The Experts below are selected from a list of 5004 Experts worldwide ranked by ideXlab platform
E. J. Corey - One of the best experts on this subject based on the ideXlab platform.
-
Studies on the Total Synthesis of Lactacystin. An Improved Aldol Coupling Reaction and a β‐Lactone Intermediate in Thiol Ester Formation.
ChemInform, 2010Co-Authors: E. J. Corey, Gregory A. Reichard, Robert S. KaniaAbstract:Abstract The recently developed total synthesis of Lactacystin (1) has been improved by using the zirconium enolate derived from (R)- or (S)-2-siloxy-1,2,2-triphenylpropionate which lead stereospecifically to either (6S, 7R) or (6R, 7S) Lactacystin, respectively. The formation of the thiol ester in the synthesis of 1 proceeds mainly via a β-lactone intermediate.
-
An Efficient and Concise Enantioselective Total Synthesis of Lactacystin.
Angewandte Chemie (International ed. in English), 1998Co-Authors: E. J. Corey, Tohru NagamitsuAbstract:A selective, irreversible inhibitor of proteasome function, Lactacystin (1) is an important experimental tool in cell biology. An efficient and direct enantioselective synthesis of Lactacystin proceeds via the intermediates shown below. This process allows for the first time easy access to analogues of Lactacystin in which the isopropyl substituent is replaced by other lipophilic groups. PMB=p-methoxybenzyl.
-
Eine effiziente und kurze enantioselektive Totalsynthese von Lactacystin
Angewandte Chemie, 1998Co-Authors: E. J. Corey, Tohru NagamitsuAbstract:Ein selektiver, irreversibler Proteasom-Inhibitor ist Lactacystin 1, das daher ein wichtiges Werkzeug in der Zellbiologie geworden ist. Eine effiziente und direkte enantioselektive Synthese von Lactacystin verlauft uber die unten dargestellten Zwischenprodukte. Dieser Ansatz eroffnet erstmals auch einen einfachen Zugang zu Analoga von Lactacystin, bei denen der Isopropylsubstituent durch andere lipophile Gruppen ersetzt ist. PMB=p-Methoxybenzyl.
-
a new magnesium catalyzed doubly diastereoselective anti aldol reaction leads to a highly efficient process for the total synthesis of Lactacystin in quantity
Journal of the American Chemical Society, 1998Co-Authors: E. J. Corey, Gregory A. ReichardAbstract:A new process is described for metal-catalyzed doubly diastereoselective Mukaiyama aldol coupling of a chiral tertiary α-amino aldehyde and an achiral silyl enol ether to form selectively an anti-aldol product. The metal requirement is strict, since of several salts tested only MgI2 functions as an effective catalyst. The MgI2-catalyzed aldol greatly facilitates the total synthesis of Lactacystin (1) and the corresponding β-lactone (2), microbial products which are potent and selective inhibitors of proteasome function, cell cycle progression, and gene regulation. The method also allows the synthesis of analogues of 1 in which the 7β-methyl group of Lactacystin is replaced by higher alkyl or aralkyl groups. Detailed experimental procedures are presented for the optimized synthesis of Lactacystin on the scale required to meet the current needs of many hundreds of biological laboratories.
-
inhibition of proteasome activities and subunit specific amino terminal threonine modification by Lactacystin
Science, 1995Co-Authors: Gabriel Fenteany, Robert F. Standaert, E. J. Corey, William S Lane, Soongyu Choi, Stuart L. SchreiberAbstract:Lactacystin is a Streptomyces metabolite that inhibits cell cycle progression and induces neurite outgrowth in a murine neuroblastoma cell line. Tritium-labeled Lactacystin was used to identify the 20S proteasome as its specific cellular target. Three distinct peptidase activities of this enzyme complex (trypsin-like, chymotrypsin-like, and peptidylglutamyl-peptide hydrolyzing activities) were inhibited by Lactacystin, the first two irreversibly and all at different rates. None of five other proteases were inhibited, and the ability of Lactacystin analogs to inhibit cell cycle progression and induce neurite outgrowth correlated with their ability to inhibit the proteasome. Lactacystin appears to modify covalently the highly conserved amino-terminal threonine of the mammalian proteasome subunit X (also called MB1), a close homolog of the LMP7 proteasome subunit encoded by the major histocompatibility complex. This threonine residue may therefore have a catalytic role, and subunit X/MB1 may be a core component of an amino-terminal-threonine protease activity of the proteasome.
