The effect of Pheniramine(Avil), a histaminergic-1 receptor blocking agent presently employed in treating various allergic diseases on pressor actions of norepinephring(NE) and tyramine (TR) was studied in the rabbit. Pheniramine, when given into a femoral vein with a dose(3mg/kg) enough to block H1-receptor, potentiated markedly the pressor responses of NE and TR. The pressor action of NE augmented by pheniramine was not affected by additional adminstration of debrisoquin (Drenergic neuron blocker) or phenelzine(monoamine oxidase inhibitor) or desipramine(U1-uptake blocker), or while potentiated by additional treatment with chlorisondamine(ganglionic blocker)or reserpine(catecholamine depleter). The hypertensive response of NE to phenelzine or desipramine was reinforced significantly by addition of pheniramine, but the response of NE in rabbits treated with reserpine or chlorisondamine or debrisoquin was not influenced by pheniramine-addition. Elevation of blood pressure to TR potentiated by pheniramine was attenuated significantly by reserpine treatment with chlorisondamine made the significant augmentation of pressor action to TR after pheniramine. Tyramine-induced response of blood pressure after pheniramine, but the response of blood pressure to TR caused by phenelzine or desipramine was enhanced markedly by pheniramine-treatment. From the above experimental results, it is thought that the pressor effect of NE and TR potentiated by pheniramine is similar to that of debrisoquin, i.e. the sensitization of effector cell, and that central action of pheniramine can not ruled out.
Blood Pressure ; Chlorisondamine ; Debrisoquin ; Desipramine ; Femoral Vein ; Neurons ; Norepinephrine* ; Oxidoreductases ; Phenelzine ; Pheniramine ; Rabbits ; Reserpine ; Tyramine*

Monoamine oxidase inhibitors (MAO-I) belong to the earliest drugs tried in Parkinson's disease (PD). They have been used with or without levodopa (L-DOPA). Non-selective MAO-I due to their side-effect/adverse reaction profile, like tranylcypromine have limited use in the treatment of depression in PD, while selective, reversible MAO-A inhibitors are recommended due to their easier clinical handling. For the treatment of akinesia and motor fluctuations selective irreversible MAO-B inhibitors selegiline and rasagiline are recommended. They are safe and well tolerated at the recommended daily doses. Their main differences are related to (1) metabolism, (2) interaction with CYP-enzymes and (3) quantitative properties at the molecular biological/genetic level. Rasagiline is more potent in clinical practise and has a hypothesis driven more favourable side effect/adverse reaction profile due to its metabolism to aminoindan. Both selegiline and rasagiline have a neuroprotective and neurorestaurative potential. A head-to head clinical trial would be of utmost interest from both the clinical outcome and a hypothesis-driven point of view. Selegiline is available as tablet and melting tablet for PD and as transdermal selegiline for depression, while rasagiline is marketed as tablet for PD. In general, the clinical use of MAO-I nowadays is underestimated. There should be more efforts to evaluate their clinical potency as antidepressants and antidementive drugs in addition to the final proof of their disease-modifying potential. In line with this are recent innovative developments of MAO-I plus inhibition of acetylcholine esterase for Alzheimer's disease as well as combined MAO-I and iron chelation for PD.
Acetylcholine ; Alzheimer Disease ; Antidepressive Agents ; Depression ; Freezing ; Handling (Psychology) ; Head ; Indans ; Iron ; Levodopa ; Moclobemide ; Monoamine Oxidase ; Monoamine Oxidase Inhibitors ; Parkinson Disease ; Phenelzine ; Selegiline ; Tranylcypromine

OBJECTIVETo investigate the effect of monoamine oxidase inhibitor phenelzine on proliferation, apoptosis and histone modulation in acute lymphoblastic leukemia cell line Molt-4 cells.

METHODSThe effect of Phenelzine on cell proliferation was detected by MTT. Apoptotic rate was measured by flow cytometry. The variation of apoptosis associated proteins Caspase-3, Bcl-2 and Bax, cyclin-dependent kinase inhibitor p21, tumor suppressor protein p15, and the expression level of histone methylation of H3K4, H3K9 and histone acetylation of H3, DNMT1 were detected by Western Blot.

RESULTS① Molt-4 cell proliferation rates were (87.68±3.54)%, (67.84±3.24)%, (51.48±3.37)%, (28.72±2.56)% respectively after exposured to phenelzine at 5, 10, 15, 20 μmol/L for 24 h, P<0.05. ② After 10 μmol/L of phenelzine exposure for 24, 48, 72 h, cell proliferation rates were (67.84±3.24)%, (50.24±2.01)%, (40.31±2.25)%, P<0.05. ③ The apoptotic rates were (13.64±2.58)%, (31.24±3.42)%, (56.37±4.26)% after phenelzine treatment at 5, 10, 20 μmol/L for 24 h, which was concentration dependent. ④ Phenelzine could upregulate the expression of Bax, caspase-3, p21, and downregulate Bcl-2 expression. Phenelzine upregulated the methylation level of histone H3K4me1, H3K4me2 and histone acetylated H3, while it didn't change the level of histone H3K4me3, H3K9me1, H3K9me2. ⑤ Phenelzine inhibited DNMT1 expression and promoted p15 expression.

CONCLUSIONSPhenelzine increased the methylation of histone H3K4me1, H3K4me2, acetylation of histone H3 and p21, and decreased the expression of DNMT1 and p15, and ultimately inhibited the proliferation and apoptosis of Molt-4 cells.

Acetylation ; Apoptosis ; drug effects ; Apoptosis Regulatory Proteins ; metabolism ; Cell Line, Tumor ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p15 ; metabolism ; Cyclin-Dependent Kinase Inhibitor p21 ; metabolism ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases ; metabolism ; Histones ; metabolism ; Humans ; Methylation ; Phenelzine ; pharmacology