Brain Immune System Signal Molecules in Protection from Aerobic and Anaerobic Infections

204 Pages·2012·3.08 MB·English

by  Armen A. Galoyan (auth.)

Advances in Neurobiology
Volume 6
SeriesEditor
AbelLajtha
Forfurthervolumes:
http://www.springer.com/series/8787
Armen A. Galoyan
Brain Immune System Signal
Molecules in Protection from
Aerobic and Anaerobic
Infections
2123
ArmenA.Galoyan
ParuirSevak5-1
Yerevan
Armenia
ISSN2190-5215 ISSN2190-5223(electronic)
ISBN978-1-4614-3666-9 ISBN978-1-4614-3667-6 (eBook)
DOI10.1007/978-1-4614-3667-6
SpringerNewYorkDordrechtHeidelbergLondon
LibraryofCongressControlNumber:2012938363
© SpringerScience+BusinessMediaNewYork2012
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Foreword
There is little doubt that our brain is the central command organ in our life. It
coordinates the activity of our muscular system – our movements, it interprets all
oursensoryinput;creatingourviewoftheworldoutsideourbody;itcontainsand
handles our memory, our ability to communicate, think, our emotions, it controls
ourphysicalandmentalworld, ourcapabilities–itdeterminesinsomedetailwho
weareandwhatweareabletodo–itisanorganforallpurposes.Itislittlewonder
thereforethatsomuchresearchisfocusedonthemechanismsandstructuresinthe
brain that participate in and determine its functions. The advances in this field are
indeedexcitingandspectacularandindicatethatitislikelythatthefunctionscanbe
elucidatedandunderstoodonbiologicaltermsinthefuture.Inspiteofthis,thereis
muchmorethatisatpresentnotknownthanwhatisunderstoodandisclear.Because
these contributions, such as those from Dr. Galoyan are welcome, those that open
upnewaspectssuchashisworkareofspecialimportance.
Dr. Galoyan’swork, someofwhichhesummarizedinthisvolumemademajor
contributiontonovelaspectsofbrainfunctionarathersurprisingfunctionthatwas
not expected before his and his colleagues pioneering contributions – the role of
braininimmunemechanisms–ayoungdisciplineofneuroimmunology.
An important role in neuroendocrinology are compounds derived and released
from a structure in a way can be taken as a structure of the brain, which act as a
centralcontrolregulatingthereleaseofvarioushormonesfromthesitesoftheirorigin
and storage.Another crucial control function of multiple activity of the organism,
Dr.Galoyan’sworkfocusedonbrainpeptides,whicharestoredandreleasedfrom
thespecialcellsofthehypothalamus,whichmodulatetheimmunesystem.Someof
thesecompoundsinhisstudiesactlikethefactorsreleasinghormones–affectthe
immunesystembyinfluencingtheformationandmobilizationoftheelementsofthe
immunesystem.Onesuchactivityofthesecompounds,theireffectsonbonemarrow
cellsisdiscussedinthisbook.Thisisofmajorimportance–weknowofveryfew
possibilitiestostrengthentheimmunesysteminpatientswhereitisweakanddoes
notsignificantlyprotectagainstinfectionsindifferentpathologicalprocesses,orhow
toinfluenceitwhenitattacksthebody’sownproteinsinautoimmunediseasessuch
asmultiplesclerosis.
v
vi Foreword
Dr.Galoyanfoundanotherimportantandexcitingeffectofthesepeptides;theirdi-
rectpotentialforprotectionagainstinfection,theirantiviralandantibacterialactivity.
Theseeffectshavegreatpracticalsignificanceofferingprotectionagainstinfections
thatwehaveatpresentonlydiminishingprotectionfrom.Thisrepresentsanewand
potentially very useful clinical use of unusual peptides and the potential to create
relatedstructuresthatcanbeusedasantibacterialandantiviralagents.Dr.Galoyan
findsthathiscompoundshavesurprisingmultiplebeneficialpotency,theyofferpro-
tectionagainsttoxins,inthisrespect,thisbookshouldleadtoworkproducinginthe
futurenewdrugsandnewresearchbasedonhisfindingtoisolateadditionalrelated
factorsfromthebrain.Thisbookfocusesonimmunologicalaspectsofthepeptides,
Dr.Galoyanfoundanotherimportanteffectofpeptidesfromthehypothalamus,they
influencecardiacbloodcirculationhavinganeffectonbloodvessels.Hehassumma-
rizedthecontributionsofhislaboratoryinthisareainanotherbook.Theimportance
of compounds that influence cardiac circulation in medicine does not need further
emphasis.
TheworkthatDr.Galoyanaccomplishedisfarfromtrivial;theisolationofactive
peptidespresentatverylowlevelsinthebrainrequiresspecialtechnique,innovative
approachesandalargeamountofwork,suchisolationinthepastwasNobleprize
