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The Mental Health Clinician Nov 2021Transcranial magnetic stimulation (TMS) is a noninvasive procedure used in the treatment of depression. We observed TMS-associated mania with psychotic symptoms in a...
Transcranial magnetic stimulation (TMS) is a noninvasive procedure used in the treatment of depression. We observed TMS-associated mania with psychotic symptoms in a 55-year-old male diagnosed with MDD and generalized anxiety disorder without history of psychosis or mania. Owing to poor pharmacotherapeutic response and worsening symptomatology, TMS was introduced while continuing phenelzine; this was initially successful in demonstrating positive effects on mood. However, the patient began to develop symptoms consistent with mania with psychosis and was hospitalized. Both TMS and phenelzine were discontinued, leading to significant improvement of the symptoms of mania and psychosis. Phenelzine was later reintroduced for maintenance treatment of depression and anxiety, with no recurrence of mania or psychosis. This case report implicates TMS as a possible cause of mania and psychosis symptoms.
PubMed: 34824963
DOI: 10.9740/mhc.2021.11.373 -
Neuroscience Bulletin Aug 2021Traumatic brain injury (TBI)-induced coagulopathy has increasingly been recognized as a significant risk factor for poor outcomes, but the pathogenesis remains poorly...
Traumatic brain injury (TBI)-induced coagulopathy has increasingly been recognized as a significant risk factor for poor outcomes, but the pathogenesis remains poorly understood. In this study, we aimed to investigate the causal role of acrolein, a typical lipid peroxidation product, in TBI-induced coagulopathy, and further explore the underlying molecular mechanisms. We found that the level of plasma acrolein in TBI patients suffering from coagulopathy was higher than that in those without coagulopathy. Using a controlled cortical impact mouse model, we demonstrated that the acrolein scavenger phenelzine prevented TBI-induced coagulopathy and recombinant ADAMTS-13 prevented acrolein-induced coagulopathy by cleaving von Willebrand factor (VWF). Our results showed that acrolein may contribute to an early hypercoagulable state after TBI by regulating VWF secretion. mRNA sequencing (mRNA-seq) and transcriptome analysis indicated that acrolein over-activated autophagy, and subsequent experiments revealed that acrolein activated autophagy partly by regulating the Akt/mTOR pathway. In addition, we demonstrated that acrolein was produced in the perilesional cortex, affected endothelial cell integrity, and disrupted the blood-brain barrier. In conclusion, in this study we uncovered a novel pro-coagulant effect of acrolein that may contribute to TBI-induced coagulopathy and vascular leakage, providing an alternative therapeutic target.
Topics: Acrolein; Animals; Autophagy; Blood Coagulation Disorders; Brain Injuries, Traumatic; Humans; Mice; von Willebrand Factor
PubMed: 33939120
DOI: 10.1007/s12264-021-00681-0 -
Pathogens (Basel, Switzerland) Apr 2021Non-typhoidal ingeniously scavenges energy for growth from tyramine (TYR) and d-glucuronic acid (DGA), both of which occur in the host as the metabolic byproducts of...
Non-typhoidal ingeniously scavenges energy for growth from tyramine (TYR) and d-glucuronic acid (DGA), both of which occur in the host as the metabolic byproducts of the gut microbial metabolism. A critical first step in energy scavenging from TYR and DGA in involves TYR-oxidation via TYR-oxidoreductase and production of free-DGA via β-glucuronidase (GUS)-mediated hydrolysis of d-glucuronides (conjugated form of DGA), respectively. Here, we report that utilizes TYR and DGA as sole sources of energy in a serotype-independent manner. Using colorimetric and radiometric approaches, we report that genes , , and encode TYR-oxidoreductases. Some serotypes produce GUS, thus can also scavenge energy from d-glucuronides. We repurposed phenelzine (monoaminoxidase-inhibitor) and amoxapine (GUS-inhibitor) to inhibit the TYR-oxidoreductases and GUS encoded by , respectively. We show that phenelzine significantly inhibits the growth of by inhibiting TYR-oxidoreductases SEN2971, SEN3065, and SEN2426. Similarly, amoxapine significantly inhibits the growth of by inhibiting GUS-mediated hydrolysis of d-glucuronides. Because TYR and DGA serve as potential energy sources for growth in vivo, the data and the novel approaches used here provides a better understanding of the role of TYR and DGA in pathogenesis and nutritional virulence.
