Cation Transport Specificity at the Blood?Brain Barrier

Lockman, Paul R.; McAfee, James H; Geldenhuys, Werner J.; Allen, David

doi:10.1007/s11064-004-7032-4

Cited by 23 publications

(13 citation statements)

References 19 publications

(37 reference statements)

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“…The blood-brain barrier permeability surface-area product for [ 3 H]choline in this study was 1.29 ± 0.07 μl/s/g, which approximates previously determined values [71]. Addition of 250 μM of TMPD to the perfusate fluid reduced [ 3 H]choline permeability surface-area product at the blood-brain barrier to 0.21 ± 0.02 μl/s/g (Fig.…”

Section: Resultssupporting

confidence: 90%

“…5), affording an apparent K i of 22.3 ± 2.5 μM. To calculate the Ki of TMPD competitive kinetics were assumed and the following relationship was used: [76,77]. In the latter studies, the Km for choline was determined using multiple concentrations (250 nM -20 mM) of unlabeled choline.…”

Section: Resultsmentioning

confidence: 99%

“…Brain uptake of [ 3 H]choline was determined by calculation of a single time point blood-to-brain transfer coefficient (K in ), as previously described [70] from the relationship K in = [C tot -V v C pf ]/(C pf / T), where C tot = C br + C vas , the sum of the amount of choline remaining in the perfusate in the blood-brain vessels and the amount of choline penetrating into brain. Cerebral vascular volume and cerebral perfusion flow rate were determined in separate experiments as previously described [71,72], where C pf is the perfusion fluid concentration of tracer choline and T is the net perfusion time with the assumption that uptake is linear. An apparent cerebrovascular permeability surface-area product (PS) was then determined using the relationship, PS = Fln …”

Section: Blood-brain Barrier [ 3 H]choline Uptake Assaymentioning

confidence: 99%

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Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD)

Dwoskin

Joyce

Zheng

et al. 2007

Biochemical Pharmacology

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Limitations in efficacy and high relapse rates of currently available smoking cessation agents reveal the need for more efficacious pharmacotherapies. One strategy is to develop subtype-selective nicotinic receptor (nAChR) antagonists that inhibit nicotine-evoked dopamine (DA) release, the primary neurotransmitter involved in nicotine reward. Simple alkylation of the pyridino N-atom converts nicotine from a potent agonist into a potent antagonist. The classical antagonists, hexamethonium and decamethonium, differentiate between peripheral nAChR subtypes. Using a similar approach, we interconnected varying quaternary ammonium moieties with a lipophilic linker to provide N,N′-bis-nicotinium analogs, affording a lead compound, N,N′-dodecyl-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), which inhibited nicotine-evoked DA release and decreased nicotine self-administration. The current work describes a novel compound, 1-(3-picolinium)-12-triethylammonium-dodecane dibromide (TMPD), a hybrid of bPiDDB and decamethonium. TMPD completely inhibited (IC 50 = 500 nM) nicotine-evoked DA release from superfused rat striatal slices, suggesting that TMPD acts as a nAChR antagonist at more than one subtype. TMPD (1 μM) inhibited the response to acetylcholine at α3β4, α4β4, α4β2, and α1β1εδ receptors expressed in Xenopus oocytes. TMPD had a 2-fold higher affinity for the blood-brain barrier choline transporter, suggesting that is brain bioavailable. TMPD did not inhibit the hyperactivity in nicotine sensitized rats, but significantly and specifically decreased nicotine self-administration. Together, the results suggest that TMPD may have the ability to reduce the rewarding effect of nicotine with minimal side effects, a pharmacological profile indicative of potential clinical utility for the treatment of tobacco dependence.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Blood-brain Barrier [ 3 H]choline Uptake Assaymentioning

confidence: 99%

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Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD)

Dwoskin

Joyce

Zheng

et al. 2007

Biochemical Pharmacology

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“…The addition of unlabeled choline reduced brain PS of (Fig. 3) 14 C]bPiDDB BBB uptake, 500 M unlabeled choline was added to the perfusate, and PS for each radiolabeled compound was determined (Allen and Smith, 2001;Lockman et al, 2004). The addition of 500 M choline did not reduce […”

Section: Vascular Volume Measurement Of [mentioning

confidence: 99%

Carrier-Mediated Transport of the Quaternary Ammonium Neuronal Nicotinic Receptor Antagonist N,N′-Dodecylbispicolinium Dibromide at the Blood-Brain Barrier

Lockman

Manda²,

Geldenhuys³

et al. 2007

J Pharmacol Exp Ther

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The quaternary ammonium compound N,NЈ-dodecyl-bispicolinium dibromide (bPiDDB) potently and selectively inhibits nicotinic receptors (nAChRs) mediating nicotine-evoked [3 H]dopamine release and decreases nicotine self-administration, suggesting that this polar, charged molecule penetrates the blood-brain barrier (BBB). This report focuses on 1) BBB penetration of bPiDDB; 2) the mechanism of permeation; and 3) comparison of bPiDDB to the cations choline and N-octylnicotinium iodide (NONI), both of which are polar, charged molecules that undergo facilitated BBB transport. 3 H]choline. The current results suggest that bPiDDB uses the BBB choline transporter for ϳ90% of its permeation into brain, and they demonstrate the carrier-mediated BBB penetration of a novel bisquaternary ammonium nAChR antagonist.

