Testing for Thyroid Peroxidase and Antineuronal Antibodies in Depression and Schizophrenia.

Dietary interventions and physical exercise may improve some symptoms in mental illnesses such as major depression and schizophrenia. Hashimoto's thyroiditis is a known risk factor for these conditions and is marked by the presence of circulating antibodies to thyroid peroxidase (TPO) and thyroglobulin (TG). This chapter presents a protocol to determine if patients with major depression or schizophrenia contain high circulating levels of these antibodies relative to healthy controls. We also describe a procedure testing for the presence of other circulating biomarkers related to brain function, including antibodies directly related to neuronal function. This analysis was performed by screening biochip mosaics of frozen tissue sections and transfected HEK293 cells expressing target antigens using patient and control sera. Finally, we describe a correlation analysis of these markers with symptom scores at baseline and after 6 weeks treatment of the patients using antipsychotics or antidepressants as appropriate.

Paeoniflorin ameliorates chronic stress-induced depression-like behavior in mice model by affecting ERK1/2 pathway.

Depression is a mental and emotional disorder that has made an opening great burden to the society. Paeoniflorin showed remarkable antidepressant-like effects in multiple animal models with depressive disorders. However, the molecule of paeoniflorin on depression is less studied. This study aims to explore the effect and the molecular mechanism of paeoniflorin on depression in a chronic restraint stress (CRS) mice model. CRS model of C57BL/6 J mice was set up. Sucrose preference test (SPT), tail suspension test (TST), open field test (OFT) and forced swimming test (FST) were used to assess depression symptoms. Immunofluorescence staining, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting were implemented to detect the expression changes of the proteins involved in extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Results showed that paeoniflorin treatment decreased the degree of depression in the CRS mice. Further analysis showed that the expression of ERK1/2 proteins was significantly downregulated, while paeoniflorin could elevate the expression of ERK1/2 proteins in CRS mice. Finally, it showed that inhibiting signaling ERK1/2 pathway could aggravate the depressive behavior when treatment with ERK-specific inhibitor U0126, while the condition could be partially relieved when treated with paeoniflorin. In conclusion, the present study demonstrated that paeoniflorin attenuated chronic stress-induced depression-like behavior in mice by affecting the ERK1/2 pathway. These findings provided the basis for the molecular mechanism of paeoniflorin on the effect of depression, which support paeoniflorin might act as an important drug in the treatment of depression.

Botanical Drug Puerarin Ameliorates Liposaccharide-Induced Depressive Behaviors in Mice via Inhibiting RagA/mTOR/p70S6K Pathways.

BACKGROUND: The depressive symptom hallmarks the progression of the neurodegenerative diseases, especially Alzheimer's disease. Bacterial infection is related to inflammation and depression. The present project thereby examined whether botanical drug puerarin could attenuate liposaccharide- (LPS-) induced depressive behaviors in mice. METHODS: Adult male C57BL/6N mice were sequentially treated with LPS and puerarin and evaluated for the depressive behaviors by tail suspension test and forced swim test. The brain tissues were profiled for the molecular targets of puerarin by next-generation RNA sequencing technique. Candidate targets were further verified in LPS-treated mice, neural stem cells, and highly differentiated PC12 cell line. RESULTS: Puerarin ameliorated LPS-induced depression in the mice. RNA sequencing profiles revealed that puerarin altered the expression of 16 genes while markedly downregulated Ras-related GTP-binding protein A (RagA) in LPS-treated mice. The effect of puerarin on RagA expression was confirmed by immunostaining, Western blot, and quantitative real-time PCR (qRT-PCR). Biochemical studies showed that puerarin inhibited RagA/mTOR/p70S6K pathway, attenuated the accumulation of mTORC1 in close proximity to lysosome, and reduced the production of proinflammatory cytokines. CONCLUSIONS: Botanical drug puerarin attenuated inflammation and depressive behaviors in LPS-challenged mice by inhibiting RagA/mTOR/p70S6K pathways. Puerarin may be a lead compound for the new antidepressant drugs.

PBMC telomerase activity in depression and the response to electroconvulsive therapy.