Tomasz Lenda - One of the best experts on this subject based on the ideXlab platform.
-
The significance of rotational behavior and sensitivity of striatal dopamine receptors in hemiparkinsonian rats: A comparative study of Lactacystin and 6-OHDA.
Neuroscience, 2016Co-Authors: Jolanta Konieczny, Tomasz Lenda, Anna M Czarnecka, Kinga Kaminska, Lucyna Antkiewicz-michalukAbstract:A growing body of evidence indicates that impairment of the ubiquitin-proteasome (UPS) system in the substantia nigra (SN) plays an important role in the pathogenesis of Parkinson's disease (PD). The aim of our study was to compare two unilateral rat models, one produced by intranigral administration of the UPS inhibitor Lactacystin or the other induced by 6-OHDA, in terms of their effect on the amphetamine- and apomorphine-induced rotational behavior, striatal dopamine (DA) D1 and D2 receptor sensitivity and tissue levels of DA and its metabolites. We found that these models did not differ in the intensity of ipsilateral rotations induced by amphetamine. In contrast, apomorphine produced contralateral rotations only in 6-OHDA-lesioned rats, and, depending on the dose, it induced either no or moderate ipsilateral rotations in the Lactacystin-lesioned group. In addition, Lactacystin induced a strong reduction in the tissue DA level and its metabolites in the lesioned striatum and SN when measured three weeks after the administration which was aggravated six weeks post-lesion, reaching the level comparable to the 6-OHDA group. Binding of [3H]raclopride to D2 receptors was increased in the lesioned striatum in both investigated (PD) models six weeks after lesion. In turn, binding of [3H]SCH23390 to the striatal D1 receptors was not changed in the Lactacystin group but was increased bilaterally in the 6-OHDA group. The present results add a new value to the study of DA receptor sensitivity and are discussed in the context of the validity of the Lactacystin model as a suitable model of Parkinson's disease.
-
ORIGINAL ARTICLE Lack of Neuroprotective Effect of Celastrol Under Conditions of Proteasome Inhibition by Lactacystin in In Vitro and In Vivo Studies: Implications for Parkinson’s Disease
2016Co-Authors: Jolanta Konieczny, Danuta Jantas, Tomasz Lenda, Helena Domin, Anna Czarnecka, Katarzyna Kuter, Władysław Lasoń, Elżbieta Lorenc-koci, Da DopamineAbstract:The Author(s) 2014. This article is published with open access at Springerlink.com Abstract A number of studies suggest that the ubiquitin– proteasome system (UPS) impairment may underlie neu-ronal death in Parkinson’s disease. Celastrol is a neuro-protective agent with anti-inflammatory and antioxidant properties. The aim of this study was to determine whether celastrol may exert neuroprotective effects both in vitro and in vivo under conditions of the Lactacystin-induced UPS inhibition. In the in vitro study, mouse primary cor-tical neurons and neuroblastoma SH-SY5Y cells were incubated with Lactacystin for 48 h (2.5 and 10 lg/ml, respectively). The animal study was performed on male Wistar rats injected unilaterally with Lactacystin (5 lg/ 2 ll) into the substantia nigra (SN) pars compacta. In the in vitro study, we did not found any protective effects o
-
early increase in dopamine release in the ipsilateral striatum after unilateral intranigral administration of Lactacystin produces spontaneous contralateral rotations in rats
