Title

A Novel Selective Inhibitor of CYP26B1 Potentiates the Effect of a Nanomolar Concentration of Retinoic Acid in Human Neuroblastoma SH-SY5Y Cells

Presentation Type

Poster

Abstract

Retinoic acid (RA) and its natural and synthetic derivatives are critical molecules for many biological processes, including cell proliferation and differentiation. Several studies demonstrated the RA therapeutic potential in neurodegenerative diseases treatment, showing higher tolerance to neurotoxicity and oxidative stress in vitro and in a Parkinson`s disease rodent model. Unfortunately, RA has a poor fate when administered externally in humans, inducing its own breakdown, resulting in activity loss during long-term treatment. Sice systemic administration of RA to overcome this situation require a high dose which can induce side effects in non-targeted organ/tissue, we sought to develop a new strategy to selectively increase RA concentration in the brain and
induce a neuroprotective effect. Among of the three CYP26 proteins indentified for mediating RA breakdown, CYP26B1 predominates in the brain whereas CYP26A1 on peripheral regions. Previously developed CYP26 inhibitors caused additional drug metabolizing enymes inhibition, resulting in limited usefulness. Therefore, is it possible to accurately and safely control RA concentrations for therapeutic benefit? Based on these evidences, we hypothesize that selective CYP26B1 inhibition will increase RA concentrations in brain and provide therapeutic advantages for patients with neurodegerative diseases without side effects associated with previously described non-specific CYP26 inhibitors. We designed a library of CYP26 inhibitors, among which are nanomolar-selective dual CYP26A1/B1 inhibitors, CYP26A1 inhibitors and selective CYP26B1 inhibitors. Cell culture were executed using human neuroblastoma SH-SY5Y cell line that can acquire neuron-like phenotypes after RA treatment. In this poster, we will report the effects on gene expression using PCR tecnic in SH-SY5Y cells treated with our CYP26 inhibitor and discuss about the neuroprotective effect of this compounds. The selected genes are modulated by RA-mediated signaling. We demonstrate RA metabolism inhibition, resulting increased RA concentration thereby inducing RA signaling in neuronal type cells.

Category

Life Sciences

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Apr 17th, 11:00 AM Apr 17th, 12:00 PM

A Novel Selective Inhibitor of CYP26B1 Potentiates the Effect of a Nanomolar Concentration of Retinoic Acid in Human Neuroblastoma SH-SY5Y Cells

South UC Ballroom

Retinoic acid (RA) and its natural and synthetic derivatives are critical molecules for many biological processes, including cell proliferation and differentiation. Several studies demonstrated the RA therapeutic potential in neurodegenerative diseases treatment, showing higher tolerance to neurotoxicity and oxidative stress in vitro and in a Parkinson`s disease rodent model. Unfortunately, RA has a poor fate when administered externally in humans, inducing its own breakdown, resulting in activity loss during long-term treatment. Sice systemic administration of RA to overcome this situation require a high dose which can induce side effects in non-targeted organ/tissue, we sought to develop a new strategy to selectively increase RA concentration in the brain and
induce a neuroprotective effect. Among of the three CYP26 proteins indentified for mediating RA breakdown, CYP26B1 predominates in the brain whereas CYP26A1 on peripheral regions. Previously developed CYP26 inhibitors caused additional drug metabolizing enymes inhibition, resulting in limited usefulness. Therefore, is it possible to accurately and safely control RA concentrations for therapeutic benefit? Based on these evidences, we hypothesize that selective CYP26B1 inhibition will increase RA concentrations in brain and provide therapeutic advantages for patients with neurodegerative diseases without side effects associated with previously described non-specific CYP26 inhibitors. We designed a library of CYP26 inhibitors, among which are nanomolar-selective dual CYP26A1/B1 inhibitors, CYP26A1 inhibitors and selective CYP26B1 inhibitors. Cell culture were executed using human neuroblastoma SH-SY5Y cell line that can acquire neuron-like phenotypes after RA treatment. In this poster, we will report the effects on gene expression using PCR tecnic in SH-SY5Y cells treated with our CYP26 inhibitor and discuss about the neuroprotective effect of this compounds. The selected genes are modulated by RA-mediated signaling. We demonstrate RA metabolism inhibition, resulting increased RA concentration thereby inducing RA signaling in neuronal type cells.