title: Comparison of phenelzine and geometric isomers of its active metabolite, β-phenylethylidenehydrazine, on rat brain levels of amino acids, biogenic amine neurotransmitters and methylamine.
abstract: Phenelzine is a monoamine oxidase (MAO) inhibitor used in treatment of depression and anxiety disorders. It also elevates brain levels of γ-aminobutyric acid (GABA) and inhibits primary amine oxidase (PrAO), an enzyme whose activity and/or expression has been reported to be increased in diabetes mellitus, Alzheimer's disease and cardiovascular disorders. Phenelzine is not only an inhibitor of, but also a substrate for, MAO and it has been suggested that an active metabolite, namely β-phenylethylidenehydrazine (PEH), is responsible for phenelzine's effects on amino acids. PEH is also a strong inhibitor of PrAO but has weak effects on MAO. PEH has a double bond and can thus exist as (E)- and (Z)-geometric isomers, but to date the two isomers have not been compared with regard to their neurochemical effects. We have investigated the effects of phenelzine, (E)- and (Z)-PEH on rat whole brain levels of amino acids, biogenic amine neurotransmitters and methylamine (an endogenous substrate of PrAO). Under the conditions used in the study, (E)- and (Z)-PEH appear to be equivalent in their neurochemical properties. Both PEH isomers and phenelzine produced marked increases in rat brain levels of GABA and alanine while decreasing brain levels of glutamine. Phenelzine increased brain levels of biogenic amine neurotransmitters (noradrenaline, dopamine and serotonin), whereas neither PEH isomer altered levels of these neurotransmitters to a considerable extent. All three drugs significantly increased rat brain levels of methylamine, with (E)- and (Z)-PEH causing a greater increase than phenelzine. These results are discussed in relation to the possible therapeutic applications of these drugs.
authors: Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, AB, T6G 2G3, Canada. dmitriym@ualberta.ca
authors: Dmitriy
authors: D
authors: Matveychuk
authors: Emerson
authors: E
authors: Nunes
authors: Nasir
authors: N
authors: Ullah
authors: Carlos A
authors: CA
authors: Velázquez-Martinez
authors: Erin M
authors: EM
authors: MacKenzie
authors: Glen B
authors: GB
authors: Baker
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D055664:Electrochemical Techniques; D008401:Gas Chromatography-Mass Spectrometry; D006834:Hydrazines / Q000494:pharmacology*; D007536:Isomerism; D008297:Male; D008744:Methylamines / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000596:Amino Acids; D000697:Central Nervous System Stimulants; D006834:Hydrazines; D008744:Methylamines; D009025:Morpholines; D018377:Neurotransmitter Agents; C444559:phenylethylidenehydrazine; C100294:phendimetrazine; C027451:methylamine
references: Toxicology. 1992;73(3):251-8
references: 1631902
references: Neurochem Res. 1997 May;22(5):615-20
references: 9131641
references: J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Dec 5;844(2):278-82
references: 16890503
references: Am J Psychiatry. 2003 Mar;160(3):577-9
references: 12611844
references: J Pain Symptom Manage. 2011 Nov;42(5):788-804
references: 22045376
references: Cerebrovasc Dis. 2012;33(1):55-63
references: 22133888
references: Br J Pharmacol. 1987 Oct;92(2):243-55
references: 2890391
references: J Neurochem. 2006 Dec;99(5):1413-24
references: 17074066
references: J Pharm Pharm Sci. 2008 May 16;11(2):14s-21s
references: 19203467
references: Brain Res Bull. 1990 Jul;25(1):179-81
references: 2207706
references: Diabet Med. 1999 Jun;16(6):514-21
references: 10391401
references: Cell Mol Neurobiol. 2001 Aug;21(4):325-39
references: 11775064
