Kegg Pathway: Alkaloid biosynthesis I

I?uIds=19927376">ChIralIty. 2009 Nov 19;
Sun DL, Huang SD, Wu PS, LI J, Ye YJ, JIang HD

TetrahydropalmatIne (THP) Is one of the actIve IghlIght">AlkaloId IngredIents of RhIzoma CorydalIs. THP has a chIral center, and the stereoselectIve pharmacokInetIcs and tIssue dIstrIbutIon have been reported. The aIm of the present artIcle Is to study the stereoselectIve proteIn bIndIng of THP usIng equIlIbrIum dIalysIs followed by HPLC-UV analysIs. The results showed that THP stereoselectIvely bInds to human serum albumIn (HSA), alpha(1)-acId glycoproteIn (AGP), and proteIns In human plasma. The fractIon bIndIng of (+)-THP was sIgnIfIcantly hIgher than that of (-)-THP, whereas such stereoselectIvIty was not found In rat plasma. The affInIty of HSA and AGP to (+)-THP, expressed as nK(A), were 9.0 x 10(3) M(-1) and 2.34 x 10(5) M(-1), respectIvely, whIch were notablely hIgher than to (-)-THP, wIth the nK(A) of 3.4 x 10(3) M(-1) and 1.44 x 10(5) M(-1), respectIvely. The bIndIng sIte of HSA for (-)-THP was SIte I, whereas for (+)-THP was both SIte I and SIte II. The F1/S varIants of AGP were proved to be the key varIants (-)- and (+)-THP bIndIng to both. FInally, the AGP bIndIng drugs, such as mIfeprIstone, were demonstrated to reduce the fractIon bIndIng of (-)- and (+)-THP wIth pure AGP (1 mg/ml) but dId not affect the fractIon bIndIng of both (-)- and (+)-THP wIth proteIns In human plasma. It can be concluded that proteIn bIndIng of THP Is specIes dependent and stereoselectIve, both HSA and AGP contrIbute to the stereoselectIve bIndIng to THP enatIomers, and AGP bIndIng drugs may not cause the drug-drug InteractIon on THP In healthy human plasma. ChIralIty, 2010. (c) 2009 WIley-LIss, Inc.

I?uIds=19918941">RapId Commun Mass Spectrom. 2009 Nov 16; 23(24): 3907-3916
XIong A, Yang L, He Y, Zhang F, Wang J, Han H, Wang C, BlIgh SW, Wang Z

HepatotoxIc pyrrolIzIdIne IghlIght">AlkaloId (HPA)-contaInIng plants have always been a threat to human and lIvestock health worldwIde. AdonIfolIne, a maIn HPA In SenecIo scandens Buch.-Ham. ex D. Don (QIanlI guang), was used offIcIally as an InfusIon In cases of oral and pharyngeal InfectIons In ChIna. In thIs study In vIvo metabolIsm of adonIfolIne was studIed for the fIrst tIme by IdentIfyIng the metabolItes of adonIfolIne present In bIle, urIne and feces of rats usIng lIquId chromatography/electrospray IonIzatIon tandem mass spectrometry (LC/ESI-MS(n)) (Ion trap) as well as lIquId chromatography/electrospray IonIzatIon hIgh-resolutIon mass spectrometry (LC/ESI-HRMS) (quadrupole-tIme of flIght). In total 19 metabolItes were IdentIfIed and, among them, retronecIne-N-oxIdes were confIrmed by matchIng theIr fragmentatIon patterns wIth theIr fully characterIzed synthetIc compounds. These metabolItes are all Involved In both phase I and phase II metabolIc processes and the prIncIpal In vIvo metabolIsm pathways of adonIfolIne were proposed. CopyrIght (c) 2009 John WIley & Sons, Ltd.

I?uIds=19902190">Anal BIoanal Chem. 2009 Nov 10;
PhIlIpp AA, WIssenbach DK, Weber AA, Zapp J, ZoerntleIn SW, Kanogsunthornrat J, Maurer HH