Telomerase, the DNA polymerase responsible for maintaining telomere length, has previously been implicated in depression and the response to antidepressant drugs. In this study, we aimed to compare telomerase activity in peripheral blood mononuclear cells between patients with severe depression recruited as part of the KEEP-WELL Trial (Ketamine for Depression Relapse Prevention Following ECT; NCT02414932) and age- and sex-matched healthy volunteers both at baseline/pre-ECT and at follow-up 1 month later for controls or in patients after a course of ECT. We found no differences in telomerase activity between patients with depression (n = 20) compared to healthy controls (n = 33) at baseline/pre-ECT, or between patients treated with ECT compared to controls at follow-up. In patients, telomerase activity was not associated with mood, as assessed by the 24-item Hamilton Rating Scale for Depression, or the duration of the current depressive episode. Additionally, we found no significant relationship between telomerase activity and exposure to recent or childhood adversity in either the patient or control groups. Overall, our results suggest that telomerase activity is not associated with depression, the therapeutic response to ECT, or exposure to adversity.

Legumain knockout improves repeated corticosterone injection-induced depression-like emotional and cognitive deficits.

Emotional and cognitive impairment has been recognized as a central feature of depression, which is closely related to hyperfunction of the hypothalamic-pituitary-adrenal (HPA) axis caused by down-regulation of glucocorticoid receptor (GR) expression in patients. A decrease in GR expression can cause pathological changes and lead to the impairment of synaptic plasticity. Legumain, a lysosomal cysteine protease, plays an important role in neurological diseases. It is reported that legumain activates the MAPK signaling pathway, which modifies the GR. Therefore, we hypothesize that regulation of the GR by legumain plays a crucial role in the pathological process of depression. The relationships between legumain, GR, synaptic plasticity and emotional and cognitive deficits were explored in this study. The results demonstrated that repeated corticosterone (CORT) injections (3 weeks) induced emotional and cognitive deficits in mice, based on behavioral experiments and the detection of synaptic plasticity. Furthermore, CORT injections decreased the expression of hippocampal synapse-related proteins, cell density and dendritic spine density in the hippocampus, accompanied by increased protein expression in the MAPK signaling pathway and decreased expression of the GR. In conclusion, our results demonstrated that legumain knockout up-regulated expression of the GR by reducing protein expression in the MAPK signaling pathway, thereby improving hippocampal synaptic plasticity as well as the emotional and cognitive impairment of model mice. This suggests that legumain may be an effective therapeutic target for emotional and cognitive deficits.

Cognitive effects of the GSK-3 inhibitor "lithium" in LPS/chronic mild stress rat model of depression: Hippocampal and cortical neuroinflammation and tauopathy.

Low-dose repeated lipopolysaccharide pre-challenge followed by chronic mild stress (LPS/CMS) protocol has been introduced as a rodent model of depression combining the roles of immune activation and chronic psychological stress. However, the impact of this paradigm on cognitive functioning has not been investigated hitherto. METHODS: This study evaluated LPS/CMS-induced cognitive effects and the role of glycogen synthase kinase-3ß (GSK-3ß) activation with subsequent neuroinflammation and pathological tau deposition in the pathogenesis of these effects using lithium (Li) as a tool for GSK-3 inhibition. RESULTS: LPS pre-challenge reduced CMS-induced neuroinflammation, depressive-like behavior and cognitive inflexibility. It also improved spatial learning but increased GSK-3ß expression and exaggerated hyperphosphorylated tau accumulation in hippocampus and prefrontal cortex. Li ameliorated CMS and LPS/CMS-induced depressive and cognitive deficits, reduced GSK-3ß over-expression and tau hyperphosphorylation, impeded neuroinflammation and enhanced neuronal survival. CONCLUSION: This study draws attention to LPS/CMS-triggered cognitive changes and highlights how prior low-dose immune challenge could develop an adaptive capacity to buffer inflammatory damage and maintain the cognitive abilities necessary to withstand threats. This work also underscores the favorable effect of Li (as a GSK-3ß inhibitor) in impeding exaggerated tauopathy and neuroinflammation, rescuing neuronal survival and preserving cognitive functions. Yet, further in-depth studies utilizing different low-dose LPS challenge schedules are needed to elucidate the complex interactions between immune activation and chronic stress exposure.

Tissue-Nonspecific Alkaline Phosphatase-A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease.

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5'-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme's role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.

e5NT inhibitor protects acute restraint stress-induced depression by regulating nucleoside release in mice.

