has become a central topic in many neurological conditions. We explored preclinical and clinical evidence for the role of the CD300f immune receptor in the fine regulation of microglial phenotype and its contribution to MDD. We found that a prevalent nonsynonymous single-nucleotide polymorphism (C/T, rs2034310) of the human CD300f receptor cytoplasmic tail inhibits the protein kinase C phosphorylation of a threonine and is associated with protection against MDD, mainly in women. Interestingly, CD300f-/- mice displayed several characteristic MDD traits such as augmented microglial numbers, increased interleukin 6 and interleukin 1 receptor antagonist messenger RNA, alterations in synaptic strength, and noradrenaline-dependent and persistent depressive-like and anhedonic behaviors in females. This behavioral phenotype could be potentiated inducing the lipopolysaccharide depression model. RNA sequencing and biochemical studies revealed an association with impaired microglial metabolic fitness. In conclusion, we report a clear association that links the function of the CD300f immune receptor with MDD in humans, depressive-like and anhedonic behaviors in female mice, and altered microglial metabolic reprogramming.
Asunto(s)
Anhedonia , Trastorno Depresivo Mayor/patología , Inflamación/etiología , Microglía/patología , Polimorfismo de Nucleótido Simple , Receptores Inmunológicos/genética , Receptores Inmunológicos/fisiología , Animales , Conducta Animal , Estudios de Cohortes , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/psicología , Femenino , Perfilación de la Expresión Génica , Humanos , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo , SinapsisRESUMEN
This narrative review will present and discuss clinical data from 16 cross-sectional and 6 longitudinal studies examining the relationship between body mass index (BMI), symptoms of depression and peripheral inflammation. Our aim is to determine which of obesity and depression contributes best to the peripheral low-grade inflammation frequently associated to both conditions. Studies including a complete evaluation of inflammatory markers are scarce and high levels of interleukin-6 (IL-6) and C-reactive protein (CRP) are the most consistent findings associated with obesity and symptoms of depression. Among the cross-sectional studies, seven studies, including a total of 9421 individuals, pointed to BMI as the major factor associated with systemic low-grade inflammation. However, in four studies, including 16,837 individuals, CRP levels remained associated with the symptoms of depression even after correction for BMI, suggestion that in the absence of overweight or obesity other sources of peripheral inflammation might contribute to presence of depressive symptoms. Additionally, another five studies, including 5569 individuals failed to find an association between depression and peripheral inflammation, reinforcing the heterogeneity of this condition. In the longitudinal data, changes in BMI were associated with a reduction in depressive scores at follow-up, after bariatric surgery or after diet. In four longitudinal studies, high levels of CRP were found to be associated with depression even after adjustment for BMI and weight loss, further corroborating the idea that other sources of peripheral inflammation might contribute to depressive symptoms. Thus it seems that both obesity and depressive symptoms can contribute to peripheral inflammation, and once installed the presence of inflammation can contribute to several behavioral alterations that reinforce the cyclic pattern of co-occurrence observed in patients with obesity and MDD. Future clinical studies should focus on strategic efforts to collect new data and to improve or standardize methods for the evaluation of depression, body composition and a more complete inflammatory profile. These approaches are essential for the development of pharmacological and/or non-pharmacological strategies designed to break this cyclic pattern of co-occurrence.
Asunto(s)
Depresión/inmunología , Depresión/fisiopatología , Obesidad/psicología , Adulto , Biomarcadores/metabolismo , Índice de Masa Corporal , Proteína C-Reactiva/metabolismo , Estudios Transversales , Depresión/complicaciones , Trastorno Depresivo/complicaciones , Femenino , Humanos , Inflamación/complicaciones , Interleucina-6/metabolismo , Masculino , Persona de Mediana Edad , Obesidad/complicacionesRESUMEN
Over the past three decades, an intricate interaction between immune activation, release of pro-inflammatory cytokines and changes in brain circuits related to mood and behavior has been described. Despite extensive efforts, questions regarding when inflammation becomes detrimental or how we can target the immune system to develop new therapeutic strategies for the treatment of psychiatric disorders remain unresolved. In this context, novel aspects of the neuroinflammatory process activated in response to stressful challenges have recently been documented in major depressive disorder (MDD). The Nod-like receptor pyrin containing 3 inflammasome (NLRP3) is an intracellular multiprotein complex responsible for a number of innate immune processes associated with infection, inflammation and autoimmunity. Recent data have demonstrated that NLRP3 activation appears to bridge the gap between immune activation and metabolic danger signals or stress exposure, which are key factors in the pathogenesis of psychiatric disorders. In this review, we discuss both preclinical and clinical evidence that links the assembly of the NLRP3 complex and the subsequent proteolysis and release of the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) in chronic stress models and patients with MDD. Importantly, we also focus on the therapeutic potential of targeting the NLRP3 inflammasome complex to improve stress resilience and depressive symptoms.