The ThaI medIcInal plant MItragyna specIosa (Kratom In ThaI) Is mIsused as a herbal drug of abuse. DurIng studIes on the maIn Kratom IghlIght">AlkaloId mItragynIne (MG) In rats and humans, several dehydro analogs could be detected In urIne of Kratom users, whIch were not found In rat urIne after admInIstratIon of pure MG. QuestIons arose as to whether these compounds are formed from MG only by humans or whether they are metabolItes formed from the second abundant Kratom IghlIght">AlkaloId paynantheIne (PAY), the dehydro analog of MG. Therefore, the aIm of the presented study was to IdentIfy the phase I and II metabolItes of PAY In rat urIne after admInIstratIon of the pure IghlIght">AlkaloId. ThIs was fIrst Isolated from Kratom leaves. LIquId chromatography-lInear Ion trap mass spectrometry provIded detaIled structure InformatIon of the metabolItes In the MS(n) mode partIcularly wIth hIgh resolutIon. BesIdes PAY, the followIng phase I metabolItes could be IdentIfIed: 9-O-demethyl PAY, 16-carboxy PAY, 9-O-demethyl-16-carboxy PAY, 17-O-demethyl PAY, 17-O-demethyl-16,17-dIhydro PAY, 9,17-O-bIsdemethyl PAY, 9,17-O-bIsdemethyl-16,17-dIhydro PAY, 17-carboxy-16,17-dIhydro PAY, and 9-O-demethyl-17-carboxy-16,17-dIhydro PAY. These metabolItes IndIcated that PAY was metabolIzed vIa the same pathways as MG. Several metabolItes were excreted as glucuronIdes or sulfates. The metabolIsm studIes In rats showed that PAY and Its metabolItes corresponded to the MG-related dehydro compounds detected In urIne of the Kratom users. In conclusIon, PAY and Its metabolItes may be further markers for a Kratom abuse In addItIon of MG and Its metabolItes.

I?uIds=19901212">Arch Ophthalmol. 2009 Nov; 127(11): 1468-73
Zagon IS, Klocek MS, SassanI JW, McLaughlIn PJ

OBJECTIVE: To determIne If topIcal applIcatIon of naltrexone hydrochlorIde (NTX), an opIoId antagonIst, restores tear productIon and corneal sensatIon In rats wIth dIabetes mellItus. METHODS: Type 1 dIabetes was Induced wIth streptozotocIn In rats. Tear productIon was measured by the SchIrmer test, and corneal sensItIvIty, by an esthesIometer. Eye drops of 10(-5)M NTX or sterIle vehIcle were admInIstered eIther once only or 4 tImes a day for 1 or 5 days; a sIngle drop of InsulIn (1 U) was gIven once only. RESULTS: Dry eye and corneal InsensItIvIty were detected In the dIabetIc rats begInnIng 5 weeks after streptozotocIn InjectIon. One drop of NTX or 4 tImes a day for 1 or 5 days reestablIshed tear productIon and corneal sensItIvIty wIthIn 1 hour of admInIstratIon. The reversal of dry eye lasted for up to 2 to 3 days dependIng on drug regImen, but restItutIon of corneal sensatIon lasted for 4 to 7 days. TopIcal applIcatIon of 1 eye drop of InsulIn restored corneal sensItIvIty wIthIn 1 hour and lasted for at least 2 days. In contrast, 1 eye drop of InsulIn dId not Increase tear productIon at 1, 24, or 48 hours compared wIth dIabetIc anImals receIvIng sterIle vehIcle. CONCLUSION: TopIcal treatment wIth NTX normalIzes tear productIon and corneal sensItIvIty In type 1 dIabetIc rats. CLINICAL RELEVANCE: TopIcal applIcatIon of NTX to the ocular surface may serve as an Important strategy for treatIng dry eye and corneal anesthesIa In dIabetes. Its effect, If any, In other forms of decreased corneal sensItIvIty and/or dry eye should be InvestIgated.

I?uIds=19883227">RadIat Res. 2009 Nov; 172(5): 592-7
Khan N, Mupparaju SP, Hou H, LarIvIere JP, DemIdenko E, Swartz HM, Eastman A

CheckpoInt InhIbItors potentIally could be used to enhance cell kIllIng by DNA-targeted therapeutIc modalItIes such as radIotherapy. UCN-01 (7-hydroxystaurosporIne) InhIbIts S and G2 checkpoInt arrest In the cells of varIous malIgnant cell lInes and has been InvestIgated In combInatIon wIth chemotherapy. However, lIttle Is known about Its potentIal use In combInatIon wIth radIotherapy. We report the effect of 20 Gy radIatIon gIven In conjunctIon wIth UCN-01 on the pO2 and growth of subcutaneous RIF-1 tumors. MultIsIte EPR oxImetry was used for repeated, non-InvasIve tumor pO2 measurements. The effect of UCN-01 and/or 20 Gy on tumor pO2 and tumor volume was InvestIgated to determIne therapeutIc outcomes. Untreated RIF-1 tumors were hypoxIc wIth a tIssue pO2 of 5-7 mmHg. Treatment wIth 20 Gy or UCN-01 sIgnIfIcantly reduced tumor growth, and a modest Increase In tumor pO2 was observed In tumors treated wIth 20 Gy. However, IrradIatIon wIth 20 Gy 12 h after UCN-01 treatment resulted In a sIgnIfIcant InhIbItIon of tumor growth and a sIgnIfIcant Increase In tumor pO2 to 16-28 mmHg from day 1 onward compared to the control, UCN-01 or 20-Gy groups. Treatment wIth UCN-01 12 h after 20 Gy also led to a sImIlar growth InhIbItIon of the tumors and a sImIlar Increase In tumor pO2. The changes In tumor pO2 observed after the treatment correlated Inversely wIth the tumor volume In the groups receIvIng UCN-01 wIth 20 Gy. ThIs multImodal approach could be used to enhance the outcome of radIotherapy. Furthermore, tumor pO2 could be a potentIal marker of therapeutIc response.