OBJECTIVES: To determine whether ecto-5'-nucleotidase (e5NT) contributes to the release of adenosine and uridine and whether is establishes the role of e5NT in acute restraint stress-induced depression and anxiety-like behaviours in mice. METHODS: Acute restraint stress was induced to detect the level of nucleoside in the hippocampus. Mouse hippocampal brain proteins were isolated and subjected to Western blotting (WB) experiments to examine the protein expression levels of proteins that affect nucleoside release. Adenosine 5'-(α,ß-methylene)diphosphate (APCP), an e5NT inhibitor, was intraventricularly injected to investigate the regulatory effect of e5NT on nucleoside levels and behavioural changes caused by acute restraint stress in mice. KEY FINDINGS: Acute restraint stress increased the level of extracellular adenosine and uridine levels in the hippocampus of mice and significantly increased the expression of extracellular nucleoside-metabolizing enzymes were significantly increased. By administering APCP, the increase in adenosine and uridine levels caused by acute restraint stress could be suppressed. APCP inhibited behavioural changes, which were induced by acute restraint stress. CONCLUSIONS: These data suggest that acute restraint stress may alter extracellular adenosine and uridine levels content in the hippocampus of mice via e5NT, and thus, the inhibition of e5NT may improve the anxiety behaviour in mice. Therefore, e5NT may therefore be a potential therapeutic target for the treatment of anxiety in mice.

The Forebrain-Specific Overexpression of Acid Sphingomyelinase Induces Depressive-Like Symptoms in Mice.

Human and murine studies identified the lysosomal enzyme acid sphingomyelinase (ASM) as a target for antidepressant therapy and revealed its role in the pathophysiology of major depression. In this study, we generated a mouse model with overexpression of Asm (Asm-tgfb) that is restricted to the forebrain to rule out any systemic effects of Asm overexpression on depressive-like symptoms. The increase in Asm activity was higher in male Asm-tgfb mice than in female Asm-tgfb mice due to the breeding strategy, which allows for the generation of wild-type littermates as appropriate controls. Asm overexpression in the forebrain of male mice resulted in a depressive-like phenotype, whereas in female mice, Asm overexpression resulted in a social anxiogenic-like phenotype. Ceramides in male Asm-tgfb mice were elevated specifically in the dorsal hippocampus. mRNA expression analyses indicated that the increase in Asm activity affected other ceramide-generating pathways, which might help to balance ceramide levels in cortical brain regions. This forebrain-specific mouse model offers a novel tool for dissecting the molecular mechanisms that play a role in the pathophysiology of major depression.

The mood stabilizing properties of AF3581, a novel potent GSK-3ß inhibitor.

Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3ß has been linked to several disease conditions. There is now large evidence on the role of GSK-3ß in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3ß in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3ß inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3ß in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3ß activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 ß inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3ß has been linked to several disease conditions. There is now large evidence on the role of GSK-3ß in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3ß in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3ß inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3ß in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3ß activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 ß inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3ß has been linked to several disease conditions. There is now large evidence on the role of GSK-3ß in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3ß in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3ß inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3ß in the nanomolar range on purified human enzymeand highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3ß activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 ß inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3ß has been linked to several disease conditions. There is now large evidence on the role of GSK-3ß in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3ß in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3ß inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3ß in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3ß activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 ß inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3ß has been linked to several disease conditions. There is now large evidence on the role of GSK-3ß in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3ß in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3ß inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3ß in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3ß activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 ß inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3ß has been linked to several disease conditions. There is now large evidence on the role of GSK-3ß in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3ß in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3ß inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3ß in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3ß activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 ß inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3ß has been linked to several disease conditions. There is now large evidence on the role of GSK-3ß in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3ß in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3ß inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3ß in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3ß activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 ß inhibitors in the management of bipolar disorders patients.

The Antiproliferative Effects of Flavonoid MAO Inhibitors on Prostate Cancer Cells.

