Determination of in vivo steady-state unbound drug concentration in the brain interstitial fluid by microdialysis

Deguchi, Yoshiaki; Kasama, Yuko; Pardridge, William M.; Tsuji, Akira

doi:10.1016/0378-5173(92)90006-n

Cited by 46 publications

(4 citation statements)

References 30 publications

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“…These experiments were performed in awake, freely moving rats, implanted with microdialysis probes in the DLS 24 hr prior to the experiments. It has been demonstrated that the blood-brain barrier (BBB) integrity is established after such a short period following probe implantation [4,43,2,11]. Although some controversy remains regarding the integrity of the BBB following microdialysis surgeries [36], performing experiments 24 h after probe implantation is likely the most suitable method for maintaining BBB integrity.…”

Section: Resultsmentioning

confidence: 99%

CNS penetration of the opioid glycopeptide MMP-2200: A microdialysis study

Mabrouk

Falk

Sherman

et al. 2012

Neuroscience Letters

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Endogenous opioid peptides enkephalin and dynorphin are major co-transmitters of striatofugal pathways of the basal ganglia. They are involved in the genesis of levodopa-induced dyskinesia and in the modulation of direct and indirect striatal output pathways that are disrupted in Parkinson’s disease. One pharmacologic approach is to develop synthetic glycopeptides closely resembling endogenous peptides to restore their normal functions. Glycosylation promotes penetration of the blood-brain barrier. We investigated CNS penetration of the opioid glycopeptide MMP-2200, a mixed δ/μ-agonist based on leu-enkephalin, as measured by in vivo microdialysis and subsequent mass spectrometric analysis in awake, freely moving rats. The glycopeptide (10 mg/kg) reaches the dorsolateral striatum (DLS) rapidly after systemic (i.p.) administration and is stably detectable for the duration of the experiment (80 min). The detected level at the end of the experiment (around 250 pM) is about 10-fold higher than the level of the endogenous leu-enkephalin, measured simultaneously. This is one of the first studies to directly prove that glycosylation of an endogenous opioid peptide leads to excellent blood-brain barrier penetration after systemic injection, and explains robust behavioral effects seen in previous studies by measuring how much glycopeptide reaches the target structure, in this case the DLS.

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Section: Resultsmentioning

confidence: 99%

CNS penetration of the opioid glycopeptide MMP-2200: A microdialysis study

Mabrouk

Falk

Sherman

et al. 2012

Neuroscience Letters

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“…BBB damage was found to improve 2 days after probe insertion. Terasaki et al [ 68 ] measured [14C]-sucrose in interstitial fluid (ISF) and plasma to assess BBB damage, and found twofold decline in ISF/plasma ratio 48 h after probe insertion compared to 1 h, indicating that BBB permeability decreases over time. However, 3 days after probe insertion prominent elevation of gliosis markers were observed compared to control; after 1 day, significant elevation was not found [ 26 ]).…”

Section: Discussionmentioning

confidence: 99%

“…However, 3 days after probe insertion prominent elevation of gliosis markers were observed compared to control; after 1 day, significant elevation was not found [ 26 ]). However, a steady-state was reached in 1–2 h after the implantation of microdialysis probes, when extracellular levels of small molecules [ 68 ] are measured. Slow probe implantation was associated with improved result quality in the case of acute neuronal recordings measured by silicon probes [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of hippocampal extracellular space uncovers widely altered peptidome upon epileptic seizure in urethane-anaesthetized rats