Neuroscience, 2016Co-Authors: J Konieczny, Tomasz Lenda, Anna M CzarneckaAbstract:Since the discovery of the role of the ubiquitin-proteasome system (UPS) in the pathogenesis of Parkinson's disease, UPS inhibitors, such as Lactacystin have been used to investigate the relationship between UPS impairment and degeneration of dopamine (DA) neurons. However, mostly long-term neurotoxic effects of Lactacystin have been studied in animal models. Therefore, the aim of our study was to investigate behavioral and biochemical changes related to the DA system during the first week following unilateral intranigral injection of Lactacystin to rats. We found that Lactacystin produced early spontaneous contralateral rotations which were inhibited by combined administration of DA D1 and D2 receptor antagonists. Simultaneously, an increase in the extracellular level of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) was found in the ipsilateral striatum. In contrast, one week after lesion, when turning behavior was no longer visible, a decrease in the extracellular level of DA, DOPAC and HVA was demonstrated. It was accompanied by a substantial reduction in the tissue levels of DA and its metabolites in the lesioned substantia nigra and striatum. We concluded that unilateral intranigral administration of Lactacystin produces an early increase in DA neurotransmission which precedes a decrease in the striatal and nigral tissue DA content. It is manifested by the appearance of spontaneous contralateral rotations and an elevation of the extracellular DA level in the ipsilateral striatum. Since similar behavior was previously observed after intranigral administration of rotenone and MPP(+) but not 6-hydroxydopamine (6-OHDA), it may indicate a common mechanism of action shared by these neurotoxins.
-
decreased behavioral response to intranigrally administered gabaa agonist muscimol in the Lactacystin model of parkinson s disease may result from partial lesion of nigral non dopamine neurons comparison to the classical neurotoxin 6 ohda
Behavioural Brain Research, 2015Co-Authors: J Konieczny, Tomasz Lenda, Anna M Czarnecka, Kinga Kaminska, Przemyslaw NowakAbstract:Abstract Lactacystin is a selective UPS inhibitor recently used to destroy dopamine (DA) neurons in animal models of Parkinson's disease (PD). However, both in vitro and in vivo studies show discrepancies in terms of the sensitivity of non-DA neurons to its toxicity. Therefore, our study was aimed to examine the toxic effect of intranigral administration of Lactacystin on DA and non-DA neurons in the rat substantia nigra (SN), compared to the classic neurotoxin 6-OHDA. Tissue DA levels in the striatum and SN and GABA levels in the SN were also examined. Moreover, behavioral response of nigral GABA A receptors to locally administered muscimol was evaluated in these two PD models. We found that both Lactacystin and 6-OHDA induced a strong decrease in DA level in the lesioned striatum and SN but only Lactacystin slightly reduced GABA levels in the SN. A stereological analysis showed that both neurotoxins highly decreased the number of DA neurons in the SN, while only Lactacystin moderately reduced the number of non-DA ones. Finally, in the Lactacystin group, the number of contralateral rotations after intranigrally administrated muscimol was decreased in contrast to the increased response in the 6-OHDA model. Our study proves that, although Lactacystin is not a fully selective to DA neurons, these neurons are much more vulnerable to its toxicity. Partial lesion of nigral non-DA neurons in this model may explain the decreased behavioral response to the GABA A agonist muscimol.