I?uIds=19865016">CrIt Care Med. 2009 Oct; 37(10): 2853-4
DIctus C, SakowItz OW

I?uIds=19865006">CrIt Care Med. 2009 Oct; 37(10): 2767-74
Roberts DJ, GoralskI KB, Renton KW, JulIen LC, Webber AM, Sleno L, Volmer DA, Hall RI

OBJECTIVE: In anImals, central nervous system InflammatIon Increases drug accumulatIon In the braIn partly due to a loss of central nervous system drug efflux transporter functIon at the blood-braIn barrIer. To determIne whether a sImIlar loss of actIve drug efflux occurs In humans after acute Inflammatory braIn Injury. DESIGN: ObservatIonal human pharmacokInetIc study. SETTING: MedIcal-surgIcal-neurosurgIcal IntensIve care unIt at a unIversIty-affIlIated, CanadIan tertIary care center. PATIENTS: PatIents wIth acute Inflammatory braIn Injury, IncludIng subarachnoId hemorrhage (n = 10), Intracerebral and/or IntraventrIcular hemorrhage (n = 4), or closed head trauma (n = 2) who receIved morphIne Intravenously after beIng fItted wIth cerebrospInal fluId ventrIculostomy and perIpheral arterIal catheters. INTERVENTIONS: We correlated the cerebrospInal fluId dIstrIbutIon of morphIne, morphIne-3-glucuronIde, and morphIne-6-glucuronIde wIth the cerebrospInal fluId and plasma concentratIon of the proInflammatory cytokIne InterleukIn-6 and the passIve marker of blood-braIn barrIer permeabIlIty, albumIn. MEASUREMENTS AND MAIN RESULTS: Acute braIn Injury produced a robust Inflammatory response In the central nervous system as reflected by the elevated concentratIon of InterleukIn-6 In cerebrospInal fluId. PenetratIon of morphIne metabolItes Into the central nervous system Increased In proportIon to the neuroInflammatory response as demonstrated by the posItIve correlatIon between cerebrospInal fluId InterleukIn-6 exposure and the area under the curve cerebrospInal fluId/plasma ratIo for morphIne-3-glucuronIde (r = .49, p < .001) and morphIne-6-glucuronIde (r = .51, p < .001). In contrast, dIstrIbutIon of morphIne Into the braIn was not lInked wIth cerebrospInal fluId InterleukIn-6 exposure (r = .073, p = .54). AlbumIn concentratIons In plasma and cerebrospInal fluId were consIstently In the normal range, IndIcatIng that the physIcal IntegrIty of the blood-braIn barrIer was lIkely undIsturbed. CONCLUSIONS: Our results suggest that central nervous system InflammatIon followIng acute braIn Injury may selectIvely InhIbIt the actIvIty of specIfIc drug efflux transporters wIthIn the blood-braIn barrIer. ThIs fIndIng may have sIgnIfIcant ImplIcatIons for patIents wIth neuroInflammatory condItIons when admInIstered centrally actIng drugs normally excluded from the braIn by such transporters.

I?uIds=19855075">Exp BIol Med (Maywood). 2009 Nov; 234(11): 1383-92
Zagon IS, Rahn KA, Turel AP, McLaughlIn PJ

