Pharmacological Assessment of Sepiapterin Reductase Inhibition on Tactile Response in the Rat
| Autor: | William J. McCarty, Thomas Kornecook, Jonathan Roberts, Marcus Soto, Helming Tan, Brian A. Sparling, Paul S. Andrews, Hao Chen, Charles G. Knutson, James Meyer, Stephen Schneider, Maosheng Zhang |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Sepiapterin education Endogeny Pharmacology Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Dorsal root ganglion In vivo Ganglia Spinal medicine Animals Humans Enzyme Inhibitors Sepiapterin reductase Pain Measurement business.industry Tetrahydrobiopterin Biopterin Rats Alcohol Oxidoreductases 030104 developmental biology medicine.anatomical_structure chemistry Hyperalgesia Touch Neuropathic pain Neuralgia Molecular Medicine business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 371:476-486 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.119.257105 |
| Popis: | There is an unmet medical need for nonopioid pain therapies in human populations; several pathways are under investigation for possible therapeutic intervention. Tetrahydrobiopterin (BH4) has received attention recently as a mediator of neuropathic pain. Recent reports have implicated sepiapterin reductase (SPR) in this pain pathway as a regulator of BH4 production. To evaluate the role of SPR inhibition on BH4 reduction, we developed analytical methods to monitor the relationship between the plasma concentration of test article and endogenous pterins and applied these in the rat spinal nerve ligation pain model. Sepiapterin is an endogenous substrate, which accumulates upon inhibition of SPR. In response to a potent inhibitor of SPR, plasma concentrations of sepiapterin increased proportionally with exposure. An indirect-effect pharmacokinetic/pharmacodynamic model was developed to describe the relationship between the plasma pharmacokinetics of test article and plasma sepiapterin levels in the rat, which was used to determine an in vivo SPR IC50 value. SPR inhibition and mechanical allodynia were assessed coordinately with pterin biomarkers in plasma and at the site of neuronal injury (i.e., dorsal root ganglion). Upon daily oral administration for 3 consecutive days, unbound plasma concentrations of test article exceeded the unbound in vivo rat SPR IC90 throughout the dose intervals, leading to a 60% reduction in BH4 in the dorsal root ganglion. Despite evidence for pharmacological modulation of the BH4 pathway, there was no significant effect on the tactile paw withdrawal threshold relative to vehicle-treated controls. |
| Databáze: | OpenAIRE |
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