references: J Exp Med. 1998 Jul 6;188(1):17-27
references: 9653080
references: Neurosci Lett. 2002 Mar 15;321(1-2):21-4
references: 11872247
references: Diabetologia. 2004 Mar;47(3):429-438
references: 14968297
references: J Pharm Pharmacol. 1988 Sep;40(9):627-33
references: 2907029
references: Neuropsychopharmacology. 2006 Jun;31(6):1286-93
references: 16319917
references: Neurosci Lett. 2005 Aug 12-19;384(1-2):183-7
references: 15894424
references: Med Hypotheses. 2000 May;54(5):726-8
references: 10859677
references: Biochem Pharmacol. 1996 Jul 26;52(2):187-95
references: 8694842
references: J Affect Disord. 1984 Apr;6(2):131-8
references: 6233345
references: Psychopharmacol Bull. 1990;26(2):157-61
references: 2236451
references: Psychopharmacology (Berl). 1996 Sep;127(1):19-24
references: 8880939
references: J Neurochem. 1969 Jun;16(3):899-907
references: 5822631
references: J Pharmacol Exp Ther. 1983 May;225(2):320-4
references: 6842395
references: J Pharm Pharmacol. 1989 Feb;41(2):97-100
references: 2568436
references: Biochem Pharmacol. 1972 Jan 15;21(2):268-70
references: 4674909
references: J Pharmacol Exp Ther. 2004 Sep;310(3):1125-32
references: 15128865
references: Neuropathol Appl Neurobiol. 2008 Apr;34(2):194-204
references: 17971074
references: J Neurochem. 2001 Apr;77(2):353-71
references: 11299298
references: Clin Chim Acta. 2002 Sep;323(1-2):139-46
references: 12135815
references: J Biol Chem. 1952 Oct;198(2):545-51
references: 12999769
references: J Affect Disord. 1995 Dec 13;35(3):125-9
references: 8749840
references: Eur Heart J. 2000 Nov;21(22):1859-63
references: 11052858
references: Nat Rev Neurosci. 2006 Apr;7(4):295-309
references: 16552415
references: Am J Psychiatry. 2002 Apr;159(4):663-5
references: 11925309
references: Metabolism. 1999 Jan;48(1):113-7
references: 9920154
references: Arch Gen Psychiatry. 2004 Jul;61(7):705-13
references: 15237082
references: Clin Chim Acta. 2001 Oct;312(1-2):107-14
references: 11580915
references: Biochim Biophys Acta. 2003 Apr 11;1647(1-2):193-9
references: 12686132
references: Methods. 2001 Jan;23(1):11-20
references: 11162146
references: Biol Psychiatry. 2003 Oct 15;54(8):792-9
references: 14550678
references: Am J Psychiatry. 1981 Aug;138(8):1098-101
references: 7258390
references: Am J Psychiatry. 1980 Mar;137(3):362-4
references: 7356067
references: J Affect Disord. 1991 Mar;21(3):207-11
references: 1648582
references: Bioorg Med Chem. 2008 Sep 1;16(17):8254-63
references: 18693021
references: Neuroscience. 2004;126(2):423-32
references: 15207360
references: Brain Res. 2006 Nov 29;1122(1):184-90
references: 17026969
references: Cell Biochem Funct. 2007 Jul-Aug;25(4):413-8
references: 16397905
references: Diabetologia. 1997 Nov;40(11):1243-50
references: 9389414
references: J Neurochem. 2010 Sep 1;114(5):1405-13
references: 20557421
references: Clin Sci (Lond). 1995 Jun;88(6):675-9
references: 7634751
references: Int J Biochem Cell Biol. 1996 Mar;28(3):259-74
references: 8920635
references: Biochemistry. 2008 May 20;47(20):5616-25
references: 18426226
references: Arch Gen Psychiatry. 1999 Nov;56(11):1043-7
references: 10565505
references: J Pharm Pharmacol. 1990 Dec;42(12):882-4
references: 1983156
references: Cardiovasc Res. 1997 Feb;33(2):387-91
references: 9074703
references: Biol Psychiatry. 1992 Aug 15;32(4):354-63
references: 1420649
references: Neuropathol Appl Neurobiol. 2008 Aug;34(4):394-402
references: 18005095
references: Biochem Pharmacol. 1992 Jun 9;43(11):2486-9
references: 1610412
references: Biochem Pharmacol. 1992 Apr 1;43(7):1409-14
references: 1567465
references: Prog Brain Res. 1995;106:181-6
references: 8584653
references: J Neural Transm (Vienna). 2007;114(6):835-9
references: 17401529