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“…A nyers hal, bételdió, nagy mennyiségű tea és kávé fogyasztása károsítja a tiamint, mivel antitiaminfaktort (tiaminázenzimet) tartalmaznak [2,7]. A tiamin a vér-agy gáton aktív és passzív mechanizmusokkal jut át, és az ideg-, illetve gliasejtekben hatékony formává, tiamin-pirofoszfáttá alakul [2,9,10]. A tiamin-pirofoszfát három kulcsenzim kofaktora: α-ketoglutarát-dehidrogenázé, piruvát-dehidrogenázé és transzketolázé.…”

Section: Megbeszélésunclassified

Wernicke’s encephalopathy induced by the use of diet pills and unbalanced diet

et al. 2014

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A Wernicke-encephalopathia akutan kialakuló, életet veszélyeztető neurológiai kórkép, amely a tiaminhiány követ-keztében alakul ki. A betegséget nagyon gyakran nem diagnosztizálják időben, így megfelelő terápia hiányában a krónikus forma, a Korsakoff-szindróma kialakulásához vagy egyes esetekben halálhoz is vezethet. A tiaminhiány fejlett országokban leggyakrabban krónikus alkoholfogyasztás következtében alakul ki, de az utóbbi időben az alkoholfogyasztással nem összefüggő esetek száma is gyarapodott. A szerzők egy 23 éves nőbeteg esetét mutatják be, akinél drasztikus diéta és fogyasztótabletta használata következtében alakult ki szemmozgászavar, zavartság és ataxia, amelyek hátterében Wernicke-encephalopathia igazolódott. A diagnózist támogatta, hogy a tünetek parenteralis tiaminpótlás hatására napokon belül megszűntek. A szerzők az esetet etiológiai ritkasága és diagnosztikai nehézsége miatt közlik, illetve rámutatnak a legfrissebb ajánlásokra a kórkép diagnosztikáját és terápiáját illetően. Orv. Hetil., 2014, 155(12), 469-474.Kulcsszavak: Wernicke-encephalopathia, tiamin, diéta, fogyasztótabletta Wernicke's encephalopathy induced by the use of diet pills and unbalanced dietWernicke's encephalopathy is an acute, potentially life-threatening, neurological syndrome resulting from thiamine deficiency. The disorder is still greatly underdiagnosed and, without prompt treatment, the condition can lead to the chronic form of the disease, Korsakoff's syndrome or even death. In developed countries Wernicke's encephalopathy has been associated with alcoholism, but in recent years there has been an increasing number of non-alcoholic cases. Authors report the case of a 23-year-old woman who developed oculomotor dysfunction, encephalopathy and ataxia as a result of an extreme diet and use of diet pills. The diagnosis of Wernicke's encephalopathy was supported by the resolution of neurological signs after parenteral thiamine replacement. This case is presented because of the rare etiology and diagnostic difficulty, and the latest diagnostic and therapic guidelines are also highlighted.Keywords: Wernicke's encephalopathy, thiamine, diet, diet pill Tóth, A., Aradi, G., Várallyay, Gy., Arányi, Zs., Bereczki, D., Vastagh, I. [Wernicke's encephalopathy induced by the use of diet pills and unbalanced diet]. Orv. Hetil., 2014, 155(12), 469-474. (Beérkezett: 2014 elfogadva: 2014. január 30.) Rövidítések ATP = adenozin-trifoszfát; CRP = C-reaktív protein; CT = komputertomográfia; DNS = dezoxiribonukleinsav; DWI = diffúziósúlyozott képalkotás; EEG = elektroenkefalográfia; EFNS = Neurológiai Társaságok Európai Szövetsége; EKG = elektrokardiográfia; FLAIR = Fluid Attenuation Inversion Recovery; GABA = gamma-amino-vajsav; HPLC = nagy teljesítményű folyadékkromatográfia; HHV1 = humán herpeszvírus 1; HHV2 = humán herpeszvírus 2; HHV3 = humán herpeszvírus 3; HHV4 = humán herpeszvírus 4; HHV5 = humán herpeszvírus 5; KS = Korsakoff-szindróma; LDH = laktát-dehidrogenáz; MRI = mágneses magrezonanciás képalkotás; UH = ultrahang; WE = Werni...

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Cation Transport Specificity at the Blood?Brain Barrier

Abstract: (1) The molecular family of the blood-brain barrier (BBB) choline transporter may be elucidated in vitro by its interaction with physiologic thiamine levels, and (2) two cationic transporters at the BBB may be responsible for thiamine brain uptake.

Cited by 23 publications

References 19 publications

Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD)

Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD)

Carrier-Mediated Transport of the Quaternary Ammonium Neuronal Nicotinic Receptor Antagonist N,N′-Dodecylbispicolinium Dibromide at the Blood-Brain Barrier

Wernicke’s encephalopathy induced by the use of diet pills and unbalanced diet

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