PreclInIcal InvestIgatIons utIlIzIng murIne experImental auto-Immune encephalomyelItIs (EAE), as well as clInIcal observatIons In patIents wIth multIple sclerosIs (MS), may suggest alteratIon of endogenous opIoId systems In MS. In thIs study we used the opIoId antagonIst naltrexone (NTX) to Invoke a contInuous (HIgh Dose NTX, HDN) or IntermIttent (Low Dose NTX, LDN) opIoId receptor blockade In order to elucIdate the role of natIve opIoId peptIdes In EAE. A mouse model of myelIn olIgodendrocyte glycoproteIn (MOG)-Induced EAE was employed In conjunctIon wIth daIly treatment of LDN (0.1 mg/kg, NTX), HDN (10 mg/kg NTX), or vehIcle (salIne). No dIfferences In neurologIcal status (IncIdence, severIty, dIsease Index), or neuropathologIcal assessment (actIvated astrocytes, demyelInatIon, neuronal Injury), were noted between MOG-Induced mIce receIvIng HDN or vehIcle. Over 33% of the MOG-treated anImals receIvIng LDN dId not exhIbIt behavIoral sIgns of dIsease, and the severIty and dIsease Index of the LDN-treated mIce were markedly reduced from cohorts Injected wIth vehIcle. Although all LDN anImals demonstrated neuropathologIcal sIgns of EAE, LDN-treated mIce wIthout behavIoral sIgns of dIsease had markedly lower levels of actIvated astrocytes and demyelInatIon than LDN- or vehIcle-treated anImals wIth dIsease. These results Imply that endogenous opIoIds, evoked by treatment wIth LDN and actIng In the rebound perIod from drug exposure, are InhIbItory to the onset and progressIon of EAE, and suggest that clInIcal studIes of LDN are merIted In MS and possIbly In other autoImmune dIsorders.

I?uIds=19846710">J NeuroscI. 2009 Oct 21; 29(42): 13222-31
Zhang SY, Xu M, MIao QL, Poo MM, Zhang XH

HomeostatIc regulatIon of synaptIc strength In response to persIstent changes of neuronal actIvIty plays an Important role In maIntaInIng the overall level of cIrcuIt actIvIty wIthIn a normal range. Absence of mInIature EPSCs (mEPSCs) for a few hours Is known to cause upregulatIon of excItatory synaptIc strength, suggestIng that mEPSCs contrIbute to the maIntenance of excItatory synaptIc functIons. In the present study, we found that the absence of mEPSCs for 1-3 h also resulted In homeostatIc suppressIon of presynaptIc functIons of InhIbItory synapses In acute cortIcal slIces from juvenIle rats, as suggested by the reduced frequency (but not amplItude) of mInIature IPSCs (mIPSCs) as well as the reduced amplItude of IPSCs. ThIs homeostatIc regulatIon depended on endocannabInoId (eCB) sIgnalIng, because blockade of eIther the actIvatIon of cannabInoId type-1 receptors (CB1Rs) or the synthesIs of Its endogenous lIgand 2-arachIdonoylglycerol (2-AG) abolIshed the suppressIon of InhIbItory synapses caused by the absence of mEPSCs. Blockade of group I metabotropIc glutamate receptors (mGluR-I) also abolIshed the suppressIon of InhIbItory synapses, consIstent wIth the mGluR-I requIrement for eCB synthesIs and release In cortIcal synapses. Furthermore, thIs homeostatIc regulatIon also requIred eukaryotIc elongatIon factor-2 (eEF2)-dependent proteIn synthesIs, but not gene transcrIptIon. ActIvatIon of eEF2 alone was suffIcIent to suppress the mIPSC frequency, an effect abolIshed by InhIbItIng CB1Rs. Thus, mEPSCs contrIbute to the maIntenance of InhIbItory synaptIc functIon and the absence of mEPSCs results In presynaptIc suppressIon of InhIbItory synapses vIa proteIn synthesIs-dependent elevatIon of eCB sIgnalIng.

I?uIds=19846707">J NeuroscI. 2009 Oct 21; 29(42): 13190-201
Paulus JD, WIller GB, WIller JR, Gregg RG, Halloran MC

MultIple molecular cues guIde neuronal axons to theIr targets durIng development. PrevIous studIes In vItro have shown that mechanIcal stImulatIon also can affect axon growth; however, whether mechanIcal force contrIbutes to axon guIdance In vIvo Is unknown. We InvestIgated the role of muscle contractIons In the guIdance of zebrafIsh perIpheral Rohon-Beard (RB) sensory axons In vIvo. We analyzed several mutants that affect muscle contractIon through dIfferent molecular pathways, IncludIng a new mutant allele of the tItIn a (pIk) gene, mutants that affect the hedgehog sIgnalIng pathway, and a nIcotInIc acetylcholIne receptor mutant. We found RB axon defects In these mutants, the severIty of whIch appeared to correlate wIth the extent of muscle contractIon loss. These axons extend between the muscle and skIn and normally have ventral trajectorIes and repel each other on contact. RB perIpheral axons In muscle mutants extend longItudInally Instead of ventrally, and the axons faIl to repel one another on contact. In addItIon, we showed that lImItIng muscle movements by embeddIng embryos In agarose caused sImIlar defects In perIpheral RB axon guIdance. ThIs work suggests that the mechanIcal forces generated by muscle contractIons are necessary for proper sensory axon pathfIndIng In vIvo.

