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TMPyP4, a Stabilizer of Nucleic Acid Secondary Structure, Is a Novel Acetylcholinesterase Inhibitor.

Fujiwara N, Mazzola M, Cai E, Wang M, Cave JW - PLoS ONE (2015)

Bottom Line: 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.Age-dependent differences in HO-2 expression levels may account for some of the variable in vivo effects of high TMPyP4 doses.

View Article: PubMed Central - PubMed

Affiliation: Burke Medical Research Institute, White Plains, New York, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Gender-based analysis of AChE activity.A and B, fluorometric AChE activity assays with liver and skeletal muscle tissue lysates, respectively, from young adult mice (aged 1.5–3 months). For both males and females, data points are the combination of four individuals. AChE activities of tissue lysates are reported relative to the activity of an AChE standard supplied with the assay kit.
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pone.0139167.g005: Gender-based analysis of AChE activity.A and B, fluorometric AChE activity assays with liver and skeletal muscle tissue lysates, respectively, from young adult mice (aged 1.5–3 months). For both males and females, data points are the combination of four individuals. AChE activities of tissue lysates are reported relative to the activity of an AChE standard supplied with the assay kit.

Mentions: To establish whether inherent differences in AChE activity could underlie the gender-dependent sensitivities to TMPyP4, we measured AChE activity in liver and skeletal muscle lysates from young adult mice (Fig 5). These studies, however, showed no significant gender-based difference in AChE activity in either tissue.


TMPyP4, a Stabilizer of Nucleic Acid Secondary Structure, Is a Novel Acetylcholinesterase Inhibitor.

Fujiwara N, Mazzola M, Cai E, Wang M, Cave JW - PLoS ONE (2015)

Gender-based analysis of AChE activity.A and B, fluorometric AChE activity assays with liver and skeletal muscle tissue lysates, respectively, from young adult mice (aged 1.5–3 months). For both males and females, data points are the combination of four individuals. AChE activities of tissue lysates are reported relative to the activity of an AChE standard supplied with the assay kit.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581631&req=5

pone.0139167.g005: Gender-based analysis of AChE activity.A and B, fluorometric AChE activity assays with liver and skeletal muscle tissue lysates, respectively, from young adult mice (aged 1.5–3 months). For both males and females, data points are the combination of four individuals. AChE activities of tissue lysates are reported relative to the activity of an AChE standard supplied with the assay kit.
Mentions: To establish whether inherent differences in AChE activity could underlie the gender-dependent sensitivities to TMPyP4, we measured AChE activity in liver and skeletal muscle lysates from young adult mice (Fig 5). These studies, however, showed no significant gender-based difference in AChE activity in either tissue.

Bottom Line: 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.Age-dependent differences in HO-2 expression levels may account for some of the variable in vivo effects of high TMPyP4 doses.

View Article: PubMed Central - PubMed

Affiliation: Burke Medical Research Institute, White Plains, New York, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus