The utility of 2-hydroxypropyl-β-cyclodextrin as a vehicle for the intracerebral and intrathecal administration of drugs

Yaksh, Tony L.; Jang, Jongdae; Nishiuchi, Yukiko; Braun, Karen P.; Ro, Seonggu; Goodman, Murray

doi:10.1016/0024-3205(91)90537-l

Cited by 67 publications

(42 citation statements)

References 11 publications

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“…Ifenprodil, a non-competitive, selective NR2B-containing NMDA receptor antagonist (Williams, 2001), was dissolved in distilled water for systemic studies, and for intra-amygdala infusions was dissolved in artificial cerebrospinal fluid, which depending on the ifenprodil dose (1 or 5 mg), respectively, contained 2 or 10% (2-hydroxypropyl)-b-cyclodextrin (Sigma-Aldrich Co.; Yaksh et al, 1991), adjusted to pH ¼ 7.4 using hydrochloric acid. CPP, a competitive, non subunitselective NMDA antagonist, was dissolved in physiological saline (0.9%) and only used in systemic studies.…”

Section: Drugsmentioning

confidence: 99%

Acquisition of Fear Extinction Requires Activation of NR2B-Containing NMDA Receptors in the Lateral Amygdala

Sotres-Bayón

Bush

LeDoux

2007

Neuropsychopharmacol

257

207

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N-methyl-D-aspartate receptors (NMDARs) contribute to synaptic plasticity underlying learning in a variety of brain systems. Fear extinction, which involves learning to suppress the expression of previously learned fear, appears to require NMDAR activation in the amygdala. However, it is unclear whether amygdala NMDARs are required for the acquisition of extinction learning, and it is unknown whether NR2B-containing NMDARs are required in fear extinction. Here, we assessed the effects of selective NR2B blockade with ifenprodil on fear extinction learning, and found that both systemic and intra-amygdala ifenprodil treatment, given before extinction training, impaired the initial acquisition, and subsequent retrieval of fear extinction. These results confirm previous evidence showing that NMDARs in the amygdala are involved in fear extinction, and additionally show that NR2B-containing NMDARs are required. Contrary to the conclusion of previous studies, our findings demonstrate NMDARs are required for the initial acquisition, rather than only the retention, of fear extinction learning. Thus, our results support a previously not known role for NMDA-dependent plasticity in the lateral amygdala during the acquisition of fear extinction.

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Section: Drugsmentioning

confidence: 99%

Acquisition of Fear Extinction Requires Activation of NR2B-Containing NMDA Receptors in the Lateral Amygdala

Sotres-Bayón

Bush

LeDoux

2007

Neuropsychopharmacol

257

207

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“…Binding occurs primarily through hydrogen bonding, van der Waal's forces and hydrophobic interactions with the CD cavity [22]. Cyclodextrins, were chosen as an affinity agent because they are inexpensive, widely available, used in pharmaceutical [24] and food preparations [25], have significant published thermodynamic binding data for numerous compounds [26], and have been reported to bind to opioid peptides [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

An in vitro comparison of microdialysis relative recovery of Met- and Leu-enkephalin using cyclodextrins and antibodies as affinity agents