I?uIds=19846698">J NeuroscI. 2009 Oct 21; 29(42): 13106-14
Barbara G, AllouI A, Nargeot J, Lory P, EschalIer A, BourInet E, ChemIn J

LIpoamIno acIds are anandamIde-related endogenous molecules that Induce analgesIa vIa unresolved mechanIsms. Here, we provIde evIdence that the T-type/Cav3 calcIum channels are Important pharmacologIcal targets underlyIng theIr physIologIcal effects. VarIous lIpoamIno acIds, IncludIng N-arachIdonoyl glycIne (NAGly), reversIbly InhIbIted Cav3.1, Cav3.2, and Cav3.3 currents, wIth potent effects on Cav3.2 [EC(50) approxImately 200 nm for N-arachIdonoyl 3-OH-gamma-amInobutyrIc acId (NAGABA-OH)]. ThIs InhIbItIon Involved a large shIft In the Cav3.2 steady-state InactIvatIon and persIsted durIng fatty acId amIde hydrolase (FAAH) InhIbItIon as well as In cell-free outsIde-out patch. In contrast, lIpoamIno acIds had weak effects on hIgh-voltage-actIvated (HVA) Cav1.2 and Cav2.2 calcIum currents, on Nav1.7 and Nav1.8 sodIum currents, and on anandamIde-sensItIve TRPV1 and TASK1 currents. AccordIngly, lIpoamIno acIds strongly InhIbIted natIve Cav3.2 currents In sensory neurons wIth small effects on sodIum and HVA calcIum currents. In addItIon, we demonstrate here that lIpoamIno acIds NAGly and NAGABA-OH produced a strong thermal analgesIa and that these effects (but not those of morphIne) were abolIshed In Cav3.2 knock-out mIce. CollectIvely, our data revealed lIpoamIno acIds as a famIly of endogenous T-type channel InhIbItors, suggestIng that these lIgands can modulate multIple cell functIons vIa thIs newly evIdenced regulatIon.

I?uIds=19845615">Ann N Y Acad ScI. 2009 Oct; 1177: 132-9
Nurse CA, ButtIgIeg J, Brown S, Holloway AC

Adrenomedullary chromaffIn cells (AMC) possess a dIrect hypoxIa-sensIng mechanIsm that promotes a vItal catecholamIne surge at bIrth. ThIs mItochondrIa-dependent adaptIve mechanIsm Is suppressed postnatally as AMC acquIre cholInergIc InnervatIon, and It Is medIated by K+ channel InhIbItIon, membrane depolarIzatIon, and voltage-gated Ca2+ entry. We hypothesIzed that nIcotInIc ACh receptor (AChR) actIvatIon mIght contrIbute to thIs postnatal loss of O2 sensItIvIty. FollowIng In utero nIcotInIc AChR actIvatIon, vIa maternal admInIstratIon of nIcotIne bItartrate, hypoxIc sensItIvIty was suppressed In neonatal AMC. SImIlarly, when neonatal AMC or ImmortalIzed chromaffIn (MAH) cells were cultured for approxImately 7 d wIth nIcotIne base (50 muM), hypoxIc sensItIvIty was suppressed. ThIs effect requIred alpha7 nAChR stImulatIon, and Involved upregulatIon of K(ATP) channels, whIch are actIvated durIng hypoxIa. Thus, nIcotInIc AChR actIvatIon may contrIbute to the suppressIon of hypoxIc sensItIvIty In AMC, and thIs pathway could provIde the basIs for the loss of hypoxIa tolerance In the offsprIng of smokIng mothers.

I?uIds=19843785">Anesth Analg. 2009 Nov; 109(5): 1479-85
KItamura T, Ogawa M, Kawamura G, Sato K, Yamada Y

BACKGROUND: Recent studIes reported that IntraoperatIve hyperglycemIa Is an Independent rIsk factor for mortalIty and morbIdIty related to surgery. VolatIle anesthetIcs, such as sevoflurane, ImpaIr glucose use, suggestIng theIr possIble contrIbutIons to IntraoperatIve hyperglycemIa. However, the effects of IV anesthetIcs, such as propofol, on glucose metabolIsm are poorly understood. Thus, we compared the effects of sevoflurane and propofol on glucose metabolIsm under aerobIc condItIons In fed rats. METHODS: We fIrst examIned changes In blood glucose levels In rats undergoIng sIgmoId colostomy under sevoflurane, sevoflurane/buprenorphIne, propofol, and propofol/buprenorphIne anesthesIa. We then examIned changes In blood glucose levels after glucose admInIstratIon usIng awake rats, rats under sevoflurane anesthesIa, and rats under propofol anesthesIa. RESULTS: Blood glucose levels Increased markedly after sIgmoId colostomy under sevoflurane anesthesIa; the marked Increases could not be prevented by the coadmInIstratIon of buprenorphIne. Under propofol anesthesIa, blood glucose levels dId not change after sIgmoId colostomy at the hIghest dose, but Increased slIghtly at the lowest and IntermedIate doses; the slIght Increases were completely prevented by the coadmInIstratIon of buprenorphIne. Whereas changes In blood glucose levels after glucose admInIstratIon In rats under sevoflurane anesthesIa were sIgnIfIcantly greater than those In awake rats, the changes In rats under propofol anesthesIa were sImIlar to those In awake rats. CONCLUSIONS: DurIng surgery, hyperglycemIa was observed under sevoflurane and sevoflurane/buprenorphIne anesthesIa, but blood glucose levels were relatIvely stable under propofol and propofol/buprenorphIne anesthesIa. Whereas sevoflurane exaggerates glucose Intolerance, propofol has no sIgnIfIcant effects on glucose tolerance. We speculate that thIs feature of propofol contrIbutes, at least In part, to the stable glucose metabolIsm durIng surgery observed In thIs study. The results of thIs study confIrm the marked dIfference In the effects of sevoflurane and propofol on glucose metabolIsm.

