Hydrolytic deactivation of kyotorphin by the rodent brain homogenates and sera.

Matsubayashi, Kyuichi; Kojima, Chieko; Kawajiri, Shin‐Ichi; Ono, Kenji; Takegoshi, Toshio; Ueda, Hiroshi; Takagi, Hiroshi

doi:10.1248/bpb1978.7.479

Cited by 9 publications

(11 citation statements)

References 14 publications

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“…For KTP, the evidence supporting the greater role of peptidases has come from the enhanced analgesia with D-KTP, which is peptidase resistant, compared to L-KTP (Matsubayashi et al, 1984) and the fact that bestatin, a peptidase inhibitor, can increase the L-KTP-induced analgesia (Matsubayashi et al, 1984; Ueda et al, 1985). As noted above, though, evidence in this study and others (Teuscher et al, 2001) indicates that, as well as being hydrolysis resistant, D-KTP is not a substrate for PEPT2 and that bestatin can affect peptide transport as well as peptidase activity (Hori et al, 1993; Inui et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…This is an endogenous analgesic that can cause receptor-mediated release of enkephalins within the brain (Takagi et al, 1979b). Compared to L-KTP, D-KTP (L-Tyr-D-Arg) has been reported to have a greater analgesic effect and it has been postulated that this is because it is resistant to hydrolysis by peptidases (Matsubayashi et al, 1984; Takagi et al, 1979a; Takagi et al, 1979b). Peptidases degrading L-KTP have been identified in brain homogenates and synaptosomes (Akasaki et al, 1991; Orawski and Simmons, 1992; Ueda et al, 1985), however, whether astrocytes can degrade L-KTP has not been examined.…”

Section: Introductionmentioning

confidence: 99%

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Kyotorphin transport and metabolism in rat and mouse neonatal astrocytes

Xiang

Jiang

et al. 2010

Brain Research

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Introduction Neuropeptide inactivation is generally thought to occur via peptidase-mediated degradation. However, a recent study found increased analgesia after L-kyotorphin (L-Tyr-L-Arg; L-KTP) administration in mice lacking an oligopeptide transporter, PEPT2. The current study examines the role of PEPT2 in L-KTP uptake by astrocytes and compares it to astrocytic L-KTP degradation. Methods L-[3H]KTP uptake was measured in primary cultures of neonatal astrocytes from rats and from Pept2+/+ and Pept2-/- mice. Uptake was further characterized using potential inhibitors. L-[3H]KTP degradation was examined in primary astrocyte cultures from Pept2-/- mice by following the formation of L-[3H]tyrosine. Results The uptake of L-[3H]KTP in both rat and Pept2+/+ mouse neonatal astrocytes was inhibited by known PEPT2 inhibitors. L-[3H]KTP uptake was also reduced in Pept2-/- astrocytes as compared to those from Pept2+/+ mice. Kinetic analysis indicated the presence of a high affinity (Km ∼50 μM) transporter for L-[3H]KTP, identified as Pept2, and a low affinity transporter (Km ∼3-4 mM), inhibited by amastatin, bestatin and tyrosine. Astrocytes also degraded L-KTP through a low affinity peptidase (Km ∼2 mM). Conclusions Astrocytic clearance of L-KTP occurs via both peptidase activity and transport. These processes occur at similar rates and may be linked. This supports the contention that oligopeptide transport may have an impact on the extracellular clearance (and potentially activity) of certain neuropeptides.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kyotorphin transport and metabolism in rat and mouse neonatal astrocytes

Xiang

Jiang

et al. 2010

Brain Research

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“…To account for these differences, it was suggested that l ‐KTP is more susceptible to aminopeptidase degradation than d ‐KTP, thereby reducing its analgesic potency. In support of this contention, l ‐, but not d ‐KTP, was found to be rapidly hydrolyzed by enzymes in brain homogenates (Matsubayashi et al. 1984).…”

mentioning

confidence: 82%

“…1984). Moreover, l ‐KTP hydrolysis was inhibited by the aminopeptidase inhibitor bestatin, which potentiates analgesia (Matsubayashi et al. 1984; Ueda et al.…”

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confidence: 99%

Enhanced antinociceptive response to intracerebroventricular kyotorphin in Pept2 null mice

Jiang

Keep

et al. 2009

Journal of Neurochemistry

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l‐Kyotorphin (l‐KTP), an endogenous analgesic neuropeptide, is a substrate for aminopeptidases and a proton‐coupled oligopeptide transporter, PEPT2. This study examined the CSF efflux, antinociceptive response, and hydrolysis kinetics in brain of l‐KTP and its synthetic diastereomer d‐kyotorphin (d‐KTP) in wild‐type and Pept2 null mice. CSF clearance of l‐KTP was slower in Pept2 null mice than in wild‐type animals, and this difference was reflected in greater l‐KTP‐induced analgesia in Pept2 null mice. Moreover, dose‐response analyses showed that the ED50 of l‐KTP in Pept2‐deficient animals was one‐fifth of the value observed in Pept2‐competent animals (4 vs. 21 nmol for null vs. wild‐type mice, respectively). In contrast, the ED50 of d‐KTP was very similar between the two genotypes (9–10 nmol). Likewise, there was little difference between genotypes in slope factor or baseline effects of l‐KTP and d‐KTP. The enhanced antinociceptive response to l‐KTP in Pept2 null mice could not be explained by differences in neuropeptide degradation as Vmax and Km values did not differ between genotypes. Our results demonstrate that PEPT2 can significantly impact the analgesic response to an endogenous neuropeptide by altering CSF (and presumably brain interstitial fluid) concentrations and that it may influence the disposition and response to exogenous peptide/mimetic substrates.

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“…In this report, we summarize the experimental and analytical procedures for the evaluation of intestinal absorption based on the metabolic inhibition model. KTP is an endogenous compound, which releases methionine enkephalin, possessing analgesic activity (3), from the striatum (4), and is hydrolyzed by peptidases such as aminopeptidase (5-8). Leucine enkephalin (LE), an opioid peptide, is easily degraded to destyrosyl LE by aminopeptidase in the intestine (9, 10).…”

Section: Introductionmentioning

confidence: 99%

The metabolic inhibition model which predicts the intestinal absorbability and Metabolizability of drug: Theory and experiment

Mizuma

Awazu

1998

Biol Proced Online

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The intestinal absorption of analgesic peptides (leucine enkephalin and kyotorphin) and modified peptides in rat were studied. Although these peptides were not absorbed, the absorbability (absorption clearance) of these peptides were increased in the presence of peptidase inhibitors. In order to kinetically analyze these phenomena, we proposed the metabolic inhibition model, which incorporated the metabolic clearance (metabolizability) with the absorption clearance. Metabolic activity was determined with intestinal homogenates. The higher the metabolic clearance was, the lower was the absorption clearance. The relationships between the absorption clearance and the metabolic clearance of the experimental data as well as of the theoretical values were hyperbolic. This model predicted the maximum absorption clearances of cellobiose-coupled leucine enkephalin (0.654 l/min/cm) and kyotorphin (0.247 l/min/cm). Details of the experimental methods are described.

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Hydrolytic deactivation of kyotorphin by the rodent brain homogenates and sera.

Cited by 9 publications

References 14 publications

Kyotorphin transport and metabolism in rat and mouse neonatal astrocytes

Kyotorphin transport and metabolism in rat and mouse neonatal astrocytes

Enhanced antinociceptive response to intracerebroventricular kyotorphin in Pept2 null mice

The metabolic inhibition model which predicts the intestinal absorbability and Metabolizability of drug: Theory and experiment

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