Kyotorphin transport and metabolism in rat and mouse neonatal astrocytes

Xiang, Jianming; Jiang, Huidi; Hu, Yongjun; Smith, David Eugene; Keep, Richard F.

doi:10.1016/j.brainres.2010.05.094

Cited by 9 publications

(6 citation statements)

References 30 publications

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“…Several kyotorphin derivatives, which are enzymatically stable, have more potent and longer analgesic actions than kyotorphin ( 34 – 37 ). An increasing number of reports also suggest an alternative inactivation mechanism wherein kyotorphin is excreted into the cerebrospinal fluid (CSF) or taken up by the astrocytes through a transporter PEPT2 ( 38 ). Thus, it is plausible that both enzymatic degradation and PEPT2-mediated excretion play roles in the in vivo inactivation (signaling turn-off) system for kyotorphin neurotransmission ( Figure 2 ).…”

Section: Molecular Physiological and Pharmacological Characterization Of Kyotorphinmentioning

confidence: 99%

Review of Kyotorphin Research: A Mysterious Opioid Analgesic Dipeptide and Its Molecular, Physiological, and Pharmacological Characteristics

Ueda

2021

Front. Med. Technol.

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Tyrosine-arginine (kyotorphin), an opioid analgesic dipeptide, was discovered more than 40 years ago in 1979. The evidence accumulated during this period has established the physiological significance of kyotorphin as a neuromodulating peptide, and pharmacological applications. Some of the following important findings have been discussed in this review: (1) kyotorphin is unevenly distributed in the brain; it is found in high concentrations in the pain pathway, which involves the regions associated with morphine analgesia; (2) kyotorphin is subcellularly localized in the synaptosome fraction or nerve-ending particles; (3) a specific synthetase generates kyotorphin from tyrosine and arginine; (4) kyotorphin may be also processed from calpastatin by a novel calcium-activated neutral protease or calpain; (5) kyotorphin preloaded into the synaptosome is released by high K+ depolarization in a Ca2+-dependent manner; (6) kyotorphin has a specific G protein coupled receptor, which mediates the activation of phospholipase C (PLC) and inhibition of adenylyl cyclase through Gi; (7) leucine-arginine works as a specific kyotorphin receptor antagonist; 8) membrane-bound aminopeptidase or excretion through a peptide transporter, PEPT2, may contribute to the inactivation of kyotorphin; and (9) kyotorphin causes increased Met-enkephalin release from brain and spinal slices. It is also known that the opening of plasma membrane Ca2+ channels through a conformational coupling of the InsP3 receptor with the transient receptor potential C1, which is downstream of the kyotorphin receptor-mediated activation of Gi and PLC, could be a potential underlying mechanism of Met-enkephalin release. Considering these findings, translational research is an exciting domain that can be explored in the future. As kyotorphin is a small molecule, we could design function-added kyotorphin derivatives. These studies would include not only the brain-permeable kyotorphin derivatives but also hybrid kyotorphin derivatives conjugated with small compounds that have additional pharmacological actions. Further, since there are reports of kyotorphin being involved in either the etiology or treatment of Alzheimer's disease, epilepsy, inflammation, and chronic pain, studies on the beneficial effects of kyotorphin derivatives should also be expected in the future.

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Section: Molecular Physiological and Pharmacological Characterization Of Kyotorphinmentioning

confidence: 99%

Review of Kyotorphin Research: A Mysterious Opioid Analgesic Dipeptide and Its Molecular, Physiological, and Pharmacological Characteristics

Ueda

2021

Front. Med. Technol.

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“…As a result, the CSF-to-blood concentration ratio of cefadroxil in wild-type mice was markedly lower than that in PEPT2 knockout mice [ 20 , 28 ]. In addition, cefadroxil inhibited the uptake of PEPT2 substrates in rodent neonatal astrocytes, demonstrating an uptake function of PEPT2 in brain cells [ 19 , 29 , 30 ]. However, there are no studies on the influence of transporters on the distribution of cefadroxil in brain extracellular fluid (ECF).…”

Section: Introductionmentioning

confidence: 99%

Effect of transporter inhibition on the distribution of cefadroxil in rat brain

Chen

Loryan

Payan

et al. 2014

Fluids Barriers CNS

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BackgroundCefadroxil, a cephalosporin antibiotic, is a substrate for several membrane transporters including peptide transporter 2 (PEPT2), organic anion transporters (OATs), multidrug resistance-associated proteins (MRPs), and organic anion transporting polypeptides (OATPs). These transporters are expressed at the blood–brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB), and/or brain cells. The effect of these transporters on cefadroxil distribution in brain is unknown, especially in the extracellular and intracellular fluids within brain.MethodsIntracerebral microdialysis was used to measure unbound concentrations of cefadroxil in rat blood, striatum extracellular fluid (ECF) and lateral ventricle cerebrospinal fluid (CSF). The distribution of cefadroxil in brain was compared in the absence and presence of probenecid, an inhibitor of OATs, MRPs and OATPs, where both drugs were administered intravenously. The effect of PEPT2 inhibition by intracerebroventricular (icv) infusion of Ala-Ala, a substrate of PEPT2, on cefadroxil levels in brain was also evaluated. In addition, using an in vitro brain slice method, the distribution of cefadroxil in brain intracellular fluid (ICF) was studied in the absence and presence of transport inhibitors (probenecid for OATs, MRPs and OATPs; Ala-Ala and glycylsarcosine for PEPT2).ResultsThe ratio of unbound cefadroxil AUC in brain ECF to blood (Kp,uu,ECF) was ~2.5-fold greater during probenecid treatment. In contrast, the ratio of cefadroxil AUC in CSF to blood (Kp,uu,CSF) did not change significantly during probenecid infusion. Icv infusion of Ala-Ala did not change cefadroxil levels in brain ECF, CSF or blood. In the brain slice study, Ala-Ala and glycylsarcosine decreased the unbound volume of distribution of cefadroxil in brain (Vu,brain), indicating a reduction in cefadroxil accumulation in brain cells. In contrast, probenecid increased cefadroxil accumulation in brain cells, as indicated by a greater value for Vu,brain.ConclusionsTransporters (OATs, MRPs, and perhaps OATPs) that can be inhibited by probenecid play an important role in mediating the brain-to-blood efflux of cefadroxil at the BBB. The uptake of cefadroxil in brain cells involves both the influx transporter PEPT2 and efflux transporters (probenecid-inhibitable). These findings demonstrate that drug-drug interactions via relevant transporters may affect the distribution of cephalosporins in both brain ECF and ICF.

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“…These compounds include oral hypoglycemic agent nateglinide (61), the ACE inhibitor quinapril (28), cephalosporin (62), L-4,4′-biphenylalanine-L-proline (36), and amastatin (63). The shortage of information about regulation limits the development of drugs and prodrugs that target PEPT2.…”

Section: Regulationmentioning

confidence: 99%