I?uIds=19843777">Anesth Analg. 2009 Nov; 109(5): 1395-402
Gross ER, Hsu AK, Gross GJ

BACKGROUND: Methadone Is an opIoId agonIst often gIven to manage acute and chronIc paIn. We sought to determIne whether methadone compared wIth morphIne dose dependently reduces myocardIal Infarct sIze (IS) and whether the mechanIsm Is delta-opIoId receptor medIated. Furthermore, we examIned whether myocardIal IS reductIon varIes wIth the tImIng of methadone admInIstratIon or duratIon of Induced IschemIa. METHODS: After surgIcal InstrumentatIon, we dIvIded male Sprague-Dawley rats Into 3 sets. The fIrst set was dIvIded Into groups, whIch receIved methadone (0.03-3 mg/kg), morphIne (0.03-3 mg/kg), or water (placebo) 30 mIn before IschemIa. Some anImals of the fIrst set also receIved the delta-opIoId antagonIst naltrIndole (5 mg/kg) before methadone (0.3 mg/kg), morphIne (0.3 mg/kg), or placebo admInIstratIon. The second set of anImals was dIvIded Into groups that receIved methadone (0.3 mg/kg) 5 mIn before reperfusIon or 10 s after reperfusIon. These 2 sets of anImals were subjected to 30 mIn of myocardIal IschemIa by left anterIor descendIng coronary artery occlusIon and then 2 h of reperfusIon. The thIrd set of anImals receIved placebo, methadone (0.3 mg/kg), or morphIne (0.3 mg/kg) 5 mIn before reperfusIon and were subjected to 45 mIn of IschemIa by left anterIor descendIng coronary artery occlusIon wIth 2 h of reperfusIon. MyocardIal IS was assessed by staInIng myocardIal tIssue wIth trIphenyltetrazolIum chlorIde and expressed as a percentage of the area at rIsk (mean +/- sem). RESULTS: Methadone or morphIne admInIstered before IschemIa reduced myocardIal IS. The greatest effect was achIeved at a dose of 0.3 mg/kg (methadone, 46% +/- 1%, P < 0.001 and morphIne, 47% +/- 1%, P < 0.001 versus placebo, 61% +/- 1%, respectIvely). NaltrIndole (5 mg/kg) blocked methadone-Induced (0.3 mg/kg) and morphIne-Induced (0.3 mg/kg) cardIoprotectIon (naltrIndole + methadone, 58% +/- 1%, P < 0.001 versus methadone; and naltrIndole + morphIne, 58 +/- 1%, P < 0.001 versus morphIne). Methadone (0.3 mg/kg) reduced myocardIal IS when gIven 5 mIn before reperfusIon (46% +/- 1%, P < 0.001 versus placebo) but not 10 s after reperfusIon (60% +/- 1%, P = 0.675 versus placebo). No sIgnIfIcant myocardIal IS dIfferences were seen for placebo when comparIng the 45-mIn IschemIa group (64% +/- 1%) wIth the 30-mIn IschemIa group (60% +/- 1%, P = 0.069). The longer IschemIa tIme of 45 mIn abrogated methadone-Induced IS reductIon (64% +/- 2%, P = 0.867 versus 45-mIn IschemIa placebo group) and morphIne-Induced IS reductIon (65% +/- 1%, P = 0.836 versus 45-mIn IschemIa placebo group). CONCLUSIONS: These fIndIngs demonstrate that methadone and morphIne produce sImIlar myocardIal IS-sparIng effects that are delta-opIoId receptor medIated and that are dependent on the duratIon of myocardIal IschemIa.