PubMed: 33924374
DOI: 10.3390/pathogens10040469 -
Cellular and Molecular Neurobiology Jan 2022Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and... (Review)
Review
Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and neurochemical effects in addition to inhibition of MAO, and findings on these effects have contributed to a body of evidence indicating that PLZ also has neuroprotective/neurorescue properties. These attributes are reviewed in this paper and include catabolism to the active metabolite β-phenylethylidenehydrazine (PEH) and effects of PLZ and PEH on the GABA-glutamate balance in brain, sequestration of reactive aldehydes, and inhibition of primary amine oxidase. Also discussed are the encouraging findings of the effects of PLZ in animal models of stroke, spinal cord injury, traumatic brain injury, and multiple sclerosis, as well other actions such as reduction of nitrative stress, reduction of the effects of a toxin on dopaminergic neurons, potential anticonvulsant actions, and effects on brain-derived neurotrophic factor, neural cell adhesion molecules, an anti-apoptotic factor, and brain levels of ornithine and N-acetylamino acids.
Topics: Animals; Antidepressive Agents; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Phenelzine; Rats; Rats, Sprague-Dawley
PubMed: 33839994
DOI: 10.1007/s10571-021-01078-3 -
Frontiers in Genetics 2021Variability in the enzymatic activity of -acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is...
Variability in the enzymatic activity of -acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in -acetylation activities according to NAT2 phenotypes, i.e., rapid, intermediate, slow, and ultra-slow acetylators, between different substrate drugs. Here, we estimated genotypes in 990 Japanese individuals and compared the frequencies of different genotypes with those of different populations. We then calculated kinetic parameters of four NAT2 alleles (NAT24, 5, 6, and 7) for -acetylation of aminoglutethimide, diaminodiphenyl sulfone, hydralazine, isoniazid, phenelzine, procaineamide, sulfamethazine (SMZ), and sulfapyrizine. NAT25, 6, and 7 exhibited significantly reduced -acetylation activities with lower Vmax and CLint values of all drugs when compared with NAT24. Hierarchical clustering analysis revealed that 10 genotypes were categorized into three or four clusters. According to the results of metabolic experiments using SMZ as a substrate, the frequencies of ultra-slow acetylators were calculated to be 29.05-54.27% in Europeans, Africans, and South East Asians, whereas Japanese and East Asian populations showed lower frequencies (4.75 and 11.11%, respectively). Our findings will be helpful for prediction of responses to drugs primarily metabolized by NAT2.
PubMed: 33815485
DOI: 10.3389/fgene.2021.652704 -
Clinical Pharmacology : Advances and... 2021[This retracts the article DOI: 10.2147/CPAA.S67271.].
[This retracts the article DOI: 10.2147/CPAA.S67271.].
PubMed: 33688272
DOI: 10.2147/CPAA.S308255 -
Translational Research : the Journal of... May 2021Oligodendrocyte progenitor cells (OPCs) in the infant brain give rise to mature oligodendrocytes that myelinate CNS axons. OPCs are particularly vulnerable to oxidative...
Oligodendrocyte progenitor cells (OPCs) in the infant brain give rise to mature oligodendrocytes that myelinate CNS axons. OPCs are particularly vulnerable to oxidative stress that occurs in many forms of brain injury. One common cause of infant brain injury is neonatal intraventricular hemorrhage (IVH), which releases blood into the CSF and brain parenchyma of preterm infants. Although blood contains the powerful oxidant hemoglobin, the direct effects of hemoglobin on OPCs have not been studied. We utilized a cell culture system to test if hemoglobin induced free radical production and mitochondrial dysfunction in OPCs. We also tested if phenelzine (PLZ), an FDA-approved antioxidant drug, could protect OPCs from hemoglobin-induced oxidative stress. OPCs were isolated from Sprague Dawley rat pups and exposed to hemoglobin with and without PLZ. Outcomes assessed included intracellular reactive oxygen species levels using 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescent dye, oxygen consumption using the XFe96 Seahorse assay, and proliferation measured by BrdU incorporation assay. Hemoglobin induced oxidative stress and impaired mitochondrial function in OPCs. PLZ treatment reduced hemoglobin-induced oxidative stress and improved OPC mitochondrial bioenergetics. The effects of hemoglobin and PLZ on OPC proliferation were not statistically significant, but showed trends towards hemoglobin reducing OPC proliferation and PLZ increasing OPC proliferation (P=0.06 for both effects). Collectively, our results indicate that hemoglobin induces mitochondrial dysfunction in OPCs and that antioxidant therapy reduces these effects. Therefore, antioxidant therapy may hold promise for white matter diseases in which hemoglobin plays a role, such as neonatal IVH.
