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International Journal of Molecular... Jun 2022There has been growing recognition that major depressive disorder is a serious medical disorder that also affects children. This has been accompanied by an increased use...
There has been growing recognition that major depressive disorder is a serious medical disorder that also affects children. This has been accompanied by an increased use of antidepressant drugs in adolescents; however, not all classes of antidepressants are effective in children and adolescents. There is an increasing need to understand the differences in antidepressant action in different developmental stages. There are some data indicating that the behavioral effect of chronic antidepressant treatment in adult rodents is dependent on hippocampal neurogenesis; however, it is not known which classes of antidepressant drugs induce hippocampal neurogenesis in adolescent rodents. Three classes of antidepressant drugs were tested in two age groups of Sprague Dawley rats, pre-adolescent (postnatal days 11-24) and adolescent (postnatal days 21-34): monoamine oxidase inhibitors (MAOIs); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); and tricyclic antidepressants (TCAs). To address which classes of antidepressant drugs might alter the rate of mitogenesis in neural progenitor cells in an adolescent rodent model, adolescent Sprague Dawley rats were treated with the thymidine analog 5-bromo-deoxy-2'-uridine (BrdU) on postnatal days 21 and 22 and antidepressant drugs or vehicle for 14 days (postnatal days 21-34). To address which classes of antidepressant drugs might alter the rate of neurogenesis, postnatal day-21 Sprague Dawley rats were treated with antidepressant drugs or vehicle for 14 days (postnatal days 21-34) and BrdU on postnatal days 33 and 34. In both experimental paradigms, BrdU-positive cells in the subgranular zone and the granule cell layer were counted. Newborn neurons were identified in the neurogenic paradigm by identifying cells expressing both the neuronal specific marker NeuN and BrdU using confocal microscopy. Only the SSRI fluoxetine significantly altered the basal mitogenic and neurogenic rates in adolescent rats. Treatment with the monoamine oxidase inhibitor (MAOI) tranylcypromine (TCP) and the TCA desipramine did not alter the rate of hippocampal neurogenesis in the adolescent rats. This is consistent with human clinical observations, where only SSRIs have efficacy for treatment of depression in patients under the age of 18. In pre-adolescent rats, postnatal days 11-24, none of the drugs tested significantly altered the basal mitogenic or neurogenic rates. All of the classes of antidepressant drugs are known to induce hippocampal neurogenesis in adult rats. The mechanisms of action underlying this developmental difference in antidepressant drug action between juveniles and adults are not known.
Topics: Animals; Antidepressive Agents; Bromodeoxyuridine; Depressive Disorder, Major; Monoamine Oxidase Inhibitors; Neurogenesis; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors
PubMed: 35805924
DOI: 10.3390/ijms23136919 -
Drugs in Context 2022Diabetic peripheral neuropathy (DPN) is a major complication of diabetes mellitus. Tight glycaemic management focused on lowering haemoglobin A1C and increasing time in... (Review)
Review
Diabetic peripheral neuropathy (DPN) is a major complication of diabetes mellitus. Tight glycaemic management focused on lowering haemoglobin A1C and increasing time in the target glucose range along with metabolic risk factor management form the cornerstone of DPN prevention. However, there is limited evidence supporting the efficacy of glycaemic and metabolic control in reducing the symptoms and complications of DPN, including pain once painful DPN develops. DPN treatments include pharmacological agents and non-pharmacological interventions such as foot care and lifestyle modifications. Pharmacological agents primarily address pain symptoms, which affect 25-35% of people with DPN. First-line agents include the anticonvulsants pregabalin and gabapentin, the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine, and secondary amine tricyclic antidepressants, including nortriptyline and desipramine. All agents have unique pharmacological, safety and clinical profiles, and agent selection should be guided by the presence of comorbidities, potential for adverse effects, drug interactions and costs. Even with the current treatment options, people are commonly prescribed less than the recommended dose of medications, leading to poor management of DPN symptoms and treatment discontinuation. By keeping up with the latest therapy algorithms and treatment options, healthcare professionals can improve the care for people with DPN.