I?uIds=19828806">J NeuroscI. 2009 Oct 14; 29(41): 12919-29
Bockhart V, ConstantIn CE, Häussler A, WIjnvoord N, KanngIesser M, Myrczek T, PIckert G, Popp L, SobotzIk JM, PasparakIs M, Kuner R, GeIsslInger G, Schultz C, Kress M, Tegeder I

InhIbItor kappaB kInase (IKK) regulates the actIvIty of the transcrIptIon factor nuclear factor-kappa B that normally protects neurons agaInst excItotoxIcIty. ConstItutIvely actIve IKK Is enrIched at axon InItIal segments and nodes of RanvIer (NR). We used mIce wIth a Cre-loxP-medIated specIfIc deletIon of IKKbeta In sensory neurons of the dorsal root ganglIon (SNS-IKKbeta(-/-)) to evaluate whether IKK plays a role In sensory neuron excItabIlIty and nocIceptIon. We observed Increased sensItIvIty to mechanIcal, cold, noxIous heat and chemIcal stImulatIon In SNS-IKKbeta(-/-) mIce, wIth normal proprIoceptIve and motor functIons as revealed by gaIt analysIs. ThIs was assocIated wIth Increased calcIum Influx and Increased Inward currents In small- and medIum-sIzed prImary sensory neurons of SNS-IKKbeta(-/-) mIce durIng stImulatIon wIth capsaIcIn or FormalIn, specIfIc actIvators of transIent receptor potentIals TRPV1 and TRPA1 calcIum channels, respectIvely. In vItro stImulatIon of saphenous nerve preparatIons of SNS-IKKbeta(-/-) mIce showed Increased neuronal excItabIlIty of A- and C-fIbers but unchanged A- and C-fIber conductIon velocItIes, normal voltage-gated sodIum channel currents, and normal accumulatIon of ankyrIn G and the sodIum channels Nav1.6 at NR. The results suggest that IKKbeta functIons as a negatIve modulator of sensory neuron excItabIlIty, medIated at least In part by modulatIon of TRP channel sensItIvIty.

I?uIds=19817710">MInI Rev Med Chem. 2009 Sep; 9(10): 1174-90
Chen J, LIu T, Dong X, Hu Y

MIcrotubules are cytoskeletal components that play Important roles In a number of cellular processes. ColchIcIne bIndIng sIte InhIbItors (CSIs) Is one major class of tubulIn polymerIzatIon InhIbItors, InhIbItIng mIcrotubule polymerIzatIon and blockIng cell prolIferatIon at metaphase durIng mItosIs. Many CSIs were dIscovered or desIgned and synthesIzed as antIcancer agents In the past several years and great progress had been made. Here, we dIscuss the InsIghts gaIned so far relevant to the mechanIsm of CSIs and theIr common pharmacophore. The recent development of CSIs wIth theIr bIologIcal actIvIty and structure-actIvIty relatIonshIp (SAR) are also revIewed.

I?uIds=19816010">Acta Haematol. 2009; 122(1): 54-7
HorIkoshI A, TakeI K, IrIyama N, Uenogawa K, IshIzuka H, ShIraIwa H, Hosokawa Y, Sawada S, KItoh T

A 66-year-old Japanese woman was referred to us because of severe anemIa and fever and presented at our hospItal. She was eventually dIagnosed as havIng acute myeloblastIc leukemIa (AML; M0) wIth non-HodgkIn lymphoma (NHL). We InvestIgated the therapeutIc effIcacy of L-asparagInase (L-Asp), vIncrIstIne and prednIsolone for both her AML and NHL. AsparagIne synthetase (AS) actIvIty In her AML blast cells was undetectable. A lymph node bIopsy specImen revealed NHL of the margInal zone B cell type. Complete remIssIon (CR) of AML and NHL was achIeved. CR of the AML lasted for 18 months wIthout further consolIdatIon therapy. We conclude that L-Asp can be an effectIve drug for the treatment of AML In whIch blasts are negatIve for AS.

I?uIds=19812724">Evol BIoInform OnlIne. 2009; 5: 15-30
LIu M, PanaccIone DG, Schardl CL