Asunto(s)
Trastorno Depresivo Mayor/metabolismo , Encefalitis/metabolismo , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Psicológico/complicaciones , Animales , Trastorno Depresivo Mayor/complicaciones , Trastorno Depresivo Mayor/inmunología , Encefalitis/inmunología , Microbioma Gastrointestinal , Humanos , Inflamasomas/inmunología , Microglía/fisiología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Receptores de Reconocimiento de Patrones/metabolismo , Transducción de Señal , Estrés Psicológico/inmunología , Estrés Psicológico/metabolismoRESUMEN
INTRODUCTION: Studies have already pointed out the contribution of oxidative stress in the pathophysiology of major depressive disorder (MDD). The aim of the present study was to investigate the oxidative-antioxidative systems in MDD and in response to cognitive psychotherapies. Oxidative stress were analyzed in 49 MDD patients at baseline, post-treatment, and follow-up; and 49 control subjects without history of psychiatric disorders. RESULTS: MDD subjects presented an increase in oxidative damage related to control subjects for thiobarbituric acid reactive species (TBARS), nitric oxide, and a decrease in total thiol content. Cognitive psychotherapies were able to counteract peripheral oxidative stress in MDD patients, reducing TBARS levels (p<0.001) in the follow-up, nitric oxide (p<0.001) in the post-treatment and follow-up, and increasing the total thiol content (p<0.01) in the post-treatment and follow-up. CONCLUSION: Oxidative stress was associated with MDD and the regulation of these parameters might represent an important mechanism associated with the clinical improvement of cognitive psychotherapy.
Asunto(s)
Terapia Cognitivo-Conductual , Trastorno Depresivo Mayor/terapia , Estrés Oxidativo/fisiología , Adulto , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/psicología , Femenino , Humanos , Masculino , Óxido Nítrico/metabolismo , Compuestos de Sulfhidrilo/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Cecropia species are widely used in traditional medicine by its anti-diabetic, anti-hypertensive and anti-inflammatory properties. In the present study, we investigated the neuroprotective and antioxidant effects of the crude aqueous extract from Cecropia pachystachya leaves in a rat model of mania induced by ketamine. The results indicated that ketamine treatment (25 mg/kg i.p., for 8 days) induced hyperlocomotion in the open-field test and oxidative damage in prefrontal cortex and hippocampus, evaluated by increased lipid peroxidation, carbonyl protein formation and decreased total thiol content. Moreover, ketamine treatment reduced the activity of the antioxidant enzymes superoxide dismutase and catalase in hippocampus. Pretreatment of rats with C. pachystachya aqueous extract (200 and 400 mg/kg p.o., for 14 days) or with lithium chloride (45 mg/kg p.o., for 14 days, used as a positive control) prevented both behavioral and pro-oxidant effects of ketamine. These findings suggest that C. pachystachya might be a useful tool for preventive intervention in bipolar disorder, reducing the episode relapse and the oxidative damage associated with the manic phase of this disorder .
Asunto(s)
Trastorno Bipolar/prevención & control , Ketamina/toxicidad , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Urticaceae/química , Animales , Conducta Animal , Cromatografía Líquida de Alta Presión , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Locomoción/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas WistarRESUMEN
Bipolar disorder (BD) is a chronic and debilitating illness characterized by recurrent manic and depressive episodes. Our research investigates the protective effects of curcumin, the main curcuminoid of the Indian spice turmeric, in a model of mania induced by ketamine administration in rats. Our results indicated that ketamine treatment (25 mg/kg, for 8 days) induced hyperlocomotion in the open-field test and oxidative damage in prefrontal cortex (PFC) and hippocampus (HP), evaluated by increased lipid peroxidation and decreased total thiol content. Moreover, ketamine treatment reduced the activity of the antioxidant enzymes superoxide dismutase and catalase in the HP. Pretreatment of rats with curcumin (20 and 50 mg/kg, for 14 days) or with lithium chloride (45 mg/kg, positive control) prevented behavioral and pro-oxidant effects induced by ketamine. These findings suggest that curcumin might be a good compound for preventive intervention in BD, reducing the episode relapse and the oxidative damage associated with the manic phase of this disorder.