Electrospray ionization mass spectrometric and liquid chromatographic–mass spectrometric studies on the metabolism of synthetic dynorphin A peptides in brain tissue in vitro and in vivo

Prókai, László; Kim, Ho-Seung; Zharikova, Alevtina D.; Roboz, John; Ma, Longhua; Deng, Lin; Simonsick, William J.

doi:10.1016/s0021-9673(97)01295-8

Cited by 39 publications

(25 citation statements)

References 21 publications

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“…Experiments were performed according to a procedure involving in vivo cerebral microdialysis (26) in the rat hippocampus. Perfusion of the probes with the solution containing E1-quinol (10 pmols͞microliter) in artificial cerebrospinal fluid was done at 1.0 l͞min for 12 h. Sample preparation for LC͞MS analyses included extraction of the collected microdialysates with ethyl acetate.…”

Section: Methodsmentioning

confidence: 99%

Quinol-based cyclic antioxidant mechanism in estrogen neuroprotection

Prókai

Prókai-Tátrai

Perjési

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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158

175

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Substantial evidence now exists that intrinsic free-radical scavenging contributes to the receptor-independent neuroprotective effects of estrogens. This activity is inherently associated with the presence of a phenolic A-ring in the steroid. We report a previously unrecognized antioxidant cycle that maintains the ''chemical shield'' raised by estrogens against the most harmful reactive oxygen species, the hydroxyl radical ( • OH) produced by the Fenton reaction. In this cycle, the capture of • OH was shown to produce a nonphenolic quinol with no affinity to the estrogen receptors. This quinol is then rapidly converted back to the parent estrogen via an enzyme-catalyzed reduction by using NAD(P)H as a coenzyme (reductant) and, unlike redox cycling of catechol estrogens, without the production of reactive oxygen species. Due to this process, protection of neuronal cells against oxidative stress is also possible by quinols that essentially act as prodrugs for the active hormone. We have shown that the quinol obtained from a 17␤-estradiol derivative was, indeed, able to attenuate glutamate-induced oxidative stress in cultured hippocampus-derived HT-22 cells. Estrone quinol was also equipotent with its parent estrogen in reducing lesion volume in ovariectomized rats after transient middle carotid artery occlusion followed by a 24-h reperfusion. These findings may establish the foundation for a rational design of neuroprotective antioxidants focusing on steroidal quinols as unique molecular leads.hydroxyl radical ͉ ischemia ͉ prodrug

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Section: Methodsmentioning

confidence: 99%

Quinol-based cyclic antioxidant mechanism in estrogen neuroprotection

Prókai

Prókai-Tátrai

Perjési

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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158

175

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“…Unlike OLs and neurons, astrocytes do not express the prodynorphin gene (Hauser et al, 1990;Shinoda et al, 1989;Vilijn et al, 1988). Dynorphin A is typically cleaved into multiple bioactive metabolites that can differ pharmacologically from the parent peptide (Evans et al, 1988) and that may possess much different half lives (Prokai et al, 1998;Young et al, 1987). The diversity of dynorphin A peptides makes it challenging to predict with any certainly how much dynorphin bioactivity will be encountered by OL plasma membrane receptors at any particular time.…”

Section: Expression Of Dynorphin a (1-17) And Proenkephalin By Olsmentioning

confidence: 99%

“…The fact that the volume and geometry of the CNS extracellular compartment are highly dynamic and that physiologic changes in extracellular space are tightly coupled to neural cell function increases this uncertainty (Sykova, 1997;Sykova et al, 1999;Ziak et al, 1998;Zoli et al, 1999). However, depending on the dynorphin A metabolite measured, concentrations ranging from nanomolar to micromolar have been suggested to occur within the confined extracellular space of the CNS (Chen et al, 1995;Prokai et al, 1998). Importantly, only transient exposure to dynorphin may be required to trigger lasting changes in cell functions and a "hit and run" phenomenon may be operative (Hauser et al, 1999).…”