Prostate cancer (PCa) patients commonly experience clinical depression. Recent reports indicated that monoamine oxidase-A (MAO-A) levels elevate in PCa, and antidepressant MAO-Is show anti-PCa properties. In this work, we aimed to find potential drugs for PCa patients suffering from depression by establishing novel anti-PCa reversible monoamine oxidase-A inhibitors (MAO-AIs/RIMA); with an endeavor to understand their mechanism of action. In this investigation, twenty synthesized flavonoid derivatives, defined as KKR compounds were screened for their inhibitory potentials against human MAO-A and MAO-B isozymes. Meanwhile, the cytotoxic and antiproliferative effects were determined in three human PCa cell lines. MAO-A-kinetics, molecular docking, SAR, cell morphology, and cell migration were investigated for the most potent compounds. The screened KKRs inhibited MAO-A more potently than MAO-B, and non-toxically inhibited LNCaP cell proliferation more than the DU145 and PC3 cell lines, respectively. The results showed that the three top MAO-AI KKRs compounds (KKR11, KKR20, and KKR7 (IC50s 0.02-16 µM) overlapped with the top six antiproliferative KKRs against LNCaP (IC50s ~9.4 µM). While KKR21 (MAO-AI) and KKR2A (MAO-I) were ineffective against the PCa cells. Furthermore, KKR21 and KKR11 inhibited MAO-A competitively (Kis ≤ 7.4 nM). Molecular docking of the two compounds predicted shared hydrophobic and distinctive hydrophilic interactions-between the KKR molecule and MAO-A amino acid residues-to be responsible for their reversibility. The combined results and SAR observations indicated that the presence of specific active groups-such as chlorine and hydroxyl groups-are essential in certain MAO-AIs with anti-PCa effects. Additionally, MAO-A inhibition was found to be associated more with anti-PCa property than MAO-B. Distinctively, KKR11 [(E)-3-(3,4-dichlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one] exhibited anti-metastatic effects on the DU145 cell line. The chlorine substitution groups might play vital roles in the KKR11 multiple actions. The obtained results indicated that the flavonoid derivative KKR11 could present a novel candidate for PCa patients with depression, through safe non-selective potent inhibition of MAOs.

The Advances of the Structure and Function of Indoleamine 2, 3- dioxygenase 1 and Its Inhibitors.

Indoleamine 2, 3-dioxygenase 1 (IDO1) is the only rate-limiting enzyme outside the liver that catalyzes the oxidation and cracking of indole rings in the tryptophan along the kynurenine pathway (KP). The overactivation of IDO1 is closely related to the pathogenesis of various human immune and neurological diseases. As an important target for the treatment of many human serious diseases, including malignant tumors, the development of IDO1 inhibitors is of great practical significance. In this work, the structure and function of IDO1 both are summarized from the aspects of the signal pathway, catalytic mechanism, structural biology, and so on. Moreover, the current development status of IDO1 inhibitors is also systematically reviewed, which provides assistance for anti-cancer drug design based on the structure of receptors.

Anxiety and Depression Are Related to Higher Activity of Sphingolipid Metabolizing Enzymes in the Rat Brain.

Changes in sphingolipid metabolism have been suggested to contribute to the pathophysiology of major depression. In this study, we investigated the activity of acid and neutral sphingomyelinases (ASM, NSM) and ceramidases (AC, NC), respectively, in twelve brain regions of female rats selectively bred for high (HAB) versus low (LAB) anxiety-like behavior. Concomitant with their highly anxious and depressive-like phenotype, HAB rats showed increased activity of ASM and NSM as well as of AC and NC in multiple brain regions associated with anxiety- and depressive-like behavior, including the lateral septum, hypothalamus, ventral hippocampus, ventral and dorsal mesencephalon. Strong correlations between anxiety-like behavior and ASM activity were found in female HAB rats in the amygdala, ventral hippocampus and dorsal mesencephalon, whereas NSM activity correlated with anxiety levels in the dorsal mesencephalon. These results provide novel information about the sphingolipid metabolism, especially about the sphingomyelinases and ceramidases, in major depression and comorbid anxiety.

Impact of CYP2C19 genotype-predicted enzyme activity on hippocampal volume, anxiety, and depression.

Cytochrome P450 C19 (CYP2C19) metabolizes exogenous and endogenous compounds. Although CYP2C19 is highly expressed in the liver, it is also expressed in the brain during early life. Previous human and animal studies have linked CYP2C19 genotype-predicted enzyme activity to hippocampal volumes, depressive symptoms, and anxiety-like behaviors. We examined these promising associations in a general community sample comprising 386 Caucasian adults with no history of psychiatric or neurological illnesses. Contrary to previous findings, CYP2C19 genotype-predicted enzyme activity was not associated with hippocampal volumes, nor depressive and anxiety symptoms. Interstudy differences in CYP2C19 frequencies and/or study methodology may explain this discrepancy.

The effects of fluoxetine on oligodendrocytes in the hippocampus of chronic unpredictable stress-induced depressed model rats.

