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ABSTRACT: A series of β-amino acids sharing a lipophilic diaromatic side chain was synthesized and characterized pharmacologically on mouse γ-amino butyric acid (GABA) transporter subtypes mGAT1-4. The parent amino acids were also characterized. Three compounds, 13a, 13b, and 17b displayed more than 6-fold selectivity for mGAT2 over mGAT1. Compound 17b displayed anticonvulsive properties inferring a role of mGAT2 in epilepsy. These studies provide new neuropharmacological tools and a strategy for designing subtype selective GABA transport inhibitors.
Journal of Medicinal Chemistry 02/2013; · 4.80 Impact Factor
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ABSTRACT: Delivery of neuropeptides into the central or/and peripheral nervous systems supports development of novel neurotherapeutics for the treatment of pain, epilepsy and other neurological diseases. Our previous work showed that the combination of lipidization and cationization applied to anticonvulsant neuropeptides galanin (GAL) and neuropeptide Y (NPY) improved their penetration across the blood-brain barrier yielding potent antiepileptic lead compounds, such as Gal-B2 (NAX 5055) or NPY-B2. To dissect peripheral and central actions of anticonvulsant neuropeptides, we rationally designed, synthesized and characterized GAL and NPY analogs containing monodisperse (discrete) oligoethyleneglycol-lysine (dPEG-Lys). The dPEGylated analogs Gal-B2-dPEG24, Gal-R2-dPEG24 and NPY-dPEG24 displayed analgesic activities following systemic administration, while avoiding penetration into the brain. Gal-B2-dPEG24 was synthesized by a stepwise deprotection of orthogonal 4-methoxytrityl and allyloxycarbonyl groups, and subsequent on-resin conjugations of dPEG24- and palmitic acids, respectively. All the dPEGylated analogs exhibited substantially decreased hydrophobicity (expressed as logD values), increased in vitro serum stabilities, and pronounced analgesia in the formalin and carrageenan inflammatory pain assays following systemic administration, while lacking apparent antiseizure activities. These results suggest that discrete PEGylation of neuropeptides offers an attractive strategy for developing neurotherapeutics with restricted penetration into the central nervous system.
Molecular Pharmaceutics 12/2012; · 4.78 Impact Factor
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ABSTRACT: Hydrocarbon stapling is an effective strategy to stabilize the helical conformation of bioactive peptides. Here we describe application of stapling to anticonvulsant neuropeptides, galanin (GAL) and neuropeptide Y (NPY), that are implicated in modulating seizures in the brain. Dicarba bridges were rationally introduced into minimized analogs of GAL and NPY resulting in increased α-helical content, in vitro metabolic stability and n-octanol/water partitioning coefficient (logD). The stapled analogs retained agonist activities towards their respective receptors and suppressed seizures in a mouse model of epilepsy.
Bioorganic & medicinal chemistry 10/2012; · 2.82 Impact Factor
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Konkallu Hanumae Gowd,
Tiffany S Han,
Vernon Twede,
Joanna Gajewiak,
Misty D Smith,
Maren Watkins,
Randall J Platt,
Gabriela Toledo, H Steve White,
Baldomero M Olivera,
Grzegorz Bulaj
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ABSTRACT: Using molecular phylogeny has accelerated the discovery of peptidic ligands targeted to ion channels and receptors. One clade of venomous cone snails, Asprella, appears to be significantly enriched in conantokins, antagonists of N-methyl d-aspartate receptors (NMDARs). Here, we describe the characterization of two novel conantokins from Conus rolani, including conantokin conRl-B that has shown an unprecedented selectivity for blocking NMDARs that contain NR2B subunits. ConRl-B shares only some sequence similarity with the most studied NR2B selective conantokin, conG. The divergence between conRl-B and conG in the second inter-Gla loop was used to design analogues for structure-activity studies; the presence of Pro10 was found to be key to the high potency of conRl-B for NR2B, whereas the ε-amino group of Lys8 contributed to discrimination in blocking NR2B- and NR2A-containing NMDARs. In contrast to previous findings for Tyr5 substitutions in other conantokins, conRl-B[L5Y] showed potencies on the four NR2 NMDA receptor subtypes that were similar to those of the native conRl-B. When delivered into the brain, conRl-B was active in suppressing seizures in the model of epilepsy in mice, consistent with NR2B-containing NMDA receptors being potential targets for antiepileptic drugs. Circular dichroism experiments confirmed that the helical conformation of conRl-B is stabilized by divalent metal ions. Given the clinical applications of NMDA antagonists, conRl-B provides a potentially important pharmacological tool for understanding the differential roles of NMDA receptor subtypes in the nervous system. This work shows the effectiveness of coupling molecular phylogeny, chemical synthesis, and pharmacology for discovering new bioactive natural products.