-
Lack of Neuroprotective Effect of Celastrol Under Conditions of Proteasome Inhibition by Lactacystin in In Vitro and In Vivo Studies: Implications for Parkinson’s Disease
Neurotoxicity Research, 2014Co-Authors: Jolanta Konieczny, Danuta Jantas, Tomasz Lenda, Helena Domin, Anna Czarnecka, Katarzyna Kuter, Maria Śmiałowska, Władysław Lasoń, Elżbieta Lorenc-kociAbstract:A number of studies suggest that the ubiquitin–proteasome system (UPS) impairment may underlie neuronal death in Parkinson’s disease. Celastrol is a neuroprotective agent with anti-inflammatory and antioxidant properties. The aim of this study was to determine whether celastrol may exert neuroprotective effects both in vitro and in vivo under conditions of the Lactacystin-induced UPS inhibition. In the in vitro study, mouse primary cortical neurons and neuroblastoma SH-SY5Y cells were incubated with Lactacystin for 48 h (2.5 and 10 μg/ml, respectively). The animal study was performed on male Wistar rats injected unilaterally with Lactacystin (5 μg/2 μl) into the substantia nigra (SN) pars compacta. In the in vitro study, we did not found any protective effects of celastrol, given either in the pre- or co-treatment mode. Moreover, in the higher concentrations, celastrol itself reduced cell viability, and enhanced the Lactacystin-induced cell death in both types of cells. In the in vivo study, none of the celastrol doses (0.3–3 mg/kg) attenuated the Lactacystin-induced decrease in the level of dopamine (DA) and its metabolites or protected nigral dopaminergic neurons against the Lactacystin-induced degeneration. The highest celastrol dose potentiated the Lactacystin-induced decrease in the level of DA and its metabolites in the lesioned striatum, and accelerated the Lactacystin-induced increase in the oxidative and total metabolism of DA. Moreover, when given alone, this dose of celastrol bilaterally decreased the number and/or density of dopaminergic neurons in the SN. Our results demonstrate that celastrol does not induce neuroprotective effects under conditions of UPS inhibition.
Gregory A. Reichard - One of the best experts on this subject based on the ideXlab platform.
-
Studies on the Total Synthesis of Lactacystin. An Improved Aldol Coupling Reaction and a β‐Lactone Intermediate in Thiol Ester Formation.
ChemInform, 2010Co-Authors: E. J. Corey, Gregory A. Reichard, Robert S. KaniaAbstract:Abstract The recently developed total synthesis of Lactacystin (1) has been improved by using the zirconium enolate derived from (R)- or (S)-2-siloxy-1,2,2-triphenylpropionate which lead stereospecifically to either (6S, 7R) or (6R, 7S) Lactacystin, respectively. The formation of the thiol ester in the synthesis of 1 proceeds mainly via a β-lactone intermediate.
-
a new magnesium catalyzed doubly diastereoselective anti aldol reaction leads to a highly efficient process for the total synthesis of Lactacystin in quantity
Journal of the American Chemical Society, 1998Co-Authors: E. J. Corey, Gregory A. ReichardAbstract:A new process is described for metal-catalyzed doubly diastereoselective Mukaiyama aldol coupling of a chiral tertiary α-amino aldehyde and an achiral silyl enol ether to form selectively an anti-aldol product. The metal requirement is strict, since of several salts tested only MgI2 functions as an effective catalyst. The MgI2-catalyzed aldol greatly facilitates the total synthesis of Lactacystin (1) and the corresponding β-lactone (2), microbial products which are potent and selective inhibitors of proteasome function, cell cycle progression, and gene regulation. The method also allows the synthesis of analogues of 1 in which the 7β-methyl group of Lactacystin is replaced by higher alkyl or aralkyl groups. Detailed experimental procedures are presented for the optimized synthesis of Lactacystin on the scale required to meet the current needs of many hundreds of biological laboratories.
-
A beta-lactone related to Lactacystin induces neurite outgrowth in a neuroblastoma cell line and inhibits cell cycle progression in an osteosarcoma cell line.
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Gabriel Fenteany, Gregory A. Reichard, Ellas J. Corey, Robert F. Standaert, Stuart L. SchreiberAbstract:Abstract Lactacystin, a microbial natural product, induces neurite outgrowth in Neuro 2A mouse neuroblastoma cells and inhibits progression of synchronized Neuro 2A cells and MG-63 human osteosarcoma cells beyond the G1 phase of the cell cycle. A related beta-lactone, clasto-Lactacystin beta-lactone, formally the product of elimination of N-acetylcysteine from Lactacystin, is also active, whereas the corresponding clastoLactacystin dihydroxy acid is completely inactive. Structural analogs of Lactacystin altered only in the N-acetylcysteine moiety are active, while structural or stereochemical modifications of the gamma-lactam ring or the hydroxyisobutyl group lead to partial or complete loss of activity. The inactive compounds do not antagonize the effects of Lactacystin in either neurite outgrowth or cell cycle progression assays. The response to Lactacystin involves induction of a predominantly bipolar morphology that is maximal 16-32 h after treatment and is distinct from the response to several other treatments that result in morphological differentiation. Neurite outgrowth in response to Lactacystin appears to be dependent upon microtubule assembly, actin polymerization, and de novo protein synthesis. The observed structure-activity relationships suggest that Lactacystin and its related beta-lactone may act via acylation of one or more relevant target molecule(s) in the cell.