Depression is a mental illness which is harmful seriously to the society. This study investigated the effects of fluoxetine on the CNPase+ oligodendrocytes in hippocampus of the depressed rats to explore the new target structure of antidepressants. Male Sprague-Dawley rats were used to build chronic unpredictable stress (CUS) depressed model of rats. Then, the depressed rats were divided into the CUS standard group and the CUS + fluoxetine (CUS/FLX) group. The CUS/FLX group was treated with fluoxetine at dose of 5 mg/(kg·d) from the fifth week to seventh week. After 7 weeks CUS intervention, the sucrose preference of the CUS standard group was significantly lower than that of the control group and the CUS/FLX group. The stereological results showed that the total number of the CNPase+ cells in the CA1, CA3, and DG subfield of the hippocampus in the CUS standard group were significantly decreased, when compared with the CNPase+ cells in the control group. However, the total number of the CNPase+ cells in the CA1 and CA3 subfield of the hippocampus in the CUS standard group was significantly decreased when it compared with CNPase+ cells in the CUS/FLX group. Therefore, fluoxetine might prevent the loss of CNPase+ oligodendrocytes in CA1 and CA3 subfields of hippocampus of the depressed rats. The oligodendrocytes in hippocampus may play an important role in the pathogenesis of depression. The current result might provide structural basis for the future studies that search for new antidepressant strategies.

Acid Sphingomyelinase Inhibition Mitigates Histopathological and Behavioral Changes in a Murine Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) can lead to the development of chronic traumatic encephalopathy as a result of neuronal phosphorylated tau (p-tau) protein aggregation and neuroinflammation. Acid sphingomyelinase (Asm) may also contribute to post-TBI neurodegenerative disorders. We hypothesized that Asm inhibition would ameliorate p-tau aggregation, neuroinflammation, and behavioral changes after TBI in a murine model. TBI was generated using a weight-drop method. Asm inhibition in wild-type mice was achieved with a single injection of amitriptyline 1 h after TBI. Genetic Asm ablation was achieved using Asm-deficient mice (Asm-/-). Thirty days after TBI, mice underwent behavioral testing with the forced swim test for symptoms of depression or were euthanized for neurohistological analysis. Neuroinflammation was quantified using the microglial markers, ionized calcium-binding adaptor molecule 1 and transmembrane protein 119. Compared to sham mice, TBI mice demonstrated increased hippocampal p-tau. Mice that received amitriptyline after TBI demonstrated decreased p-tau compared to mice that received a saline control. Further, post-TBI Asm-/- mice demonstrated lower levels of p-tau compared to wild-type mice. Though a decrease in neuroinflammation was observed at 1 month post-TBI, no change was demonstrated with mice treated with amitriptyline. Similarly, TBI mice were more likely to show depression compared to mice that received amitriptyline after TBI. Utilizing a weight-drop method to induce moderate TBI, we have shown that genetic deficiency or pharmacological inhibition of Asm prevented hippocampal p-tau aggregation 1 month after injury as well as decreased symptoms of depression. These findings highlight an opportunity to potentially reduce the long-term consequences of TBI.

Ketamine induces rapid and sustained antidepressant-like effects in chronic pain induced depression: Role of MAPK signaling pathway.

Chronic pain produces psychologic distress, which often leads to mood disorders such as depression. Co-existing chronic pain and depression pose a serious socio-economic burden and result in disability affecting millions of individuals, which urges the development of treatment strategies targeting this comorbidity. Ketamine, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, is shown to be efficient in treating both pain and depression-related symptoms. However, the molecular characteristics of its role in chronic pain-induced depression remain largely unexplored. Hence, we studied the behavioral and molecular effects of a single systemic administration of ketamine (15 mg/kg, i.p.) on mechanical hypersensitivity and depressive-like consequences of chronic neuropathic pain. We showed that ketamine transiently alleviated mechanical hypersensitivity (lasting <24 h), while its antidepressant effect was observed even 72 h after administration. In addition, ketamine normalized the upregulated expression of the mitogen activated protein kinase (MAPK) phosphatase 1 (MKP-1) and the downregulated phosphorylation of extracellular signal-regulated kinase (pERK) in the anterior cingulate cortex (ACC) of mice displaying neuropathic pain-induced depressive-like behaviors. This effect of ketamine on the MKP-1 was first detected 30 min after the ketamine administration and persisted until up to 72 h. Altogether, these findings provide insight into the behavioral and molecular changes associated with single ketamine administration in the comorbidity of chronic pain and depression.