Tukacs,

Mittli,

Hunyadi-Gulyás

et al. 2024

Fluids Barriers CNS

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Background The brain extracellular fluid (ECF), composed of secreted neurotransmitters, metabolites, peptides, and proteins, may reflect brain processes. Analysis of brain ECF may provide new potential markers for synaptic activity or brain damage and reveal additional information on pathological alterations. Epileptic seizure induction is an acute and harsh intervention in brain functions, and it can activate extra- and intracellular proteases, which implies an altered brain secretome. Thus, we applied a 4-aminopyridine (4-AP) epilepsy model to study the hippocampal ECF peptidome alterations upon treatment in rats. Methods We performed in vivo microdialysis in the hippocampus for 3–3 h of control and 4-AP treatment phase in parallel with electrophysiology measurement. Then, we analyzed the microdialysate peptidome of control and treated samples from the same subject by liquid chromatography-coupled tandem mass spectrometry. We analyzed electrophysiological and peptidomic alterations upon epileptic seizure induction by two-tailed, paired t-test. Results We detected 2540 peptides in microdialysate samples by mass spectrometry analysis; and 866 peptides—derived from 229 proteins—were found in more than half of the samples. In addition, the abundance of 322 peptides significantly altered upon epileptic seizure induction. Several proteins of significantly altered peptides are neuropeptides (Chgb) or have synapse- or brain-related functions such as the regulation of synaptic vesicle cycle (Atp6v1a, Napa), astrocyte morphology (Vim), and glutamate homeostasis (Slc3a2). Conclusions We have detected several consequences of epileptic seizures at the peptidomic level, as altered peptide abundances of proteins that regulate epilepsy-related cellular processes. Thus, our results indicate that analyzing brain ECF by in vivo microdialysis and omics techniques is useful for monitoring brain processes, and it can be an alternative method in the discovery and analysis of CNS disease markers besides peripheral fluid analysis.

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“…While BBI-11008 has a significant antinociceptive effect in the tail-withdrawal assay [33], the parent peptide deltorphin lacks this activity in mice after intravenous administration (Bilsky and Polt, personal communication), indicating less CNS availability after systemic administration. While microdialysis is invasive, it has been demonstrated that the BBB integrity is not acutely compromised by probe implantation established at the time of our measurement [27,[39][40][41]. Although some controversy remains regarding the integrity of the BBB following microdialysis surgeries [42], performing experiments 24 h after probe implantation as done here is considered the most suitable method for maintaining BBB integrity.…”

Section: Discussionmentioning

confidence: 99%

The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia

Bartlett

Mabrouk

Szabó

et al. 2020

IJMS

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In previous work we evaluated an opioid glycopeptide with mixed μ/δ-opioid receptor agonism that was a congener of leu-enkephalin, MMP-2200. The glycopeptide analogue showed penetration of the blood–brain barrier (BBB) after systemic administration to rats, as well as profound central effects in models of Parkinson’s disease (PD) and levodopa (L-DOPA)-induced dyskinesia (LID). In the present study, we tested the glycopeptide BBI-11008 with selective δ-opioid receptor agonism, an analogue of deltorphin, a peptide secreted from the skin of frogs (genus Phyllomedusa). We tested BBI-11008 for BBB-penetration after intraperitoneal (i.p.) injection and evaluated effects in LID rats. BBI-11008 (10 mg/kg) demonstrated good CNS-penetrance as shown by microdialysis and mass spectrometric analysis, with peak concentration levels of 150 pM in the striatum. While BBI-11008 at both 10 and 20 mg/kg produced no effect on levodopa-induced limb, axial and oral (LAO) abnormal involuntary movements (AIMs), it reduced the levodopa-induced locomotor AIMs by 50% after systemic injection. The N-methyl-D-aspartate receptor antagonist MK-801 reduced levodopa-induced LAO AIMs, but worsened PD symptoms in this model. Co-administration of MMP-2200 had been shown prior to block the MK-801-induced pro-Parkinsonian activity. Interestingly, BBI-11008 was not able to block the pro-Parkinsonian effect of MK-801 in the LID model, further indicating that a balance of mu- and delta-opioid agonism is required for this modulation. In summary, this study illustrates another example of meaningful BBB-penetration of a glycopeptide analogue of a peptide to achieve a central behavioral effect, providing additional evidence for the glycosylation technique as a method to harness therapeutic potential of peptides.

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Determination of in vivo steady-state unbound drug concentration in the brain interstitial fluid by microdialysis

Cited by 46 publications

References 30 publications

CNS penetration of the opioid glycopeptide MMP-2200: A microdialysis study

CNS penetration of the opioid glycopeptide MMP-2200: A microdialysis study

Comparative analysis of hippocampal extracellular space uncovers widely altered peptidome upon epileptic seizure in urethane-anaesthetized rats

The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia

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