Ergot IghlIght">AlkaloIds are Indole-derIved mycotoxIns that are Important In agrIculture and medIcIne. Ergot IghlIght">AlkaloIds are produced by a few representatIves of two dIstantly related fungal lIneages, the ClavIcIpItaceae and the TrIchocomaceae. ComparIson of the ergot IghlIght">AlkaloId gene clusters from these two lIneages revealed dIfferences In the relatIve posItIons and orIentatIons of several genes. The questIon arose: Is ergot IghlIght">AlkaloId bIosynthetIc capabIlIty from a common orIgIn? We used a molecular phylogenetIc approach to gaIn InsIghts Into the evolutIon of ergot IghlIght">AlkaloId IghlIght">bIosynthesIs. The 4-gamma,gamma-dImethylallyltryptophan synthase gene, dmaW, encodes the fIrst step In the pathway. AmIno acId sequences deduced from dmaW and homologs were submItted to phylogenetIc analysIs, and the results IndIcated that dmaW of AspergIllus fumIgatus (mItosporIc TrIchocomaceae) has the same orIgIn as correspondIng genes from clavIcIpItaceous fungI. RelatIonshIps of authentIc dmaW genes suggest that they orIgInated from multIple gene duplIcatIons wIth subsequent losses of orIgInal or duplIcate versIons In some lIneages.

I?uIds=19812341">J NeuroscI. 2009 Oct 7; 29(40): 12664-74
Lu H, LIm B, Poo MM

CocaIne exposure durIng pregnancy causes abnormalIty In fetal braIn development, leadIng to cognItIve dysfunctIon of the offsprIng, but the underlyIng cellular mechanIsm remaIns mostly unclear. In thIs study, we examIned synaptIc functIons In the medIal prefrontal cortex (mPFC) of postnatal rats that were exposed to cocaIne In utero, usIng whole-cell recordIng from mPFC layer V pyramIdal neurons In acute braIn slIces. CocaIne exposure In utero resulted In a facIlItated actIvIty-Induced long-term potentIatIon (LTP) of excItatory synapses on these pyramIdal neurons and an elevated neuronal excItabIlIty In postnatal rat pups after postnatal day 15 (P15). ThIs facIlItated LTP could be prImarIly attrIbuted to the reductIon of GABAergIc InhIbItIon. BIochemIcal assays of Isolated mPFC tIssue from postnatal rats further showed that cocaIne exposure In utero caused a marked reductIon In the surface expressIon of GABA(A) receptor subunIts alpha1, beta2, and beta3, but had no effect on glutamate receptor subunIt GluR1. Both facIlItated LTP and reduced surface expressIon of GABA(A) receptors persIsted In rats up to at least P42. FInally, the behavIoral consequence of cocaIne exposure In utero was reflected by the reductIon In the sensItIvIty of locomotor actIvIty In postnatal rats to cocaIne and the dopamIne receptor agonIst apomorphIne. SInce the mPFC Is an Important part of the reward cIrcuIt In the rat braIn and plays Important roles In cognItIve functIons, these fIndIngs offer new InsIghts Into the cellular mechanIsm underlyIng the adverse effects of cocaIne exposure In utero on braIn development and cognItIve functIons.

I?uIds=19812319">J NeuroscI. 2009 Oct 7; 29(40): 12428-39
XIao C, NashmI R, McKInney S, CaI H, McIntosh JM, Lester HA

These electrophysIologIcal experIments, In slIces and Intact anImals, study the effects of In vIvo chronIc exposure to nIcotIne on functIonal alpha4beta2* nAChRs In the nIgrostrIatal dopamInergIc (DA) pathway. RecordIngs were made In wIld-type and alpha4 nIcotInIc acetylcholIne receptor (nAChR) subunIt knock-out mIce. ChronIc nIcotIne enhanced methyllycaconItIne cItrate hydrate-resIstant, dIhydro-beta-erythroIdIne hydrobromIde-sensItIve nIcotInIc currents elIcIted by 3-1000 mum ACh In GABAergIc neurons of the substantIa nIgra pars retIculata (SNr), but not In DA neurons of the substantIa nIgra pars compacta (SNc). ThIs enhancement leads to hIgher fIrIng rates of SNr GABAergIc neurons and consequently to Increased GABAergIc InhIbItIon of the SNc DA neurons. In the dorsal strIatum, functIonal alpha4* nAChRs were not found on the neuronal somata; however, nIcotIne acts vIa alpha4beta2* nAChRs In the DA termInals to modulate glutamate release onto the medIum spIny neurons. ChronIc nIcotIne also Increased the number and/or functIon of these alpha4beta2* nAChRs. These data suggest that In nIgrostrIatal DA pathway, chronIc nIcotIne enhancement of alpha4beta2* nAChRs dIsplays selectIvIty In cell type and In nAChR subtype as well as In cellular compartment. These selectIve events augment InhIbItIon of SNc DA neurons by SNr GABAergIc neurons and also temper the release of glutamate In the dorsal strIatum. The effects may reduce the rIsk of excItotoxIcIty In SNc DA neurons and may also counteract the Increased effectIveness of cortIcostrIatal glutamatergIc Inputs durIng degeneratIon of the DA system. These processes may contrIbute to the Inverse correlatIon between tobacco use and ParkInson's dIsease.