-
Synthesis of (6R,7S)-Lactacystin and 6-deoxyLactacystin from a common intermediate
Tetrahedron Letters, 1993Co-Authors: E. J. Corey, Gregory A. ReichardAbstract:Abstract The stereocontrolled syntheses of (6R,7S)-Lactacystin and (6)-deoxyLactacystin, analogs of the neurotrophic agent Lactacystin, are described.
-
Studies on the total synthesis of Lactacystin. An improved aldol coupling reaction and a β-lactone intermediate in thiol ester formation
Tetrahedron Letters, 1993Co-Authors: E. J. Corey, Gregory A. Reichard, Robert S. KaniaAbstract:Abstract The recently developed total synthesis of Lactacystin (1) has been improved by using the zirconium enolate derived from (R)- or (S)-2-siloxy-1,2,2-triphenylpropionate which lead stereospecifically to either (6S, 7R) or (6R, 7S) Lactacystin, respectively. The formation of the thiol ester in the synthesis of 1 proceeds mainly via a β-lactone intermediate.
Jolanta Konieczny - One of the best experts on this subject based on the ideXlab platform.
-
The significance of rotational behavior and sensitivity of striatal dopamine receptors in hemiparkinsonian rats: A comparative study of Lactacystin and 6-OHDA.
Neuroscience, 2016Co-Authors: Jolanta Konieczny, Tomasz Lenda, Anna M Czarnecka, Kinga Kaminska, Lucyna Antkiewicz-michalukAbstract:A growing body of evidence indicates that impairment of the ubiquitin-proteasome (UPS) system in the substantia nigra (SN) plays an important role in the pathogenesis of Parkinson's disease (PD). The aim of our study was to compare two unilateral rat models, one produced by intranigral administration of the UPS inhibitor Lactacystin or the other induced by 6-OHDA, in terms of their effect on the amphetamine- and apomorphine-induced rotational behavior, striatal dopamine (DA) D1 and D2 receptor sensitivity and tissue levels of DA and its metabolites. We found that these models did not differ in the intensity of ipsilateral rotations induced by amphetamine. In contrast, apomorphine produced contralateral rotations only in 6-OHDA-lesioned rats, and, depending on the dose, it induced either no or moderate ipsilateral rotations in the Lactacystin-lesioned group. In addition, Lactacystin induced a strong reduction in the tissue DA level and its metabolites in the lesioned striatum and SN when measured three weeks after the administration which was aggravated six weeks post-lesion, reaching the level comparable to the 6-OHDA group. Binding of [3H]raclopride to D2 receptors was increased in the lesioned striatum in both investigated (PD) models six weeks after lesion. In turn, binding of [3H]SCH23390 to the striatal D1 receptors was not changed in the Lactacystin group but was increased bilaterally in the 6-OHDA group. The present results add a new value to the study of DA receptor sensitivity and are discussed in the context of the validity of the Lactacystin model as a suitable model of Parkinson's disease.