Fletcher

Stenken

2008

Analytica Chimica Acta

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Cyclodextrins and antibodies have been used as affinity agents to improve relative recovery during microdialysis sampling. Two neuropeptides, methionine-enkephalin (ME) and leucine-enkephalin (LE), were chosen to compare the use of cyclodextrins and antibodies as possible affinity agents for improving their relative recovery across polycarbonate and polyethersulfone membranes during in vitro sampling. Cyclodextrins (CD) including β-CD, 2-hydroxypropyl-β-cyclodextrin (2HPβ-CD), and γ-CD gave improvements of relative recovery for both peptides of less than 2-fold as compared to controls. Comparisons of relative recovery between tyrosine-glycine-glycine, tyrosine, and phenylalanine using different cyclodextrins in the perfusion fluid were also obtained. Inclusion of an antibody against met-enkephalin in the microdialysis perfusion fluid resulted in relative recovery increases of up to 2.5-fold. These results show that using antibodies as affinity agents during microdialysis sampling may be more effective agents to improve the relative recovery of these opioid neuropeptides.Keywords microdialysis sampling; neuropeptides; affinity agents; cyclodextrins; antibodies IntroductionNeuropeptides are a class of neurotransmitters that are the most structurally diverse group of neuromodulators [1]. Enkephalins are endogenous opioid neuropeptides that have morphinelike action or pain relief in the body and are readily associated with the neurochemistry of addiction [2]. Enkephalins also play significant roles in mediating body temperature control, food intake, reward mechanisms, and stress [3].Microdialysis sampling has been used for over thirty years for chemical sampling applications in neuroscience, pharmacokinetics, and drug metabolism [4][5][6]. It is by far the most commonly used method for the collection of low molecular weight hydrophilic neurotransmitters, such as acetylcholine, dopamine, and glutamate from mammalian brain with high relative recovery Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptAnal Chim Acta. Author manuscript; available in PMC 2009 July 14. Published in final edited form as:Anal Chim Acta. 2008 July 14; 620(1-2): 170-175. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript [7][8][9]. Despite the successful applications of microdialysis sampling, the main limitations for sampling large neuropeptides are a combination of their low relative recoveries and low basal concentrations. A neuropeptide with a high molecular weight will exhibit a smaller aqueous diffusion coefficient, which directly aff...

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“…As noted in the Kapur study (Kapur et al 2003), it is difficult to attain the concentrations required for central administration with drugs as insoluble as clozapine. The present studies assessed formulation of clozapine using hydroxypropyl-β-cyclodextrin (HPBCD), a compound with demonstrated acceptable toxicity when administered intrathecally (Yaksh et al 1991, Jang et al, 1992. In vitro toxicology was performed to establish an indication of the level of neurotoxicity of direct application of HPBCD alone and clozapine formulated with HPBCD.…”

Section: Introductionmentioning

confidence: 99%

An initial animal proof-of-concept study for central administration of clozapine to schizophrenia patients

Abrams¹,

Zheng²,

Choo³

et al. 2008

Schizophrenia Research

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While clozapine is the acknowledged superior pharmacotherapeutic for the treatment of schizophrenia, the side effect profile, which includes potentially fatal complications, limits its usefulness. Central administration of clozapine directly into the brain could circumvent many of the side effect issues due to the dramatic reduction in dose and the limitation of the drug primarily to the CNS. The present study demonstrates that clozapine can be formulated as a stable solution at physiological pH, which does not have in vitro neurotoxic effects at concentrations which may be effective at treating symptoms. Acute central administration improved auditory gating deficits in a mouse model of schizophrenia-like deficits. Assessment of behavioral alterations in rats receiving chronic central infusions of clozapine via osmotic minipump were performed with the open field and elevated plus mazes. Neither paradigm revealed any detrimental effects of the infusion. While these data represent only an initial investigation, they none-the-less suggest that central administration of clozapine may be a viable alternate therapeutic approach for schizophrenia patients which may be effective in symptom reduction without causing behavioral or neurotoxic effects.

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The utility of 2-hydroxypropyl-β-cyclodextrin as a vehicle for the intracerebral and intrathecal administration of drugs

Cited by 67 publications

References 11 publications

Acquisition of Fear Extinction Requires Activation of NR2B-Containing NMDA Receptors in the Lateral Amygdala

Acquisition of Fear Extinction Requires Activation of NR2B-Containing NMDA Receptors in the Lateral Amygdala

An in vitro comparison of microdialysis relative recovery of Met- and Leu-enkephalin using cyclodextrins and antibodies as affinity agents

An initial animal proof-of-concept study for central administration of clozapine to schizophrenia patients

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