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Biomedical Reports Nov 2018Peroxynitrite can be produced in the vasculature from a superoxide anion reaction with nitric oxide. A surplus of peroxynitrite in the intravascular compartment is a...
Peroxynitrite can be produced in the vasculature from a superoxide anion reaction with nitric oxide. A surplus of peroxynitrite in the intravascular compartment is a common feature of several chronic diseases. The development of pharmacological modalities that interfere with the formation of peroxynitrite or inhibit its oxidative damage may be of utility for the prevention and/or treatment of several pathologies. Our previous investigations showed that catalytically inactivating peroxynitrite-derived free radicals with tempol or scavenging reactive aldehyde species with phenelzine protects the blood plasma and platelets from the oxidative damage of peroxynitrite. However, the degree of inhibition of the cytotoxic effects of peroxynitrite using tempol or phenelzine was modest. In the present study, the aim was to examine if scavenging lipid peroxyl radicals with U-83836E can achieve superior protection from peroxynitrite. This was assessed by treating blood plasma or platelets with 100 µM peroxynitrite alone or in combination with U-83836E, and then measuring the levels of thiobarbituric acid reactive substances (TBARS) and protein carbonyl formation as indices of lipid peroxidation and protein oxidation, respectively. It was observed that scavenging lipid peroxyl radicals with 75-100 µM U-83836E increasingly reversed protein carbonylation induced by peroxynitrite in blood plasma and platelets, in addition to TBARS formation in blood plasma. These findings are further discussed in the context of the mechanisms by which U-83836E may protect against the cell-damaging effects of peroxynitrite.
PubMed: 30345039
DOI: 10.3892/br.2018.1144 -
International Journal of Molecular... Sep 2018Phenelzine has been suggested to have an antiobesity effect by inhibiting de novo lipogenesis, which led us to investigate the metabolic effects of oral chronic...
Phenelzine has been suggested to have an antiobesity effect by inhibiting de novo lipogenesis, which led us to investigate the metabolic effects of oral chronic phenelzine treatment in high-sucrose-drinking mice. Sucrose-drinking mice presented higher body weight gain and adiposity versus controls. Phenelzine addition did not decrease such parameters, even though fat pad lipid content and weights were not different from controls. In visceral adipocytes, phenelzine did not impair insulin-stimulated de novo lipogenesis and had no effect on lipolysis. However, phenelzine reduced the mRNA levels of glucose transporters 1 and 4 and phosphoenolpyruvate carboxykinase in inguinal white adipose tissue (iWAT), and altered circulating levels of free fatty acids (FFA) and glycerol. Interestingly, glycemia was restored in phenelzine-treated mice, which also had higher insulinaemia. Phenelzine-treated mice presented higher rectal temperature, which was associated to reduced mRNA levels of uncoupling protein 1 in brown adipose tissue. Furthermore, unlike sucrose-drinking mice, hepatic malondialdehyde levels were not altered. In conclusion, although de novo lipogenesis was not inhibited by phenelzine, the data suggest that the ability to re-esterify FFA is impaired in iWAT. Moreover, the effects on glucose homeostasis and oxidative stress suggest that phenelzine could alleviate obesity-related alterations and deserves further investigation in obesity models.
Topics: Adipose Tissue, White; Adiposity; Administration, Oral; Animals; Fatty Acids, Nonesterified; Lipogenesis; Male; Mice; Mice, Inbred C57BL; Monoamine Oxidase Inhibitors; Obesity; Oxidative Stress; Phenelzine; Sucrose; Weight Gain
PubMed: 30257452
DOI: 10.3390/ijms19102904 -
Experimental and Therapeutic Medicine Sep 2018Lipid peroxidation is associated with several metabolic diseases. Lipid peroxidation causes cellular damage through reactive aldehyde species such as 4-hydroxyonenal...
Lipid peroxidation is associated with several metabolic diseases. Lipid peroxidation causes cellular damage through reactive aldehyde species such as 4-hydroxyonenal (4-HNE). The exact mechanism(s) by which 4-HNE causes damage in the intravascular compartment is not yet exactly understood. Using an system, the damage induced by 4-HNE on the blood was investigated by measuring protein carbonyl groups and thiobarbituric acid reactive substances (TBARS) following 4-HNE treatment. The findings demonstrated that treatment with 4-HNE increased the carbonylation of protein and the formation of TBARS in the blood plasma. It was also tested whether phenelzine, a scavenger of aldehyde species, or U-83836E, a scavenger of lipid peroxy radicals, attenuated the damage caused by 4-HNE. It was demonstrated that phenelzine or U-83836E both mitigated the effects of 4-HNE on the proteins and the lipids of the blood plasma. The findings of the current study suggest that phenelzine, U-83836E or functionally similar therapeutics may prevent or treat diseases that involve an increased production of 4-HNE in the intravascular compartment.
