Chronic Administration of Lithium or Other Antidepressants Increases Levels of DARPP-32 in Rat Frontal Cortex

Abstract: We studied the chronic actions of lithium on rat brain by investigating its effects on cyclic AMP-dependent protein phos-phorylation by use of a back-phosphorylation procedure. We identified one heavily regulated phosphoprotein in frontal cortex as the 32-kDa dopamine- and cyclic AMP-regulated phosphoprotein (DARPP-32). Immunoblot experiments demonstrated that chronic lithium regulation of DARPP-32 back-phosphorylation is associated with equivalent increases in levels of DARPP-32 immunoreactivity. Lithium regulation of DARPP-32 immunoreactivity required chronic drug administration and was not observed in several other brain regions examined. Moreover, chronic administration of the antidepressant imipramine or tranylcypromine produced a similar increase in levels of DARPP-32 in frontal cortex, whereas other types of psychotropic drugs, including haloperidol. morphine, and cocaine, did not influence DARPP-32 levels. Increased levels of DARPP-32 could reflect a common functional effect on frontal cortex of long-term exposure to lithium and some other antidepressant medications, an effect possibly related to the clinical actions of these drugs.     

Fluorinated 2-Arylcyclopropan-1-amines – A new class of sigma receptor ligands

Stereoisomeric 2-aryl-2-fluoro-cyclopropan-1-amines have been discovered as a new class of σ receptor ligands showing different selectivity for the two subtypes of the receptor. Generally, compounds substituted in 4-position are much more active than corresponding 3-substituted isomers. trans-2-Fluoro-2-(4-methoxyphenyl)cyclopropan-1-amine (19a) was the most potent (K_i = 4.8 nM) σ₁ receptor ligand, while cis-2-fluoro-2-(4-trifluoromethylphenyl)cyclopropan-1-amine (20b) was the most potent (K_i = 95 nM) σ₂ receptor ligand.     

Phenelzine Causes an Increase in Brain Ornithine that is Prevented by Prior Monoamine Oxidase Inhibition

Phenelzine (PLZ), a nonselective irreversible inhibitor of monoamine oxidase (MAO), also inhibits GABA-transaminase (GABA-T), markedly increasing brain GABA levels. PLZ is also a substrate for MAO, and studies suggest that a metabolite formed by the action of this enzyme on PLZ may be responsible for the increase in GABA observed. We have recently found that PLZ also elevates brain ornithine (ORN), an amino acid precursor to both glutamate (and GABA) and the polyamines, and have conducted dose- and time-response studies on this effect. Rats were treated with vehicle or PLZ doses (7.5, 15 or 30 mg/kg i.p.), and brains were collected 3 h later. In the time-response study, animals were treated with vehicle or PLZ (15 mg/kg i.p.) and brains were collected 1–24 h later. To determine whether a metabolite formed by the action of MAO on PLZ may be responsible for the elevation in brain ORN observed, animals were pretreated with vehicle or the MAO inhibitor tranylcypromine (TCP) before vehicle or PLZ (15 mg/kg), and brains collected 3 h later. ORN levels (measured by an HPLC procedure) were dose- and time-dependently increased in PLZ-treated animals, with levels reaching approximately 650% of control at 6 and 12 h. Pretreatment with TCP completely abolished the PLZ-induced increase in brain ORN, suggesting, as with GABA, that a metabolite of PLZ formed by the action of MAO is responsible for the elevation of brain ORN observed. The possible contribution of increased ORN to therapeutic and/or neuroprotective properties of PLZ is discussed.     

Discovery of tranylcypromine analogs with an acylhydrazone substituent as LSD1 inactivators: Design,synthesis and their biological evaluation

Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression, has been reported to be up-regulated and involved in numbers of solid malignant tumors. In this study, we identified a series of phenylalanyl hydrazones based LSD1 inhibitors, and the most potent one, compound 4q, can inactivate LSD1 with IC₅₀?=?91.83?nM. In cellular level, compound 4q can induce the accumulation of CD86 as well as H3K4me2, and inhibit gastric cancer cell proliferation by inactivating LSD1. Our findings indicated that compound 4q may serve as a potential leading compound to target LSD1 overexpressed gastric cancer.     

Tranylcypromine and 6-trifluoroethyl thienopyrimidine hybrid as LSD1 inhibitor

Tranylcypromine moiety extracted from LSD1 inhibitors and 6-trifluoroethyl thienopyrimidine moiety from menin-MLL1 PPI inhibitors were merged to give new chemotypes for medicinal chemistry study. Among 15 new compounds prepared in this work, some exhibited nanomolar LSD1 activity and good selectivity over MAO-A/B, low micromolar menin-MLL1 PPI inhibitory activity, as well as submicromolar MV4-11 antiprofilative activities. Intracellular LSD1 engagement of compounds with higher enzymatic and antiproliferative activities was confirmed by CD86 mRNA up-regulation experiments.     

Plasma 5-Hydroxyindoleacetic Acid as an Indicator of Monoamine Oxidase-A Inhibition in Rat Brain and Peripheral Tissues

We have examined the changes induced by the monoamine oxidase (MAO; EC 1.4.3.4) inhibitors tranylcypromine, clorgyline, and deprenyl on MAO activity and 5-hydroxytryptamine (serotonin, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content in rat brain and blood (plasma and whole blood). The decreases of MAO-A activity observed in the liver and lungs after different doses of clorgyline or tranylcypromine correlated significantly (r > 0.80 in all cases) with the decline of plasma 5-HIAA. This was unaffected by 0.25 and 5 mg kg^?1 of deprenyl, indicating that 5-HT was deaminated exclusively in the periphery by MAO-A. It is interesting that very potent and significant correlations (r > 0.75) were found between plasma 5-HIAA and MAO-A activity, 5-HIAA and 5-HT content in brain tissue. These results suggest that plasma 5-HIAA can be used confidently as a peripheral indicator of the inhibition of MAO-A in brain. This may represent a favorable alternative to the analysis of 5-HIAA in CSF in psychiatric patients undergoing antidepressant treatment with nonspecific MAO inhibitors or with the new selective MAO-A inhibitors.