Biochemistry 05/2012; 51(23):4685-92. · 3.42 Impact Factor
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ABSTRACT: Conantokins are short peptides derived from the venoms of marine cone snails that act as antagonists of the N-methyl-D-aspartate (NMDA) receptor family of excitatory glutamate receptors. These peptides contain γ-carboxyglutamic acid residues typically spaced at i,i+4 and/or i,i+7 intervals, which by chelating divalent cations induce and stabilize helical conformation of the peptide. Introduction of a dicarba bridge (or a staple) can covalently stabilize peptide helicity and improve its pharmacological properties. To test the hypothesis that stapling can effectively replace γ-carboxyglutamic acid residues in stabilizing the helical conformation of conantokins, we designed, synthesized, and characterized several stapled analogs of conantokin G (conG), with varying connectivities in terms of staple length and location along the face of the α-helix. NMR studies confirmed that the ring-closing metathesis reaction yielded a single product with the Z configuration of the olefinic bond. Based on circular dichroism and molecular modeling, the stapled analogs exhibited significantly enhanced helicity compared with the native peptide in a metal-free environment. Stapling i,i+4 was benign with respect to effects on in vitro and in vivo pharmacological properties. One analog, namely conG[11-15,S(i,i+4)S(8)], blocked NR2B-containing NMDA receptors with IC(50) = 0.7 μm and provided significant protection in the 6-Hz psychomotor model of pharmacoresistant epilepsy in mice. Remarkably, unlike native conG, conG[11-15,S(i,i+4)S(8)] produced no behavioral motor toxicity. Our results extend the applications of peptide stapling to helical peptides with extracellular targets and provide a means for engineering conantokins with improved pharmacological properties.
Journal of Biological Chemistry 04/2012; 287(24):20727-36. · 4.77 Impact Factor
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ABSTRACT: The endogenous neuropeptide galanin has anticonvulsant and analgesic properties mediated by galanin receptors expressed in the central and peripheral nervous systems. Our previous work showed that by combining truncation of the galanin peptide with N- and C-terminal modifications afforded analogues that suppress seizures or pain upon intraperitoneal (i.p.) administration. To generate orally active galanin analogues, the previously reported lead compound Gal-B2 (NAX 5055) was redesigned by 1) central truncation, (2) introduction of D-amino acids, and 3) addition of backbone spacers. Analogue D-Gal(7-Ahp)-B2, containing 7-aminoheptanoic acid as a backbone spacer and an oligo-D-lysine motif at the C terminus, exhibits anticonvulsant and analgesic activity post-i.p. administration. Oral administration of D-Gal(7-Ahp)-B2 demonstrates analgesic activity with decreases in both acute and inflammatory pain in the mouse formalin model of pain at doses as low as 8 mg kg(-1) .
ChemMedChem 02/2012; 7(5):903-9. · 3.15 Impact Factor
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ABSTRACT: The synthesis, release, reuptake, and metabolism of the excitatory and inhibitory neurotransmitters glutamate and GABA, respectively, are tightly controlled. Given the role that these two neurotransmitters play in normal and abnormal neurotransmission, it is important to consider the processes whereby they are regulated. This brief review is focused entirely on the metabolic aspects of glutamate and GABA synthesis and neurotransmission. It describes in limited detail the synthesis, release, reuptake, metabolism, cellular compartmentation and pharmacology of the glutamatergic and GABAergic synapse. This review also provides a summary and brief description of the pathologic and phenotypic features of the various genetic animal models that have been developed in an effort to provide a greater understanding of the role that each of the aforementioned metabolic processes plays in controlling excitatory and inhibitory neurotransmission and how their use will hopefully facilitate the development of safer and more efficacious therapies for the treatment of epilepsy and other neurological disorders.