Section: Expression Of Dynorphin a (1-17) And Proenkephalin By Olsmentioning

confidence: 99%

Endogenous opioids and oligodendroglial function: Possible autocrine/paracrine effects on cell survival and development

Knapp

Itkis

Zhang

et al. 2001

Glia

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Previous work has shown that oligodendrocytes (OLs) express both micro- and kappa-opioid receptors. In developing OLs, micro receptor activation increases OL proliferation, while the kappa-antagonist nor-binaltorphimine (NorBNI) affects OL differentiation. Because exogenous opioids were not present in our defined culture medium, we hypothesized that NorBNI blocked endogenous opioids produced by the OLs themselves. To test this, intact and partially processed proenkephalin and prodynorphin-derived peptides were assessed in OLs using immunocytochemistry or Western blot analysis, or both. Immature OLs possessed large amounts of intact and partially processed proenkephalin precursors, as well as posttranslational products of prodynorphin including dynorphin A (1-17). With maturation, however, intact or partially processed proenkephalin was expressed by only about 50% of OLs, while dynorphin A (1-17) was undetectable. To assess the function of OL-derived opioids, the effect of kappa-agonists/antagonists on OL differentiation and death was explored. kappa-Agonists alone had no effect. In contrast, NorBNI significantly increased OL death. Additive OL losses were evident when NorBNI was paired with toxic levels of glutamate, suggesting that kappa-receptor blockade alone is sufficient to induce OL death. Thus, the results indicate that OLs express proenkephalin and prodynorphin peptides in a developmentally regulated manner, and further suggest that opioids produced by OLs modulate OL maturation and survival through local (i.e., autocrine and/or paracrine) mechanisms.

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“…Mass spectrometry [utilizing fast atom bombardment, matrix-assisted laser desorption/ionization and electrospray ionization (ESI)] has presented itself as the method of choice in this field. [7][8][9] However, mass spectrometric studies related to synaptic metabolism of neuropeptides do not appear to have been presented previously. This paper explores the benefits of ESI mass spectrometry and tandem mass spectrometry for the characterization of the metabolism of Dyn A (1-8) [TyrGly-Gly-Phe-Leu-Arg-Arg-Ile (YGGFLRRI)], a short dynorphin present in brain tissue, 10,11 by synaptosomes and synaptosomal plasma membranes in vitro.…”

mentioning

confidence: 99%

Identification of synaptic metabolites of dynorphin A (1-8) by electrospray ionization and tandem mass spectrometry

Prókai

Zharikova

1998

Rapid Commun. Mass Spectrom.

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Synaptic metabolism of the endogenous opioid octapeptide dynorphin (Dyn) A (1-8) (Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile) was studied in vitro upon its incubation with synaptosomes and with synaptosomal plasma membranes isolated from rat brain tissue. Electrospray ionization (ESI) and tandem mass spectromety were performed using an ion trap instrument, and afforded the identification of Dyn A (2-8), Dyn A (1-6) and leucine enkephalin [Dyn A (1-5)] as major metabolites. Preliminary quantitative data on the kinetics of Dyn A (1-8) degradation and metabolite formation was obtained by size-exclusion chromatography/ESI tandem mass spectrometry, and revealed an apparent involvement of several enzymes in the metabolism upon incubation with synaptosomes. Predominant formation of Dyn A (1-6) was observed with the synaptosomal plasma membranes.

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Electrospray ionization mass spectrometric and liquid chromatographic–mass spectrometric studies on the metabolism of synthetic dynorphin A peptides in brain tissue in vitro and in vivo

Cited by 39 publications

References 21 publications

Quinol-based cyclic antioxidant mechanism in estrogen neuroprotection

Quinol-based cyclic antioxidant mechanism in estrogen neuroprotection

Endogenous opioids and oligodendroglial function: Possible autocrine/paracrine effects on cell survival and development

Identification of synaptic metabolites of dynorphin A (1-8) by electrospray ionization and tandem mass spectrometry

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