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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 -
Restorative Neurology and Neuroscience 2018Neural cell adhesion molecule L1 contributes to nervous system development and maintenance by promoting neuronal survival, neuritogenesis, axonal regrowth/sprouting,...
BACKGROUND
Neural cell adhesion molecule L1 contributes to nervous system development and maintenance by promoting neuronal survival, neuritogenesis, axonal regrowth/sprouting, myelination, and synapse formation and plasticity. L1 also enhances recovery after spinal cord injury and ameliorates neurodegenerative processes in experimental rodent models. Aiming for clinical translation of L1 into therapy we screened for and functionally characterized in vitro the small organic molecule phenelzine, which mimics characteristic L1 functions.
OBJECTIVE
The present study was designed to evaluate the potential of this compound in vivo in a mouse model of spinal cord injury.
METHODS AND RESULTS
In mice, intraperitoneal injection of phenelzine immediately after severe thoracic compression, and thereafter once daily for 6 weeks, improved hind limb function, reduced astrogliosis and promoted axonal regrowth/sprouting at 4 and 5 weeks after spinal cord injury compared to vehicle control-treated mice. Phenelzine application upregulated L1 expression in the spinal cord and stimulated the cognate L1-mediated intracellular signaling cascades in the spinal cord tissue. Phenelzine-treated mice showed decreased levels of pro-inflammatory cytokines, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α in the injured spinal cord during the acute phase of inflammation.
CONCLUSIONS
This study provides new insights into the role of phenelzine in L1-mediated neural functions and modulation of inflammation. The combined results raise hopes that phenelzine may develop into a therapeutic agent for nervous system injuries.
Topics: Analysis of Variance; Animals; Biogenic Amines; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Locomotion; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Monoamine Oxidase Inhibitors; Myelin Basic Protein; Neural Cell Adhesion Molecule L1; Phenelzine; Recovery of Function; Spinal Cord Injuries; TOR Serine-Threonine Kinases; Time Factors
PubMed: 29889084
DOI: 10.3233/RNN-170808 -
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 Aug 2018Besides physical insult, spinal cord injury (SCI) can also result from transient ischemia, such as ischemia-reperfusion SCI (I/R SCI) as a postoperative complication....
Besides physical insult, spinal cord injury (SCI) can also result from transient ischemia, such as ischemia-reperfusion SCI (I/R SCI) as a postoperative complication. Increasing evidence has suggested that oxidative stress and related reactive aldehyde species are key contributors to cellular injury after SCI. Previous work in spinal cord contusion injury has demonstrated that acrolein, both a key product and an instigator of oxidative stress, contributes to post-traumatic hyperalgesia. It has been shown that acrolein is involved in post-SCI hyperalgesia through elevated activation, upregulating, and sensitizing transient receptor potential ankyrin 1 (TRPA1) in sensory neurons in dorsal root ganglia. In the current study, we have provided evidence that acrolein likely plays a similar role in hypersensitivity following I/R SCI. Specifically, we have documented a post-I/R SCI hypersensitivity, with parallel elevation of acrolein locally (spinal cord tissue) and systemically (urine), which was also accompanied by augmented TRPA1 mRNA in DRGs. Interestingly, known aldehyde scavenger phenelzine can significantly alleviate post-I/R SCI hypersensitivity, reduce acrolein, suppress TPRA1 upregulation, and improve motor neuron survival. Taken together, these results support the causal role of acrolein in inducing hyperalgesia after I/R SCI via activation and upregulation of TRPA1 channels. Furthermore, endogenously produced acrolein resulting from metabolic abnormality in the absence of mechanical insults appears to be capable of heightening pain sensitivity after SCI. Our data also further supports the notion of acrolein scavenging as an effective analgesic as well neuroprotective strategy in conditions where oxidative stress and aldehyde toxicity is implicated.
Topics: Acrolein; Animals; Ganglia, Spinal; Male; Neuralgia; Neurons; Oxidative Stress; Pain Measurement; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Spinal Cord; TRPA1 Cation Channel
PubMed: 29852243
DOI: 10.1016/j.neuroscience.2018.05.029 -
Pharmacology, Biochemistry, and Behavior Aug 2018Injury to the spinal cord initiates a cascade of cellular and molecular events that contribute to the tissue environment that is non-permissive for cell survival and...
Injury to the spinal cord initiates a cascade of cellular and molecular events that contribute to the tissue environment that is non-permissive for cell survival and axonal regrowth/sprouting in the adult mammalian central nervous system. The endogenous repair response is impaired in this generally inhibitory environment. Previous studies indicate that homophilic interactions of the neural cell adhesion molecule L1 (L1CAM) promote recovery after spinal cord injury and ameliorate neurodegenerative processes in experimental rodent and zebrafish models. In light of reports that phenelzine, a small organic compound that mimics L1, stimulates neuronal survival, neuronal migration, neurite outgrowth, and Schwann cell proliferation in vitro in a L1-dependent manner, we examined the restorative potential of phenelzine in a zebrafish model of spinal cord injury. Addition of phenelzine into the aquarium water immediately after spinal cord injury accelerated locomotor recovery and promoted axonal regrowth and remyelination in larval and adult zebrafish. Phenelzine treatment up-regulated the expression and proteolysis of L1.1 (a homolog of the mammalian recognition molecule L1) and phosphorylation of Erk in the spinal cord caudal to lesion site. By combining the results of the present study with those of other studies, we propose that phenelzine bears hopes for therapy of nervous system injuries.
Topics: Animals; Extracellular Signal-Regulated MAP Kinases; Locomotion; Myelin Sheath; Nerve Regeneration; Neural Cell Adhesion Molecule L1; Phenelzine; Phosphorylation; Recovery of Function; Spinal Cord Injuries; Up-Regulation; Zebrafish
PubMed: 29802870
DOI: 10.1016/j.pbb.2018.05.013 -
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