Neurochemistry International 02/2012; 61(4):546-58. · 2.86 Impact Factor
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ABSTRACT: Viral infections of the central nervous system (CNS) are associated with an increased risk for seizures during the acute infection period and the subsequent development of chronic epilepsy that is often difficult to treat. In previous work, we have shown that mice of the C57BL/6 strain infected with Theiler's murine encephalomyelitis virus (TMEV) exhibit a similar sequence, thereby providing a potential useful model of virus-induced epilepsy. The present study examines spontaneous and miniature excitatory postsynaptic currents in CA3 pyramidal cells recorded from brain slices prepared during both the acute phase during encephalitis and 2 months following TMEV infection. Animals that develop chronic epilepsy following TMEV infection exhibit considerable hippocampal sclerosis, directly implicating this brain region in the process of epileptogenesis. There are significant increases in amplitude and frequency of spontaneous and miniature excitatory currents in CA3 cells recorded in brain slices prepared during the acute infection period and 2 months after infection. However, the patterns of changes observed are markedly different during these two periods, suggesting that there are underlying changes in the network over time. These differences have implications for the treatment used during the acute infection and after chronic seizures develop.
Journal of NeuroVirology 02/2012; 18(1):30-44. · 2.31 Impact Factor
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H Steve White,
Anitha B Alex,
Amanda Pollock,
Naama Hen,
Tawfeeq Shekh-Ahmad,
Karen S Wilcox,
John H McDonough,
James P Stables,
Dan Kaufmann,
Boris Yagen,
Meir Bialer
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ABSTRACT: sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a central nervous system (CNS)-active amide derivative of valproic acid (VPA) currently in phase II clinical trials. The study reported herein evaluated the anticonvulsant activity of SPD in a battery of rodent seizure and epilepsy models and assessed its efficacy in rat and guinea pig models of status epilepticus (SE) and neuroprotection in an organotypic hippocampal slice model of excitotoxic cell death.
The anticonvulsant activity of SPD was evaluated in several rodent seizure and epilepsy models, including maximal electroshock (MES), 6-Hz psychomotor; subcutaneous (s.c.) metrazol-, s.c. picrotoxin, s.c. bicuculline, and audiogenic, corneal, and hippocampal kindled seizures following intraperitoneal administration. Results obtained with SPD are discussed in relationship to those obtained with VPA and VCD. SPD was also evaluated for its ability to block benzodiazepine-resistant SE induced by pilocarpine (rats) and soman (rats and guinea pigs) following intraperitoneal administration. SPD was tested for its ability to block excitotoxic cell death induced by the glutamate agonists N-methyl-D-aspartate (NMDA) and kainic acid (KA) using organotypic hippocampal slices and SE-induced hippocampal cell death using FluoroJade B staining. The cognitive function of SPD-treated rats that were protected against pilocarpine-induced convulsive SE was examined 10-14 days post-SE using the Morris water maze (MWM). The relationship between the pharmacokinetic profile of SPD and its efficacy against soman-induced SE was evaluated in two parallel studies following SPD (60 mg/kg, i.p.) administration in the soman SE rat model.
SPD was highly effective and displayed a wide protective index (PI = median neurotoxic dose/median effective dose [TD(50)/ED(50)]) in the standardized seizure and epilepsy models employed. The wide PI values of SPD demonstrate that it is effective at doses well below those that produce behavioral impairment. Unlike VCD, SPD also displayed anticonvulsant activity in the rat pilocarpine model of SE. Thirty minutes after the induction of SE, the calculated rat ED(50) for SPD against convulsive SE in this model was 84 mg/kg. SPD was not neuroprotective in the organotypic hippocampal slice preparation; however, it did display hippocampal neuroprotection in both SE models and cognitive sparing in the MWM, which was associated with its antiseizure effect against pilocarpine-induced SE. When administered 20 and 40 min after SE onset, SPD (100-174 mg/kg) produced long-lasting efficacy (e.g., 4-8 h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. SPD ED(50) values in guinea pigs were 67 and 92 mg/kg when administered at SE onset or 40 min after SE onset, respectively. Assuming linear pharmacokinetics (PK), the PK-PD (pharmacodynamic) results (rats) suggests that effective SPD plasma levels ranged between 8 and 40 mg/L (20 min after the onset of soman-induced seizures) and 12-50 mg/L (40 min after the onset of soman-induced seizures). The time to peak (t(max)) pharmacodynamic effect (PD-t(max)) occurred after the PK-t(max), suggesting that SPD undergoes slow distribution to extraplasmatic sites, which is likely responsible for antiseizure activity of SPD.
The results demonstrate that SPD is a broad-spectrum antiseizure compound that blocks SE induced by pilocarpine and soman and affords in vivo neuroprotection that is associated with cognitive sparing. Its activity against SE is superior to that of diazepam in terms of rapid onset, potency, and its effect on animal mortality and functional improvement.
