Limits...
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

Molecular structures of TMPyP4 and TMPyP2.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4581631&req=5

pone.0139167.g001: Molecular structures of TMPyP4 and TMPyP2.

Mentions: Both the ability to modulate gene expression and the association with disease pathology, such as cancer and neurodegeneration, have generated interest in identifying pharmaceutical agents that modify nucleic acid secondary structural stability [11–14]. One of the most extensively used compounds to manipulate nucleic acid secondary structure stability is TMPyP4 (5,10,15,20-Tetrakis-(N-methyl-4-pyridyl)porphine; Fig 1). This porphyrin molecule stabilizes both G-quadruplexes and i-motifs, whereas its structural isomer, TMPyP2 (Fig 1), does not [15–17]. Many studies using cultured cells have demonstrated that TMPyP4 can reduce cell proliferation and stabilize nucleic acid secondary structure to modify gene transcription levels [18–24], but only a handful have studied this compound in vivo [23, 25–29]. These in vivo studies have primarily focused on the ability of TMPyP4 to reduce the size of tumors either by itself or in combination with photodynamic therapy rather than demonstrating that TMPyP4 can alter either gene transcription or translation levels in vivo.


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)

Molecular structures of TMPyP4 and TMPyP2.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0139167.g001: Molecular structures of TMPyP4 and TMPyP2.
Mentions: Both the ability to modulate gene expression and the association with disease pathology, such as cancer and neurodegeneration, have generated interest in identifying pharmaceutical agents that modify nucleic acid secondary structural stability [11–14]. One of the most extensively used compounds to manipulate nucleic acid secondary structure stability is TMPyP4 (5,10,15,20-Tetrakis-(N-methyl-4-pyridyl)porphine; Fig 1). This porphyrin molecule stabilizes both G-quadruplexes and i-motifs, whereas its structural isomer, TMPyP2 (Fig 1), does not [15–17]. Many studies using cultured cells have demonstrated that TMPyP4 can reduce cell proliferation and stabilize nucleic acid secondary structure to modify gene transcription levels [18–24], but only a handful have studied this compound in vivo [23, 25–29]. These in vivo studies have primarily focused on the ability of TMPyP4 to reduce the size of tumors either by itself or in combination with photodynamic therapy rather than demonstrating that TMPyP4 can alter either gene transcription or translation levels in vivo.

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