PubMed: 30186450
DOI: 10.3892/etm.2018.6419 -
Biochemical Pharmacology Sep 2018The endocannabinoid system plays an important role in the pathophysiology of various neurological disorders, such as anxiety, depression, neurodegenerative diseases, and...
The endocannabinoid system plays an important role in the pathophysiology of various neurological disorders, such as anxiety, depression, neurodegenerative diseases, and schizophrenia; however, little information is available on the coupling of the endocannabinoid system with the monoaminergic systems in the brain. In the present study, we tested four endocannabinoids and two anandamide analogs for inhibition of recombinant human MAO-A and -B (monoamine oxidase). Virodhamine inhibited both MAO-A and -B (IC values of 38.70 and 0.71 μM, respectively) with ∼55-fold greater inhibition of MAO-B. Two other endocannabinoids (noladin ether and anandamide) also showed good inhibition of MAO-B with IC values of 18.18 and 39.98 μM, respectively. Virodhamine was further evaluated for kinetic characteristics and mechanism of inhibition of human MAO-B. Virodhamine inhibited MAO-B (K value of 0.258 ± 0.037 μM) through a mixed mechanism/irreversible binding and showed a time-dependent irreversible mechanism. Treatment of Neuroscreen-1 (NS-1) cells with virodhamine produced significant inhibition of MAO activity. This observation confirms potential uptake of virodhamine by neuronal cells. A molecular modeling study of virodhamine with MAO-B and its cofactor flavin adenine dinucleotide (FAD) predicted virodhamine's terminal -NH group to be positioned near the N5 position of FAD, but for docking to MAO-A, virodhamine's terminal -NH group was far away (∼6.52 Å) from the N5 position of FAD, and encountered bad contacts with nearby water molecules. This difference could explain virodhamine's higher potency and preference for MAO-B. The binding free energies for the computationally-predicted poses also showed that virodhamine was selective for MAO-B. These findings suggest potential therapeutic applications of virodhamine for the treatment of neurological disorders.
Topics: Animals; Cannabinoid Receptor Modulators; Cannabinoids; Endocannabinoids; Humans; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; PC12 Cells; Rats
PubMed: 29958841
DOI: 10.1016/j.bcp.2018.06.024 -
Journal of Clinical Sleep Medicine :... Jun 2018Nightmare disorder affects approximately 4% of adults, occurring in isolation or as part of other disorders such as posttraumatic stress disorder (PTSD), and can...
INTRODUCTION
Nightmare disorder affects approximately 4% of adults, occurring in isolation or as part of other disorders such as posttraumatic stress disorder (PTSD), and can significantly impair quality of life. This paper provides the American Academy of Sleep Medicine (AASM) position regarding various treatments of nightmare disorder in adults.
METHODS
A literature search was performed based upon the keywords and MeSH terms from the Best Practice Guide for the Treatment of Nightmare Disorder in Adults that was published in 2010 by the AASM. The search used the date range March 2009 to August of 2017, and sought to find available evidence pertaining to the use of behavioral, psychological, and pharmacologic therapies for the treatment of nightmares. A task force developed position statements based on a thorough review of these studies and their clinical expertise. The AASM Board of Directors approved the final position statements.
DETERMINATION OF POSITION
Positions of "recommended" and "not recommended" indicate that a treatment option is determined to be clearly useful or ineffective/harmful for most patients, respectively, based on a qualitative assessment of the available evidence and clinical judgement of the task force. Positions of "may be used" indicate that the evidence or expert consensus is less clear, either in favor or against the use of a treatment option. The interventions listed below are in alphabetical order within the position statements rather than clinical preference: this is not meant to be instructive of the order in which interventions should be used.
POSITION STATEMENTS
The following therapy is recommended for the treatment of PTSD-associated nightmares and nightmare disorder: image rehearsal therapy. The following therapies may be used for the treatment of PTSD-associated nightmares: cognitive behavioral therapy; cognitive behavioral therapy for insomnia; eye movement desensitization and reprocessing; exposure, relaxation, and rescripting therapy; the atypical antipsychotics olanzapine, risperidone and aripiprazole; clonidine; cyproheptadine; fluvoxamine; gabapentin; nabilone; phenelzine; prazosin; topiramate; trazodone; and tricyclic antidepressants. The following therapies may be used for the treatment of nightmare disorder: cognitive behavioral therapy; exposure, relaxation, and rescripting therapy; hypnosis; lucid dreaming therapy; progressive deep muscle relaxation; sleep dynamic therapy; self-exposure therapy; systematic desensitization; testimony method; nitrazepam; prazosin; and triazolam. The following are not recommended for the treatment of nightmare disorder: clonazepam and venlafaxine. The ultimate judgment regarding propriety of any specific care must be made by the clinician, in light of the individual circumstances presented by the patient, accessible treatment options, and resources.
Topics: Academies and Institutes; Antidepressive Agents; Antipsychotic Agents; Dreams; Humans; Psychotherapy; Sleep Wake Disorders; United States
PubMed: 29852917
DOI: 10.5664/jcsm.7178 -
Neuroscience Jul 2018The putative strong anti-nociceptive properties of the antidepressant phenelzine (PLZ) have not been widely explored as a treatment for pain. Antinociceptive effects of...
The putative strong anti-nociceptive properties of the antidepressant phenelzine (PLZ) have not been widely explored as a treatment for pain. Antinociceptive effects of PLZ were identified in the formalin model of tonic pain (Mifflin et al., 2016) and in allodynia associated with experimental autoimmune encephalomyelitis, (EAE) a mouse model of multiple sclerosis (Potter et al., 2016). Here, we further clarify the specific types of stimuli and contexts in which PLZ modulates nociceptive sensitivity. Our findings indicate that PLZ selectively inhibits ongoing inflammatory pain while sparing transient reflexive and acute nociception. We also investigated the cellular mechanisms of action of PLZ in the dorsal horn, and as expected of a monoamine-oxidase inhibitor, PLZ increased serotonin (5HT) immunoreactivity. We next used two approaches to test the hypothesis that PLZ inhibits the activation of spinal nociresponsive neurons. First, we evaluated the formalin-evoked protein expression of the immediate early gene, c-fos. PLZ reduced Fos expression in the superficial dorsal horn. Second, we evaluated the effects of PLZ on intracellular calcium responses to superfusion of glutamate (0.3-1.0 mM) in an ex vivo lumbar spinal cord slice preparation. Superfusion with PLZ (100-300 μM) reduced 1 mM glutamate-evoked calcium responses. This was blocked by pretreatment with the 5HT1A-receptor antagonist WAY-100,635, but not the alpha-2 adrenergic antagonist idazoxan. We conclude that PLZ exerts antinociceptive effects through a 5-HT/5HT1AR-dependent inhibition of neuronal responses within nociceptive circuits of the dorsal horn.
Topics: Animals; Antidepressive Agents; Female; Hyperalgesia; Mice; Mice, Inbred C57BL; Neurons; Pain; Phenelzine; Receptors, Serotonin, 5-HT1; Serotonin; Spinal Cord Dorsal Horn
PubMed: 29752984
DOI: 10.1016/j.neuroscience.2018.04.047 -
British Journal of Pharmacology Jun 2018Phenelzine is an antidepressant drug known to increase the risk of hypertensive crisis when dietary tyramine is not restricted. However, this MAO inhibitor inhibits...
BACKGROUND AND PURPOSE
Phenelzine is an antidepressant drug known to increase the risk of hypertensive crisis when dietary tyramine is not restricted. However, this MAO inhibitor inhibits other enzymes not limited to the nervous system. Here we investigated if its antiadipogenic and antilipogenic effects in cultured adipocytes could contribute to decreased body fat in vivo, without unwanted hypertensive or cardiovascular effects.
EXPERIMENTAL APPROACH
Mice were fed a standard chow and given 0.028% phenelzine in drinking water for 12 weeks. Body composition was determined by NMR. Cardiovascular dysfunction was assessed by heart rate variability analyses and by evaluation of cardiac oxidative stress markers. MAO activity, hydrogen peroxide release and triacylglycerol turnover were assayed in white adipose tissue (WAT), alongside determination of glucose and lipid circulating levels.