Epilepsia 12/2011; 53(1):134-46. · 3.96 Impact Factor
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ABSTRACT: Theiler's murine encephalomyelitis virus infection of C57BL/6 mice results in acute behavioral seizures in 50% of the mice. Treatment of infected mice with minocycline or infection of interleukin (IL)-6-deficient chimeric mice results in a significant decrease in the number of mice developing seizures. However, in those mice that do develop seizures, the pathological changes (neuronal cell loss, inflammation [perivascular cuffing, gliosis, activated microglia/macrophages]), and the numbers of virus infected cells in minocycline-treated or IL-6-deficient chimeric mice are very similar. Therefore, once seizures develop, the pathological changes are consistent regardless of the treatment or genetic background.
Journal of NeuroVirology 08/2011; 17(5):496-9. · 2.31 Impact Factor
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ABSTRACT: Cells that can participate in an innate immune response within the central nervous system (CNS) include infiltrating cells (polymorphonuclear leukocytes [PMNs], macrophages, and natural killer [NK] cells) and resident cells (microglia and sometimes astrocytes). The proinflammatory cytokine interleukin-6 (IL-6) is produced by all of these cells and has been implicated in the development of behavioral seizures in the Theiler's murine encephalomyelitis virus (TMEV)-induced seizure model. The assessment, via PCR arrays, of the mRNA expression levels of a large number of chemokines (ligands and receptors) in TMEV-infected and mock-infected C57BL/6 mice both with and without seizures did not clearly demonstrate the involvement of PMNs, monocytes/macrophages, or NK cells in the development of seizures, possibly due to overlapping function of the chemokines. Additionally, C57BL/6 mice unable to recruit or depleted of infiltrating PMNs and NK cells had seizure rates comparable to those of controls following TMEV infection, and therefore PMNs and NK cells do not significantly contribute to seizure development. In contrast, C57BL/6 mice treated with minocycline, which affects monocytes/macrophages, microglial cells, and PMNs, had significantly fewer seizures than controls following TMEV infection, indicating monocytes/macrophages and resident microglial cells are important in seizure development. Irradiated bone marrow chimeric mice that were either IL-6-deficient mice reconstituted with wild-type bone marrow cells or wild-type mice reconstituted with IL-6-deficient bone marrow cells developed significantly fewer behavioral seizures following TMEV infection. Therefore, both resident CNS cells and infiltrating cells are necessary for seizure development.
Journal of Virology 07/2011; 85(14):6913-22. · 5.40 Impact Factor
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ABSTRACT: Infection of C57BL/6 mice by the intracerebral route with the Daniels (DA) strain of Theiler's murine encephalomyelitis virus (TMEV) resulted in acute behavioral seizures in approximately 50% of the mice. By titration, the viral dose correlated with the percentage of mice developing seizures; however, neuropathological changes were similar over the dose range, and viral clearance from the brains occurred uniformly by day 14 postinfection (p.i.). Other TMEV strains and mutants (GDVII, WW, BeAn 8386 [BeAn], DApBL2M, H101) induced seizures in C57BL/6 mice to various degrees. The BeAn strain and DApBL2M mutant were similar to the DA strain in the percentages of mice developing seizures and neuropathological changes and in the extent of infected cells. The GDVII and WW strains caused 100% mortality by days 5 and 6 p.i., respectively, at which time neuropathological changes and neuronal infection were extensive. The H101 mutant induced seizures and caused 100% mortality by day 7 p.i.; however, only minor neuropathological changes and few infected cells were observed. Thus, in H101 mutant infections, it appears that elevated levels of cytokines, rather than neuronal cell death, play the dominant role in seizure induction.
Journal of Virology 06/2011; 85(16):8149-57. · 5.40 Impact Factor
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ABSTRACT: Activation of cAMP-dependent protein kinase A (PKA) prevents inhibition of non-NMDA glutamate receptors by the anticonvulsant topiramate. Using two-electrode voltage-clamp techniques, we demonstrate that PKA activity also modulates topiramate potentiation of recombinant GABA(A) receptors expressed in Xenpus laevis oocytes. PKA activators, dibutyryl-cAMP and forskolin, attenuate topiramate potentiation, whereas the PKA inhibitor H-89 increases topiramate potentiation. Thus, endogenous PKA activity and receptor phosphorylation states may contribute to topiramate treatment efficacy.