PubMed: 35775075
DOI: 10.7573/dic.2021-10-2 -
Drugs & Aging Jun 2022Depression is one of the most frequent and burdensome non-motor symptoms in Parkinson's disease (PD), across all stages. Even when its severity is mild, PD depression... (Review)
Review
Depression is one of the most frequent and burdensome non-motor symptoms in Parkinson's disease (PD), across all stages. Even when its severity is mild, PD depression has a great impact on quality of life for these patients and their caregivers. Accordingly, accurate diagnosis, supported by validated scales, identification of risk factors, and recognition of motor and non-motor symptoms comorbid to depression are critical to understanding the neurobiology of depression, which in turn determines the effectiveness of dopaminergic drugs, antidepressants and non-pharmacological interventions. Recent advances using in vivo functional and structural imaging demonstrate that PD depression is underpinned by dysfunction of limbic networks and monoaminergic systems, depending on the stage of PD and its associated symptoms, including apathy, anxiety, rapid eye movement sleep behavior disorder (RBD), cognitive impairment and dementia. In particular, the evolution of serotonergic, noradrenergic, and dopaminergic dysfunction and abnormalities of limbic circuits across time, involving the anterior cingulate and orbitofrontal cortices, amygdala, thalamus and ventral striatum, help to delineate the variable expression of depression in patients with prodromal, early and advanced PD. Evidence is accumulating to support the use of dual serotonin and noradrenaline reuptake inhibitors (desipramine, nortriptyline, venlafaxine) in patients with PD and moderate to severe depression, while selective serotonin reuptake inhibitors, repetitive transcranial magnetic stimulation and cognitive behavioral therapy may also be considered. In all patients, recent findings advocate that optimization of dopamine replacement therapy and evaluation of deep brain stimulation of the subthalamic nucleus to improve motor symptoms represents an important first step, in addition to physical activity. Overall, this review indicates that increasing understanding of neurobiological changes help to implement a roadmap of tailored interventions for patients with PD and depression, depending on the stage and comorbid symptoms underlying PD subtypes and their prognosis.
Topics: Antidepressive Agents; Apathy; Depression; Humans; Parkinson Disease; Quality of Life
PubMed: 35705848
DOI: 10.1007/s40266-022-00942-1 -
Theranostics 2022Radiolabeled agents that are substrates for the norepinephrine transporter (NET) can be used to quantify cardiac sympathetic nervous conditions and have been...
Radiolabeled agents that are substrates for the norepinephrine transporter (NET) can be used to quantify cardiac sympathetic nervous conditions and have been demonstrated to identify high-risk congestive heart failure (HF) patients prone to arrhythmic events. We aimed to fully characterize the kinetic profile of the novel F-labeled NET probe AF78 for PET imaging of the cardiac sympathetic nervous system (SNS) among various species. F-AF78 was compared to norepinephrine (NE) and established SNS radiotracers by employing cell assays, followed by an approach with healthy rats, rabbits and nonhuman primates (NHPs). Additionally, chase protocols were performed in NHPs with NET inhibitor desipramine (DMI) and the NE releasing stimulator tyramine (TYR) to investigate retention kinetics in cardiac SNS. Relative to other SNS radiotracers, F-AF78 showed higher transport affinity via NET in a cell-based competitive uptake assay (IC 0.42 ± 0.14 µM), almost identical to that of NE (IC, 0.50 ± 0.16 µM, n.s.). In rabbits and NHPs, initial cardiac uptake was significantly reduced by NET inhibition. Furthermore, cardiac tracer retention was not affected by a DMI chase protocol but was markedly reduced by intermittent TYR chase, thereby suggesting that F-AF78 is stored and can be released via the synaptic vesicular turnover process. Computational modeling hypothesized the formation of a T-shaped π-π stacking at the binding site, suggesting a rationale for the high affinity of F-AF78. F-AF78 demonstrated high NET affinity and advantageous radiotracer kinetics across various species, indicating that F-AF78 is an SNS imaging agent with strong potential to guide specific interventions in cardiovascular medicine.
Topics: Animals; Biomarkers; Fluorine Radioisotopes; Humans; Molecular Imaging; Norepinephrine Plasma Membrane Transport Proteins; Positron-Emission Tomography; Rabbits; Radiopharmaceuticals; Rats
PubMed: 35673571
DOI: 10.7150/thno.63205 -
Pharmacological Reports : PR Aug 2022The preclinical antidepressant-like characterization of desipramine relied almost exclusively in male rodents, with only a few contradictory reports done in females....
