Involvement of Carrier-Mediated Transport at the Blood–Cerebrospinal Fluid Barrier in Spermine Clearance from Rat Brain

Abstract

Spermine is the end-product in the polyamine biosynthetic pathway, and its excess accumulation induces neuroexcitatory responses and neurotoxicity. The purpose of this study was to elucidate the involvement of transport systems at the brain barriers in the clearance of spermine. In vivo rat spermine elimination from brain parenchyma across the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCSFB) was assessed by intracerebral and intracerebroventricular administration techniques, respectively. To characterize spermine transport at the BCSFB, a transport study using rat choroid plexus was performed. After the intracerebral microinjection of [ Spermine is a natural polyamine, and the end-product in the polyamine biosynthetic pathway.1) In the brain, spermine binds to N-methyl-D-aspartate receptors, and is involved in the modulation of learning and memory.2,3) In addition, excess accumulation of spermine induces neuroexcitatory responses and, thus, neurotoxicity. 4) Therefore, it is considered that some mechanisms for control of the cerebral spermine concentration are present in the brain to maintain homeostasis of cerebral function via spermine-related neuro-responses. The precursor of spermine is spermidine, 5) which is synthesized from putrescine and it has been reported that the biosynthesis of spermine from spermidine is superior to that of spermidine from spermine.6-8) Hence, neural spermine transport system(s) could be important for the removal of spermine from the brain, and the modulation of cerebral spermine concentration.Brain parenchyma and cerebrospinal fluid (CSF) are separated from the circulating blood by the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), respectively. The BBB and BCSFB are formed by brain capillary endothelial and choroid plexus epithelial cells, respectively, and express some transporting molecules which are involved in active elimination of compound from the brain or CSF.9) Regarding the cationic compound elimination system(s) at these barriers, mRNAs of plasma membrane monoamine transporter (PMAT/ solute carrier (SLC)29A4), organic cation/carnitine transporter 1-2 (OCTN1-2/SLC22A4-5), organic cation transporter 1-3 (OCT1-3/SLC22A1-3), and multidrug and toxin extrusion 1-2 (MATE1-2/SLC47A1-2) are expressed in rat BBB and BCSFB cell lines. 10) Among these transporters, PMAT is, at least in part, involved in brain/CSF-to-blood transport of 1-methyl-4-phenylpyridinium (MPP + ) 10) and CSF-to-blood transport of histamine.11) In addition, OCT3 takes part in the efflux transport of creatinine, a cationic guanidino compound.12) Therefore, it is possible that cerebral spermine is eliminated across these brain barriers.Some previous studies have reported that polyamines including spermine are transported in a carrier-mediated manner in some organs and it has been reported that carrier-mediated transport of polyamines is present in mammalian intestine, liver, and kidney. [13][14][15] In addition, we have demonstrated that the rat inner blood-retinal barr...

A metabolic profile of polyamines in parkinson disease: A promising biomarker

“…13,14,40 Concentrations of Spd and Spm in the basal ganglia gradually decrease in normal aging. 41 Taken together, decreased serum Spm detected in PD in the current study may indicate that brain Spm decreases via the BCSFB. 41 Taken together, decreased serum Spm detected in PD in the current study may indicate that brain Spm decreases via the BCSFB.…”

“…Concentrations of Spd and Spm in the basal ganglia gradually decrease in normal aging . Experimentally, Spm clearance from the brain parenchyma mainly occurs via the blood–CSF (BCSFB) rather than the blood–brain barrier . Taken together, decreased serum Spm detected in PD in the current study may indicate that brain Spm decreases via the BCSFB.…”

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