KEY RESULTS
Phenelzine-treated mice exhibited lower body fat content, subcutaneous WAT mass and lipid content in skeletal muscles than control, without decreased body weight gain or food consumption. A modest alteration of cardiac sympathovagal balance occurred without depressed aconitase activity. In WAT, phenelzine impaired the lipogenic but not the antilipolytic actions of insulin, MAO activity and hydrogen peroxide release. Phenelzine treatment lowered non-fasting blood glucose and phosphoenolpyruvate carboxykinase expression. In vitro, high doses of phenelzine decreased both lipolytic and lipogenic responses in mouse adipocytes.
CONCLUSION AND IMPLICATIONS
As phenelzine reduced body fat content without affecting cardiovascular function in mice, it may be of benefit in the treatment of obesity-associated complications, with the precautions of use recommended for antidepressant therapy.
Topics: Adipose Tissue; Administration, Oral; Animals; Antidepressive Agents; Cardiovascular System; Male; Mice; Mice, Inbred C57BL; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Phenelzine
PubMed: 29582416
DOI: 10.1111/bph.14211 -
Journal of Neurotrauma Jun 2018To date, all monotherapy clinical traumatic brain injury (TBI) trials have failed, and there are currently no Food and Drug Administration (FDA)-approved...
Continuous Infusion of Phenelzine, Cyclosporine A, or Their Combination: Evaluation of Mitochondrial Bioenergetics, Oxidative Damage, and Cytoskeletal Degradation following Severe Controlled Cortical Impact Traumatic Brain Injury in Rats.
To date, all monotherapy clinical traumatic brain injury (TBI) trials have failed, and there are currently no Food and Drug Administration (FDA)-approved pharmacotherapies for the acute treatment of severe TBI. Due to the complex secondary injury cascade following injury, there is a need to develop multi-mechanistic combinational neuroprotective approaches for the treatment of acute TBI. As central mediators of the TBI secondary injury cascade, both mitochondria and lipid peroxidation-derived aldehydes make promising therapeutic targets. Cyclosporine A (CsA), an FDA-approved immunosuppressant capable of inhibiting the mitochondrial permeability transition pore, and phenelzine (PZ), an FDA-approved monoamine oxidase inhibitor capable of scavenging neurotoxic lipid peroxidation-derived aldehydes, have both been shown to be partially neuroprotective following experimental TBI. Therefore, it follows that the combination of PZ and CsA may enhance neuroprotection over either agent alone through the combining of distinct but complementary mechanisms of action. Additionally, as the first 72 h represents a critical time period following injury, it follows that continuous drug infusion over the first 72 h following injury may also lead to optimal neuroprotective effects. This is the first study to examine the effects of a 72 h subcutaneous continuous infusion of PZ, CsA, and the combination of these two agents on mitochondrial respiration, mitochondrial bound 4-hydroxynonenal (4-HNE), and acrolein, and α-spectrin degradation 72 h following a severe controlled cortical impact injury in rats. Our results indicate that individually, both CsA and PZ are able to attenuate mitochondrial 4-HNE and acrolein, PZ is able to maintain mitochondrial respiratory control ratio and cytoskeletal integrity but together, PZ and CsA are unable to maintain neuroprotective effects.
Topics: Animals; Brain Injuries, Traumatic; Cyclosporine; Cytoskeleton; Energy Metabolism; Male; Mitochondria; Neuroprotective Agents; Oxidative Stress; Phenelzine; Rats; Rats, Sprague-Dawley
PubMed: 29336204
DOI: 10.1089/neu.2017.5353 -
Nature Communications Jan 2018Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis...
Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat. Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes. CoREST knockdown, gene expression, and ChIP studies suggest that corin's favorable pharmacologic effects may rely on an intact CoREST complex. Corin was also effective in slowing tumor growth in a melanoma mouse xenograft model. These studies highlight the promise of a new class of two-pronged hybrid agents that may show preferential targeting of particular epigenetic regulatory complexes and offer unique therapeutic opportunities.
Topics: Aged; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Proliferation; Co-Repressor Proteins; Drug Design; Drug Screening Assays, Antitumor; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Male; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Nerve Tissue Proteins; Oligonucleotide Array Sequence Analysis; Pyridines; Repressor Proteins; Skin Neoplasms; Tranylcypromine; Xenograft Model Antitumor Assays
PubMed: 29302039
DOI: 10.1038/s41467-017-02242-4