BACKGROUND
The preclinical antidepressant-like characterization of desipramine relied almost exclusively in male rodents, with only a few contradictory reports done in females. Given that most experiments assessed a single dose and/or timepoint of analysis after-treatment, this study evaluated potential sex-differences in the length of the antidepressant-like response induced by different doses of desipramine as well as the molecular underpinnings driving the different responses by sex.
METHODS
Male and female Sprague-Dawley rats were treated (i.p.) with 3 pulses of desipramine (5, 10 or 20 mg/kg) or vehicle (0.9% NaCl) within 24 h. The antidepressant-like effects were evaluated in the forced-swim test 1-h, 1- and 3-day post-treatment. The rate of cell proliferation and the regulation of key neuroplasticity markers (FADD, Cdk5, p35, p25) involved in antidepressant-like responses in the hippocampus were evaluated 1-h, 1-day and 5-day post-treatment.
RESULTS
Desipramine induced similar antidepressant-like effects in male and female rats (effective doses of 10 and 20 mg/kg, with effects that lasted up to 1-day post-treatment), without altering the rate of cell proliferation. However, some sex-differences emerged when evaluating neuroplasticity markers in the hippocampus, while no changes were observed for female rats, desipramine regulated FADD, Cdk-5 and p25 in males in a way that suggested neuroprotective actions.
CONCLUSIONS
Our findings imply that while desipramine induced similar antidepressant-like responses for male and female rats, some differences emerged in the regulation of certain neuroplasticity markers, suggesting that distinctive molecular mechanisms might be participating in the therapeutic response of desipramine for both sexes.
Topics: Animals; Antidepressive Agents; Desipramine; Female; Hippocampus; Male; Rats; Rats, Sprague-Dawley; Swimming
PubMed: 35653030
DOI: 10.1007/s43440-022-00372-1 -
IUCrJ May 2022The homodimeric β-lactoglobulin belongs to the lipocalin family of proteins that transport a wide range of hydrophobic molecules and can be modified by mutagenesis to...
The homodimeric β-lactoglobulin belongs to the lipocalin family of proteins that transport a wide range of hydrophobic molecules and can be modified by mutagenesis to develop specificity for novel groups of ligands. In this work, new lactoglobulin variants, FAF (I56F/L39A/M107F) and FAW (I56F/L39A/M107W), were produced and their interactions with the tricyclic drug desipramine (DSM) were studied using X-ray crystallography, calorimetry (ITC) and circular dichroism (CD). The ITC and CD data showed micromolar affinity of the mutants for DSM and interactions according to the classical one-site binding model. However, the crystal structures unambiguously showed that the FAF and FAW dimers are capable of binding DSM not only inside the β-barrel as expected, but also at the dimer interface and at the entrance to the binding pocket. The presented high-resolution crystal structures therefore provide important evidence of the existence of alternative ligand-binding sites in the β-lactoglobulin molecule. Analysis of the crystal structures highlighted the importance of shape complementarity for ligand recognition and selectivity. The binding sites identified in the crystal structures of the FAF-DSM and FAW-DSM complexes together with data from the existing literature are used to establish a systematic classification of the ligand-binding sites in the β-lactoglobulin molecule.
PubMed: 35546795
DOI: 10.1107/S2052252522004183 -
Dementia & Neuropsychologia 2021Attention deficit hyperactivity disorder (ADHD) is one of the most frequent childhood psychiatric problems.
UNLABELLED
Attention deficit hyperactivity disorder (ADHD) is one of the most frequent childhood psychiatric problems.
OBJECTIVE
The objective of this study was to identify, synthesize the results, and critically evaluate all Cochrane systematic reviews (SRs) on the pharmacological interventions for children and adolescents (up to age 18) diagnosed with ADHD.
METHODS
The search was performed in the (via Wiley) in July 2020.
RESULTS
The search strategy resulted in four SRs of high methodological quality, analyzing 51 randomized clinical trials (9,013 participants). Compared to placebo, treatment with tricyclic antidepressants (TCAs) (desipramine), amphetamine, and methylphenidate showed improvement in symptoms such as difficulty concentrating, impulsivity, and hyperactivity in the short term (up to 6 months). There was an increase in the occurrence of adverse events, such as reduced appetite, difficulty sleeping, and abdominal pain. Insufficient evidence was found to support the effects of supplementation with polyunsaturated fatty acids.