-
ORIGINAL ARTICLE Lack of Neuroprotective Effect of Celastrol Under Conditions of Proteasome Inhibition by Lactacystin in In Vitro and In Vivo Studies: Implications for Parkinson’s Disease
2016Co-Authors: Jolanta Konieczny, Danuta Jantas, Tomasz Lenda, Helena Domin, Anna Czarnecka, Katarzyna Kuter, Władysław Lasoń, Elżbieta Lorenc-koci, Da DopamineAbstract:The Author(s) 2014. This article is published with open access at Springerlink.com Abstract A number of studies suggest that the ubiquitin– proteasome system (UPS) impairment may underlie neu-ronal death in Parkinson’s disease. Celastrol is a neuro-protective agent with anti-inflammatory and antioxidant properties. The aim of this study was to determine whether celastrol may exert neuroprotective effects both in vitro and in vivo under conditions of the Lactacystin-induced UPS inhibition. In the in vitro study, mouse primary cor-tical neurons and neuroblastoma SH-SY5Y cells were incubated with Lactacystin for 48 h (2.5 and 10 lg/ml, respectively). The animal study was performed on male Wistar rats injected unilaterally with Lactacystin (5 lg/ 2 ll) into the substantia nigra (SN) pars compacta. In the in vitro study, we did not found any protective effects o
-
Lack of Neuroprotective Effect of Celastrol Under Conditions of Proteasome Inhibition by Lactacystin in In Vitro and In Vivo Studies: Implications for Parkinson’s Disease
Neurotoxicity Research, 2014Co-Authors: Jolanta Konieczny, Danuta Jantas, Tomasz Lenda, Helena Domin, Anna Czarnecka, Katarzyna Kuter, Maria Śmiałowska, Władysław Lasoń, Elżbieta Lorenc-kociAbstract:A number of studies suggest that the ubiquitin–proteasome system (UPS) impairment may underlie neuronal death in Parkinson’s disease. Celastrol is a neuroprotective agent with anti-inflammatory and antioxidant properties. The aim of this study was to determine whether celastrol may exert neuroprotective effects both in vitro and in vivo under conditions of the Lactacystin-induced UPS inhibition. In the in vitro study, mouse primary cortical neurons and neuroblastoma SH-SY5Y cells were incubated with Lactacystin for 48 h (2.5 and 10 μg/ml, respectively). The animal study was performed on male Wistar rats injected unilaterally with Lactacystin (5 μg/2 μl) into the substantia nigra (SN) pars compacta. In the in vitro study, we did not found any protective effects of celastrol, given either in the pre- or co-treatment mode. Moreover, in the higher concentrations, celastrol itself reduced cell viability, and enhanced the Lactacystin-induced cell death in both types of cells. In the in vivo study, none of the celastrol doses (0.3–3 mg/kg) attenuated the Lactacystin-induced decrease in the level of dopamine (DA) and its metabolites or protected nigral dopaminergic neurons against the Lactacystin-induced degeneration. The highest celastrol dose potentiated the Lactacystin-induced decrease in the level of DA and its metabolites in the lesioned striatum, and accelerated the Lactacystin-induced increase in the oxidative and total metabolism of DA. Moreover, when given alone, this dose of celastrol bilaterally decreased the number and/or density of dopaminergic neurons in the SN. Our results demonstrate that celastrol does not induce neuroprotective effects under conditions of UPS inhibition.
-
Different effects of intranigral and intrastriatal administration of the proteasome inhibitor Lactacystin on typical neurochemical and histological markers of Parkinson's disease in rats
Neurochemistry international, 2011Co-Authors: Elżbieta Lorenc-koci, Tomasz Lenda, Helena Domin, Maria Śmiałowska, Lucyna Antkiewicz-michaluk, Jadwiga Wardas, Jolanta KoniecznyAbstract:Impairment of the ubiquitin-proteasome system, responsible for clearing of misfolded and unwanted proteins, has been implicated in the loss of nigrostriatal dopaminergic neurons characteristic of Parkinson's disease (PD). Recently, proteasome inhibitors have been used to model parkinsonian-like changes in animals. In the present study, the effects of intrastriatal and intranigral injections of the selective proteasome inhibitor Lactacystin on key markers of PD were examined in Wistar rats. Comparisons of these two different routes of Lactacystin administration revealed that only a unilateral, intranigral injection of Lactacystin at a dose of 0.5, 1, 2.5 and 5 μg/2 μl