Peripheral administration of sepiapterin replenishes brain tetrahydrobiopterin: a pharmacodynamic study

Abstract

Abstract Background The levels of brain tetrahydrobiopterin (BH4), a coenzyme of tryptophan hydroxylase and tyrosine hydroxylase, regulate the rates of monoamine synthesis, including serotonin, dopamine, and noradrenaline. The attempt to treat congenital or acquired central nervous system (CNS) disorders caused by monoamine deficiency with synthetic BH4, 6RBH4, has failed owing to its limited permeation through the blood-brain barrier (BBB). Sepiapterin (SP), a BH4 precursor, is known to be rapidly assimilated into cellular BH4 through the BH4-salvage pathway. However, no treatment attempts with SP have been made, owing to the concerns about its ability to reach the brain parenchyma when administered peripherally. Therefore, we investigated the pharmacodynamics of SP entry into the CNS following intraperitoneal (ip) administration of SP. Methods To assess SP delivery, we derived an equation describing brain cell-uptake of SP as a function of its dose based on a tandem barrier model; the BBB and brain cell membranes. We estimated each of the clearances determining the directional component of the flow: influx through the BBB (CLin) and cell uptake (CLuptake) were determined in vitro, while pumping to plasma (CLout) was calculated using in vivo data from previous studies involving direct SP injection into the rat brain ventricle. To validate the model in vivo, we administered various SP doses to mice and measured the resulting increase in brain BH4 levels. To distinguish BH4 increases due to cellular uptake of SP from those due to influx of exogenous BH4, the quantification was performed 6 hours after administration, when BH4 influx had ceased. Results The model equation predicted a linear increase in brain BH4 with plasma SP, with a clearance CL(plasma→cells) = 5.42–10.2 µL·min-1·g-1. In vivo results showed that suprathreshold doses (> 13.3 mg/kg, mice, ip) linearly increased brain BH4 concentrations. In this context, SP reached the brain, or was taken up, with an AUCplasma = 1.3–2.45 µM·min per 1 mg/kg-body. Conclusions Peripheral administration of SP at a practical dose range increases brain BH4 levels in a dose-dependent manner. SP treatment could be a promising therapy to enhance monoamine synthesis in various monoamine neurotransmitter deficiencies.