Epilepsy research 06/2011; 96(1-2):176-9. · 2.48 Impact Factor
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ABSTRACT: The broad spectrum anticonvulsant topiramate modulates multiple voltage-gated and ligand-gated channels, including γ-aminobutyric acid type A (GABA(A)) receptors. Previously, we found a strong β-subunit influence on the effects of topiramate on heteromeric GABA(A) receptors. Here, we tested the hypothesis that homomeric GABA(A) receptors comprised of either β(1)- or β(3)-subunits will contain a functional binding site for topiramate. For comparison, we also examined the effects of pentobarbital and loreclezole which exhibit β-subunit dependence as well. We expressed β(1)- and β(3)-homomeric receptors in Xenopus laevis oocytes and acquired electrophysiological responses using two-electrode voltage clamp techniques. Oocytes expressing β-homomers were insensitive to GABA and had hyperpolarized resting membrane potentials, decreased input resistances, increased holding currents and picrotoxin-induced outward currents consistent with the expression of non-ligand-mediated, spontaneous channel openings of β-homomers. Similar to picrotoxin, application of topiramate, pentobarbital and loreclezole inhibited β(1)-homomers. In contrast, these compounds activated β(3)-homomers. As with heteromeric receptors, topiramate and pentobarbital modulation of β(1)- and β(3)-homomers exhibited rebound currents indicating an open channel block or stabilization of desensitization. Interaction studies suggested competition between topiramate, loreclezole and pentobarbital for activation of β(3)-homomers, whereas topiramate inhibitory actions were non-competitive with pentobarbital but competitive with loreclezole. In summary, β(1)- and β(3)-subunits have binding site(s) for topiramate that elicit functional effects with similarities to heteromeric receptor responses. From this foundation, contributions of residues and other subunits in binary and ternary heteromeric receptors can be explored to gain a complete understanding of topiramate actions on complex heteromeric GABA(A) receptors.
Pharmacological Research 03/2011; 64(1):44-52. · 4.44 Impact Factor
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ABSTRACT: Modulation of the extracellular levels of GABA via inhibition of the synaptic GABA transporter GAT1 by the clinically effective and selective GAT1 inhibitor tiagabine [(R)-N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid; Gabitril] has proven to be an effective treatment strategy for focal seizures. Even though less is known about the therapeutic potential of other GABA transport inhibitors, previous investigations have demonstrated that N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (EF1502), which, like tiagabine, is inactive on GABA(A) receptors, inhibits both GAT1 and the extrasynaptic GABA and betaine transporter BGT1, and exerts a synergistic anticonvulsant effect when tested in combination with tiagabine. In the present study, the anticonvulsant activity and motor impairment associated with systemic administration of gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), which, at the doses used in this study (i.e., 1-5 mg/kg) selectively activates extrasynaptic α4-containing GABA(A) receptors, was determined alone and in combination with either tiagabine or EF1502 using Frings audiogenic seizure-susceptible and CF1 mice. EF1502, when administered in combination with gaboxadol, resulted in reduced anticonvulsant efficacy and Rotarod impairment associated with gaboxadol. In contrast, tiagabine, when administered in combination with gaboxadol, did not modify the anticonvulsant action of gaboxadol or reverse its Rotarod impairment. Taken together, these results highlight the mechanistic differences between tiagabine and EF1502 and support a functional role for BGT1 and extrasynaptic GABA(A) receptors.
Journal of Pharmacology and Experimental Therapeutics 03/2011; 338(1):214-9. · 3.83 Impact Factor
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ABSTRACT: Excitatory and inhibitory neurotransmission mediated by glutamate and GABA, respectively, plays a major role in generation
of seizures. So far, emphasis has been placed on the GABA system in attempts to develop antiepileptic drugs. Tiagabine, a
selective inhibitor of GABA transporter 1 (GAT1), is marketed for treatment of certain seizure types and serves as a proof
of principle that inhibitors of GABA transport may be interesting in this context. The chapter describes the methodology available
to investigate in detail the pharmacology of GABA transporters and design of studies leading to identification of drug candidates.
Emphasis is placed on a possible role of extrasynaptic GABA transporters in seizure control.