CONCLUSIONS
The use of TCAs, amphetamine, and methylphenidate in children and adolescents with ADHD seems to present positive effects and higher rates of minor adverse events when compared to placebo.
PubMed: 35509804
DOI: 10.1590/1980-57642021dn15-040001 -
Journal of Psychiatric Research Jun 2022Tricyclic antidepressants (TCAs) are frequently prescribed in case of non-response to first-line antidepressants in Major Depressive Disorder (MDD). Treatment of MDD... (Review)
Review
Tricyclic antidepressants (TCAs) are frequently prescribed in case of non-response to first-line antidepressants in Major Depressive Disorder (MDD). Treatment of MDD often entails a trial-and-error process of finding a suitable antidepressant and its appropriate dose. Nowadays, a shift is seen towards a more personalized treatment strategy in MDD to increase treatment efficacy. One of these strategies involves the use of biomarkers for the prediction of antidepressant treatment response. We aimed to summarize biomarkers for prediction of TCA specific (i.e. per agent, not for the TCA as a drug class) treatment response in unipolar nonpsychotic MDD. We performed a systematic search in PubMed and MEDLINE. After full-text screening, 36 papers were included. Seven genetic biomarkers were identified for nortriptyline treatment response. For desipramine, we identified two biomarkers; one genetic and one nongenetic. Three nongenetic biomarkers were identified for imipramine. None of these biomarkers were replicated. Quality assessment demonstrated that biomarker studies vary in endpoint definitions and frequently lack power calculations. None of the biomarkers can be confirmed as a predictor for TCA treatment response. Despite the necessity for TCA treatment optimization, biomarker studies reporting drug-specific results for TCAs are limited and adequate replication studies are lacking. Moreover, biomarker studies generally use small sample sizes. To move forward, larger cohorts, pooled data or biomarkers combined with other clinical characteristics should be used to improve predictive power.
Topics: Antidepressive Agents; Antidepressive Agents, Tricyclic; Biomarkers; Depressive Disorder, Major; Humans; Nortriptyline
PubMed: 35397333
DOI: 10.1016/j.jpsychires.2022.03.057 -
Translational Cancer Research Jan 2022Autophagy inhibits tumorigenesis by limiting inflammation. Various lncRNAs are associated with tumour biological processes, including lung adenocarcinoma (LUAD), but the...
BACKGROUND
Autophagy inhibits tumorigenesis by limiting inflammation. Various lncRNAs are associated with tumour biological processes, including lung adenocarcinoma (LUAD), but the role of autophagy-related lncRNAs (ARlncRNAs) in LUAD has not been fully elucidated. Thus, this study aimed to construct a prognostic signature based on ARlncRNAs for LUAD.
METHODS
The RNA-seq (FPKM) data and clinical information of LUAD patients were downloaded from The Cancer Genome Atlas (TCGA) database. After differentially expressed lncRNAs in tumour and normal groups were identified, cox regression analyses were performed to construct a prognostic signature which was then assessed through independent prognostic analysis and functional enrichment analysis. Moreover, based on the mRNAs co-expressed with the ARlncRNAs, several potential small molecule drugs were explored in the Connectivity map (Cmap).
RESULTS
A signature consisting of seven ARlncRNAs (FAM83A-AS1, LINC01116, ILF3-DT, EBLN3P, AL161785.1, AC092279.1 and AC026355.2) was constructed to predict overall survival (OS) for LUAD. The signature was identified to be independent by the cox regression analysis and obtained the largest area under the curve (AUC =0.721) in the receiver operating characteristic (ROC). Six small molecule drugs (MS-275, methotrexate, desipramine, benzbromarone, rifampicin and doxazosin) were selected from Cmap.
CONCLUSIONS
A novel ARlncRNA signature for LUAD prognostic prediction was constructed, which had better efficacy than the TNM stage and used to propose potential therapeutic regimens for LUAD patients.
PubMed: 35261881
DOI: 10.21037/tcr-21-1554