title: TMPyP4, a Stabilizer of Nucleic Acid Secondary Structure, Is a Novel Acetylcholinesterase Inhibitor.
abstract: The porphyrin compound, TMPyP4 (5,10,15,20-Tetrakis-(N-methyl-4-pyridyl)porphine), is widely used as a photosensitizer and a modulator of nucleic acid secondary structure stability. Our group recently showed in cultured cells and forebrain slice cultures that this compound can also down regulate expression of Tyrosine hydroxylase (Th), which encodes the rate-limiting enzyme in catecholamine biosynthesis, by stabilizing DNA secondary structures in the Th proximal promoter. The current study sought to establish whether treatment with TMPyP4 could modify mouse Th expression levels in vivo. Intraperitoneal administration of low TMPyP4 doses (10mg/kg), similar to those used for photosensitization, did not significantly reduce Th transcript levels in several catecholaminergic regions. Administration of a high dose (40 mg/kg), similar to those used for tumor xenograph reduction, unexpectedly induced flaccid paralysis in an age and sex-dependent manner. In vitro analyses revealed that TMPyP4, but not putative metabolites, inhibited Acetylcholinesterase activity and pre-treatment of TMPyP4 with Hemeoxygenase-2 (HO-2) rescued Acetylcholinesterase function. Age-dependent differences in HO-2 expression levels may account for some of the variable in vivo effects of high TMPyP4 doses. Together, these studies indicate that only low doses of TMPyP4, such as those typically used for photosensitization, are well tolerated in vivo. Thus, despite its widespread use in vitro, TMPyP4 is not ideal for modifying neuronal gene expression in vivo by manipulating nucleic acid secondary structure stability, which highlights the need to identify more clinically suitable compounds that can modulate nucleic acid secondary structure and gene expression.
authors.affiliation: Burke Medical Research Institute, White Plains, New York, United States of America.
authors.forename: Nana
authors.initials: N
authors.lastname: Fujiwara
authors.affiliation: Burke Medical Research Institute, White Plains, New York, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Mazzola
authors.affiliation: Burke Medical Research Institute, White Plains, New York, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cai
authors.affiliation: Burke Medical Research Institute, White Plains, New York, United States of America.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Burke Medical Research Institute, White Plains, New York, United States of America; Weill Cornell Medical College, Brain and Mind Research Institute, New York, New York, United States of America.
authors.forename: John W
authors.initials: JW
authors.lastname: Cave
mesh_terms: D000375:Aging / Q000187:drug effects; D000818:Animals; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D011166:Porphyrins / Q000737:chemistry / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D011166:Porphyrins; C021096:tetra(4-N-methylpyridyl)porphine; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D014446:Tyrosine 3-Monooxygenase