Key wordsGABA-Transporters-Glutamate-Neurons-Astrocytes-Epilepsy
02/2011: pages 431-446;
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ABSTRACT: Anticonvulsant neuropeptides are best known for their ability to suppress seizures and modulate pain pathways. Galanin, neuropeptide Y, somatostatin, neurotensin, dynorphin, among others, have been validated as potential first-in-class anti-epileptic or/and analgesic compounds in animal models of epilepsy and pain, but their therapeutic potential extends to other neurological indications, including neurodegenerative and psychatric disorders. Disease-modifying properties of neuropeptides make them even more attractive templates for developing new-generation neurotherapeutics. Arguably, efforts to transform this class of neuropeptides into drugs have been limited compared to those for other bioactive peptides. Key challenges in developing neuropeptide-based anticonvulsants are: to engineer optimal receptor-subtype selectivity, to improve metabolic stability and to enhance their bioavailability, including penetration across the blood–brain barrier (BBB). Here, we summarize advances toward developing systemically active and CNS-penetrant neuropeptide analogs. Two main objectives of this review are: (1) to provide an overview of structural and pharmacological properties for selected anticonvulsant neuropeptides and their analogs and (2) to encourage broader efforts to convert these endogenous natural products into drug leads for pain, epilepsy and other neurological diseases.
Natural Product Reports 02/2011; 28(4):741-62. · 9.79 Impact Factor
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ABSTRACT: Since it was first reported approximately 40 years ago that putative amino acid neurotransmitters, including GABA, would likely be inactivated by synaptic high-affinity transporters, there has been an exponential increase in interest in delineating the pharmacological characteristics of these transporters. During the 1980s and 1990s a large series of publications was devoted to a detailed characterization of neuronal and astroglial GABA transporters demonstrating important differences between these, a notion that turned out to be of relevance for the development of anticonvulsants targeting GABA transporters. The cloning era, leading to the identification of four proteins capable of transporting GABA across plasma membranes, has further boosted this research. Ultimately the clinically active antiepileptic drug, tiagabine, was developed and it was established that its mechanism of action involved inhibition of the GABA transporter-1 (GAT1). Current and future research is directed towards a better understanding of how extrasynaptic GABA receptors may be regulated via manipulation of extrasynaptic GABA levels, possibly involving extrasynaptic GABA transporters, most likely non-GAT1 transporters.
Future medicinal chemistry 02/2011; 3(2):183-7. · 2.52 Impact Factor
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ABSTRACT: Anticonvulsant neuropeptides play an important role in controlling neuronal excitability that leads to pain or seizures. Based on overlapping inhibitory mechanisms, many anticonvulsant compounds have been found to exhibit both analgesic and antiepileptic activities. An analgesic neuropeptide W (NPW) targets recently deorphanized G-protein coupled receptors. Here, we tested the hypothesis that the analgesic activity of NPW may lead to the discovery of its antiepileptic properties. Indeed, direct administration of NPW into the brain potently reduced seizures in mice. To confirm this discovery, we rationally designed, synthesized, and characterized NPW analogues that exhibited anticonvulsant activities following systemic administration. Our results suggest that the combination of neuropeptide repositioning and engineering NPW analogues that penetrate the blood-brain barrier could provide new drug leads, not only for the treatment of epilepsy and pain but also for studying effects of this peptide on regulating feeding and energy metabolism coupled to leptin levels in the brain.
ACS Chemical Neuroscience 01/2011; 2(1):51-6. · 3.68 Impact Factor
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ABSTRACT: Seizure activity can alter GABA transporter and osmoprotective gene expression, which may be involved in the pathogenesis of epilepsy. However, the response of the betaine/GABA transporter (BGT1) is unknown. The goal of the present study was to compare the expression of BGT1 mRNA to that of other osmoprotective genes and GABA transporters following status epilepticus (SE). The possible contributory role of dehydration and inflammation was also investigated because both have been shown to be involved in the regulation of GABA transporter and/or osmoprotective gene expression. BGT1 mRNA was increased 24 h post-SE, as were osmoprotective genes. BGT1 was decreased 72 h and 4 weeks post-SE, as were the GABA transporter mRNAs. The mRNA values for osmoprotective genes following 24-h water withdrawal were significantly lower than the values obtained 24 h post-SE despite similarities in their plasma osmolality values. BGT1 mRNA was not altered by lipopolysaccharide-induced inflammation while the transcription factor tonicity-responsive enhancer binding protein and the GABA transporters 1 and 3 were. These results suggest that neither plasma osmolality nor inflammation fully account for the changes seen in BGT1 mRNA expression post-SE. However, it is evident that BGT1 mRNA expression is altered by SE and displays a temporal pattern with similarities to both GABA and osmolyte transporters. Further investigation of BGT1 regulation in the brain is warranted.
Journal of Neurochemistry 01/2011; 117(1):82-90. · 4.06 Impact Factor