Reduced chronic restraint stress in mice overexpressing hyperactive proteasomes in the forebrain.

While chronic restraint stress (CRS) results in depression-like behaviors possibly through oxidative stress in the brain, its molecular etiology and the development of therapeutic strategies remain elusive. Since oxidized proteins can be targeted by the ubiquitin-proteasome system, we investigated whether increased proteasome activity might affect the stress response in mice. Transgenic mice, expressing the N-terminally deleted version of α3 subunit (α3ΔN) of the proteasome, which has been shown to generate open-gated mutant proteasomes, in the forebrain were viable and fertile, but showed higher proteasome activity. After being challenged with CRS for 14 d, the mutant mice with hyperactive proteasomes showed significantly less immobility time in the forced swimming test compared with their wild-type littermates, suggesting that the α3ΔN transgenic mice are resistant to CRS. The accumulation of ER stress markers, such as polyubiquitin conjugates and phospho-IRE1α, was also significantly delayed in the hippocampus of the mutants. Notably, α3ΔN mice exhibited little deficits in other behavioral tasks, suggesting that stress resilience is likely due to the degradation of misfolded proteins by the open-gated proteasomes. These data strongly indicate that not only is the proteasome a critical modulator of stress response in vivo but also a possible therapeutic target for reducing chronic stress.

Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior.

Depression alters the structure and function of brain reward circuitry. Preclinical evidence suggests that medium spiny neurons (MSNs) in the nucleus accumbens (NAc) undergo structural plasticity; however, the molecular mechanism and behavioral significance is poorly understood. Here we report that atrophy of D1, but not D2 receptor containing MSNs is strongly associated with social avoidance in mice subject to social defeat stress. D1-MSN atrophy is caused by cell-type specific upregulation of the GTPase RhoA and its effector Rho-kinase. Pharmacologic and genetic reduction of activated RhoA prevents depressive outcomes to stress by preventing loss of D1-MSN dendritic arbor. Pharmacologic and genetic promotion of activated RhoA enhances depressive outcomes by reducing D1-MSN dendritic arbor and is sufficient to promote depressive-like behaviors in the absence of stress. Chronic treatment with Rho-kinase inhibitor Y-27632 after chronic social defeat stress reverses depression-like behaviors by restoring D1-MSN dendritic complexity. Taken together, our data indicate functional roles for RhoA and Rho-kinase in mediating depression-like behaviors via dendritic remodeling of NAc D1-MSNs and may prove a useful target for new depression therapeutics.

Associations of acetylcholinesterase activity with depression and anxiety symptoms among adolescents growing up near pesticide spray sites.

BACKGROUND: The cholinergic system has an important role in mood regulation. Cholinesterase inhibitor pesticides (e.g. organophosphates) appear to increase depression and anxiety symptoms in the few existing animal and human studies. Human studies have not described such associations using biomarkers of exposure and studies among children are needed. METHODS: We studied 529 adolescents (ages 11-17y) in agricultural communities in the Ecuadorian Andes (ESPINA study). Acetylcholinesterase (AChE) activity was measured in a finger-stick sample. Anxiety and depression symptoms were assessed using the CDI-2 and MASC-2 (greater scores reflect greater internalizing symptoms). Models adjusted for age, gender, hemoglobin, income among others. RESULTS: The median age was 14.38y and 51% were female. The mean (SD) of the following parameters were: AChE 3.7 U/mL (0.55), depression T-score 53.0 (9.4) and anxiety T-score: 57.6 (9.8). Lower AChE activity (reflecting greater cholinesterase inhibitor exposure) was associated with higher depression symptoms (difference per SD decrease of AChE [ß [95% CI:]]: 1.09 [0.02, 2.16]), was stronger among girls (ß = 1.61) than boys (ß = 0.69), and among younger (<14.38y, ß = 1.61) vs. older children (ß = 0.57). The associations were strongest among girls <14.38y (ß = 3.30 [0.54, 6.05], OR for elevated symptoms per SD decrease in AChE = 2.58 [1.26, 5.27]). No associations were observed with anxiety scores. Analyses of AChE change between 2008 and 2016 concurred with these findings. DISCUSSION: We observed associations between a biomarker of pesticide exposure and children's depression symptoms. Lower AChE activity may create risk for depression in teenagers, particularly among girls during early adolescence.