Topics: Animals; Animals, Newborn; Cell Proliferation; Female; Gene Expression Regulation; Hemoglobins; L-Lactate Dehydrogenase; Mitochondria; Oligodendroglia; Oxidative Stress; Oxygen Consumption; Phenelzine; Pregnancy; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Stem Cells
PubMed: 33460824
DOI: 10.1016/j.trsl.2021.01.005 -
ACS Pharmacology & Translational Science Dec 2020The purpose of this analysis was to assess, from the patients' perspective, the effectiveness and relative safety of tramadol as an off-label antidepressant and to...
The purpose of this analysis was to assess, from the patients' perspective, the effectiveness and relative safety of tramadol as an off-label antidepressant and to determine if patients' views and experiences are consistent with the biomedical literature. A data mining approach was used to analyze databases available at drugs.com. Tramadol was reported to be an effective or very effective antidepressant by 94.6% of patients (123/130) who provided ratings submitted to (https://www.drugs.com/comments/tramadol/for-depression.html). When compared to 34 other antidepressants in the database titled (https://www.drugs.com/condition/depression.html), for which there were ≥100 individual reviews for each drug, tramadol was rated as being the most effective (effectiveness rating = 9.1/10). Phenelzine (effectiveness rating = 8.7/10) was the only other antidepressant having ≥100 individual reviews coupled with a very high (8.0-10.0) effectiveness rating. Eleven patients reported significant symptoms of withdrawal upon cessation of tramadol, and five patients reported loss or reduction of libido as a side effect. Most (57/72, 79.2%) patients who reported a dose consumed experienced relief from depression at low therapeutic doses (25-150 mg/day). Fourteen patients reported taking this antidepressant for 5-10 years, and four patients reported taking tramadol for 10 or more years. Results demonstrated that most patients' comments and beliefs are consistent with the biomedical literature. Patients' reviews coupled with a survey of the biomedical literature indicate that at low therapeutic doses in the absence of interactions with other drugs, adult patients found tramadol to be a generally safe, effective, and fast-acting medication for relief from depression.
PubMed: 33344902
DOI: 10.1021/acsptsci.0c00132 -
Scientific Reports Oct 2020Over the past decade, there has been increasing evidence highlighting the implication of the gut microbiota in a variety of brain disorders such as depression, anxiety,...
Over the past decade, there has been increasing evidence highlighting the implication of the gut microbiota in a variety of brain disorders such as depression, anxiety, and schizophrenia. Studies have shown that depression affects the stability of gut microbiota, but the impact of antidepressant treatments on microbiota structure and metabolism remains underexplored. In this study, we investigated the in vitro antimicrobial activity of antidepressants from different therapeutic classes against representative strains of human gut microbiota. Six different antidepressants: phenelzine, venlafaxine, desipramine, bupropion, aripiprazole and (S)-citalopram have been tested for their antimicrobial activity against 12 commensal bacterial strains using agar well diffusion, microbroth dilution method, and colony counting. The data revealed an important antimicrobial activity (bacteriostatic or bactericidal) of different antidepressants against the tested strains, with desipramine and aripiprazole being the most inhibitory. Strains affiliating to most dominant phyla of human microbiota such as Akkermansia muciniphila, Bifidobacterium animalis and Bacteroides fragilis were significantly altered, with minimum inhibitory concentrations (MICs) ranged from 75 to 800 μg/mL. A significant reduction in bacterial viability was observed, reaching 5 logs cycle reductions with tested MICs ranged from 400 to 600 μg/mL. Our findings demonstrate that gut microbiota could be altered in response to antidepressant drugs.
Topics: Akkermansia; Antidepressive Agents; Bacteroides fragilis; Bifidobacterium animalis; Depression; Desipramine; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Gastrointestinal Microbiome; Humans; Microbial Sensitivity Tests; Phenelzine; Venlafaxine Hydrochloride
PubMed: 33087796
DOI: 10.1038/s41598-020-74934-9