produced after 7 days distinct decreases in the concentrations of dopamine (DA) and its metabolites (DOPAC, 3-MT, HVA) in the ipsilateral striatum. The used doses of Lactacystin (except for 0.5 μg/2 μl) significantly accelerated DA catabolism, i.e. the total, oxidative MAO-dependent and COMT-catalyzed pathways, as assessed by HVA/DA, DOPAC/DA and 3-MT/DA ratios, respectively, in the ipsilateral striatum. Such alterations were not observed in the striatal DA content and catabolism either 7, 14 or 21 days after a unilateral, intrastriatal high-dose Lactacystin injection (5 and 10 μg/2 μl). Intranigrally administered Lactacystin (1 μg/2 μl) caused a marked decline of tyrosine hydroxylase (TH) and α-synuclein protein levels in that structure. Neither TH nor α-synuclein protein levels in the substantia nigra (SN) were affected by high Lactacystin doses injected intrastriatally. Moreover, stereological counting of TH-immunoreactive neurons and autoradiographic analysis of [(3)H]GBR 12,935 binding to dopamine transporter confirmed a loss of nigrostriatal dopaminergic neurons after an intranigral Lactacystin (1 and 2.5 μg/2 μl) injection. An appearance of cardinal neurochemical and histological changes of parkinsonian type only after intranigral Lactacystin injection indicates that DA cell bodies in the SN, but not DA terminals in the striatum are susceptible to proteasome inhibition.
-
Time course of changes in rotational behavior and DA metabolism in rats lesioned unilaterally with the selective proteasome inhibitor Lactacystin
Pharmacological Reports, 2011Co-Authors: Jolanta Konieczny, Tomasz Lenda, Małgorzata Zapała, Elżbieta Lorenc-kociAbstract:A growing body of evidence suggests that proteasomal dysfunction may play an important role in the pathogenesis of PD. The aim of our study was to examine the effect of unilateral administration of Lactacystin, a selective proteasome inhibitor, on rotational behavior and striatal and nigral metabolism of dopamine (DA). Male Wistar rats were used for the study. The animals were injected unilaterally with a single dose of Lactacystin (2.5 μg/2 μl) into the substantia nigra (SN) pars compacta. After injection, the rats were examined for spontaneous and apomorphine (0.25 mg/kg)induced rotational behavior in rotameter bowls throughout 60 min. All the testing was done on days 1, 4, 7, 14 and 21 after Lactacystin administration. The animals were killed by decapitation on post-lesional days 1, 4, 7 and 21. The levels of DA and its metabolites were assayed in striatal and nigral homogenates using an HPLC method. Behavioral studies showed that the Lactacystin-lesioned rats, but not the shamoperated animals, displayed a strong spontaneous circling behavior contralateral to the lesioned side on the 1 and 4 day after Lactacystin treatment. This effect disappeared 1 week after the lesion. After apomorfine treatment on day 7, 14 and 21 days after surgery, no contralateral turning was observed in the lesioned rats. Biochemical studies demonstrated that Lactacystin evoked a progressive loss in DA and its metabolites in the ipsilateral striatum and SN compared to the ipsilateral striatum of the sham-operated rats. The decreases started on the 7 day after lesion except for the drop in the nigral DA level which began already on the 4 day after surgery. After 21 days, the decline in DA level exceed 90% both in the striatum and SN. As regards DA catabolism, Lactacystin evoked a progressive acceleration of MAO-dependent oxidative DA catabolism (DOPAC/DA), COMT-dependent Omethylation (3-MT/DA) and total DA catabolism (HVA/DA), both in the ipsilateral striatum and SN. The present study shows that Lactacystin produces biochemical changes characteristic of degeneration of the DA system, namely a robust progressive decrease in DA level and an increase in DA catabolism. However, the presence of spontaneous contralateral rotations on the first few days after lesion indicates that other, probably non-DA mechanisms may play a role in this phenomenon. On the other hand, the lack of contralateral rotations after apomorphine up to three weeks after surgery suggests that the Lactacystin-induced dramatic loss of striatal DA does not lead to supersensitivity of the striatal postsynaptic DA receptors.
Ian F Harrison - One of the best experts on this subject based on the ideXlab platform.
-
associated degeneration of ventral tegmental area dopaminergic neurons in the rat nigrostriatal Lactacystin model of parkinsonism and their neuroprotection by valproate
Neuroscience Letters, 2016Co-Authors: Ian F Harrison, Hiba K Anis, David T DexterAbstract:Parkinson's disease (PD) manifests clinically as bradykinesia, rigidity, and development of a resting tremor, primarily due to degeneration of dopaminergic nigrostriatal pathways in the brain. Intranigral administration of the irreversible ubiquitin proteasome system inhibitor, Lactacystin, has been used extensively to model nigrostriatal degeneration in rats, and study the effects of candidate neuroprotective agents on the integrity of the dopaminergic nigrostriatal system. Recently however, adjacent extra-nigral brain regions such as the ventral tegmental area (VTA) have been noted to also become affected in this model, yet their integrity in studies of candidate neuroprotective agents in the model have largely been overlooked. Here we quantify the extent and distribution of dopaminergic degeneration in the VTA of rats intranigrally lesioned with Lactacystin, and quantify the extent of VTA dopaminergic neuroprotection after systemic treatment with an epigenetic therapeutic agent, valproate, shown previously to protect dopaminergic SNpc neurons in this model. We found that unilateral intranigral administration of Lactacystin resulted in a 53.81% and 31.72% interhemispheric loss of dopaminergic SNpc and VTA neurons, respectively. Daily systemic treatment of Lactacystin lesioned rats with valproate however resulted in dose-dependant neuroprotection of VTA neurons. Our findings demonstrate that not only is the VTA also affected in the intranigral Lactacystin rat model of PD, but that this extra-nigral brain region is substrate for neuroprotection by valproate, an agent shown previously to induce neuroprotection and neurorestoration of SNpc dopaminergic neurons in this model. Our results therefore suggest that valproate is a candidate for extra-nigral as well as intra-nigral neuroprotection.
-
neurorestoration induced by the hdac inhibitor sodium valproate in the Lactacystin model of parkinson s is associated with histone acetylation and up regulation of neurotrophic factors
British Journal of Pharmacology, 2015Co-Authors: Ian F Harrison, William R Crum, Anthony C Vernon, David T DexterAbstract:© 2015 The British Pharmacological Society. Background and Purpose Histone hypoacetylation is associated with Parkinson's disease (PD), due possibly to an imbalance in the activities of enzymes responsible for histone (de)acetylation; correction of which may be neuroprotective/neurorestorative. This hypothesis was tested using the anti-epileptic drug sodium valproate, a known histone deacetylase inhibitor (HDACI), utilizing a delayed-start study design in the Lactacystin rat model of PD. Experimental Approach The irreversible proteasome inhibitor Lactacystin was unilaterally injected into the substantia nigra of Sprague-Dawley rats that subsequently received valproate for 28 days starting 7 days after Lactacystin lesioning. Longitudinal motor behavioural testing, structural MRI and post-mortem assessment of nigrostriatal integrity were used to track changes in this model of PD and quantify neuroprotection/restoration. Subsequent cellular and molecular analyses were performed to elucidate the mechanisms underlying valproate's effects. Key Results Despite producing a distinct pattern of structural re-modelling in the healthy and Lactacystin-lesioned brain, delayed-start valproate administration induced dose-dependent neuroprotection/restoration against Lactacystin neurotoxicity, characterized by motor deficit alleviation, attenuation of morphological brain changes and restoration of dopaminergic neurons in the substantia nigra. Molecular analyses revealed that valproate alleviated Lactacystin-induced histone hypoacetylation and induced up-regulation of brain neurotrophic/neuroprotective factors. Conclusions and Implications The histone acetylation and up-regulation of neurotrophic/neuroprotective factors associated with valproate treatment culminate in a neuroprotective and neurorestorative phenotype in this animal model of PD. As valproate induced structural re-modelling of the brain, further research is required to determine whether valproate represents a viable candidate for disease treatment; however, the results suggest that HDACIs could hold potential as disease-modifying agents in PD.