material.Testingthebiologicalactivitiesintheirmanyaspectsrequiresfamiliarity
withalargenumberofmethodsandapproachesandagreatamountofexperimental
skillandfamiliaritywithseveralapproachesandaninterdisciplinaryapproach.This
bookisproofthatwithtalentanddevotionitcanbedone;thattheeffectwasworth
while,andtheresultssummarizedaresignificant.
AbelLajtha,Ph.D.
Preface
In the reviews “The brain immune system: chemistry and biology of the signal
molecules”aswellas“Conceptsofneuroendocrinecardiologyandneuroendocrine
immunology”,(l,2)Ihavesummarizedtheresultsof45yearsoflaboratoryfindings
on the discovery of a new hormonal system produced by human and animal neu-
rosecretorycellsofthehypothalamus.Discoveryofneuroendocrineimmunesystem
of the brain (concept that the brain is an immune organ) (2) opens a new page in
our understanding of the molecular mechanisms of the immune system regulation
as a whole and immune defense of the brain itself. The proline-rich polypeptides
are a new type of brain cytokines (3,4). One of them, galarmin (PRP-1), not only
participatesintheimmunedefenseofthebrainandtheorganism,butalsoingenesis,
differentiation, proliferation, andmobilizationofbonemarrowprogenitors. Signal
molecules of the neuroendocrine immune system of the brain, galarmin, Gx-NH ,
2
andotherscontain10–15aminoacidsresiduesandpossesswideantibacterial,anti-
tumor,hematopoietic,andanti-neurodegenerativeproperties.ProfessorAbelLajtha
wrote“TheimportanceofGaloyan’sconceptisthathypothalamicpeptidesandcy-
tokines, secreted by NSO and NPV, act not only as a component of the endocrine
system,butalsoasmodulatorsoftheimmunesystemandwhatisofgreatpractical
importanceisthesystemcanbeneuroprotectiveandstrongantibacterial”(5).
Wehaveisolatedafamilyofneuropeptideswithcardiacactivityandtheirprecur-
sorprotein,asspecificregulatorsofcardiacbloodvesselsandcardiovascularsystem
fromthehumanandanimalhypothalamus(3).Moreover,in1967,Ifoundthatthe
heartisanendocrineorgan,thenervecellsofwhich(theatria)produceandsecrete
hormonesofproteinnatureintotheblood.Theywerealsotheregulatorsofcardiac
blood flow and catecholamine biosynthesis in the atria and ventricles of the heart
activityoftheneurons.Theatrialganglionarycellsexhibitafinereactivitytowards
thehypothalamuscardioactivehormonesthroughanincreaseinneurosecretionand
thetransitionofproductstotheatrialaxons(3).
Theconceptwasestablished“Thefunctionalsystemofneurosecretoryhypotha-
lamus,theendocrineheart”.
Thereisafunctionalinteractionbetweentheneuroendocrineimmunesystemof
the hypothalamus and endocrine heart. Hypothalamic cardioactive neurohormone
C stimulates biosynthesis of the gomori positive structures and produces positive
vii
viii Preface
granulesynthesisinatrialneuronsandreleaseofthesegranulesthroughtheneural
termini.Later,wediscoveredneuroendocrineimmunesystemofthebrain,andthe
signal molecules of which proline-rich peptides produced by neuroendocrine cells
ofhypothalamusprovedtobetheregulatorsofimmunesystem, andbonemarrow
function.
Theresultsofsuchinvestigationsledustothefoundationoftwoimportanttrends
ofneurobiology:neuroendocrinecardiologyandneuroenclocrineimmunology.
Thedataweobtainedprovedthatoneoftheproline-richpeptides,galarmin,isa
strongantibacterial(“non-specific”agent).Antibacterialpropertiesofgalarminwere
tested on the following species of bacteria; Salmonella typhumurium, Salmonella
choleraesuis,Salmonellatyphi,Escherichiacoli,ShigellaFlexneri,Pseudomonas
aeruginosa„ Shigella Sonnei, Staphylococcus aureus, Streptococcus pneumoniae
(4), Bacillus anthracis (6), Clostridium perfringens as well as Mycobacterium
tuberculosis,Methicillin-resistantS.aureusetc.(seechapter5–8).
Female, pathogen-free lines of mice, i.e. BALB/c, C57BL/61, C H/Hej,
3
CBAxC57BL/6,F age5–8weekswereusedintheexperiments.
1
Experimental data suggests that PRPs, mainly galarmin, Gx-NH , and d-15
2
GalarminanaloguesareeffectiveantibacterialdrugsagainstBacillusanthracis;the
etiologicalagentofanthrax,whichisagram-positive,aerobic,sporeforming,rod-
shapedbacterium.B.anthracisdevelopmentinmacrophagesleadstotheirdestruction
duringwhichthebacillusentersthebloodstreamandstartstoreplicatetolargequan-
titiesforlongperiods.Thisdataindicatestheavailabilityofastrongdefensivereserve
inthebraintofightagainstinfections.
Epidemiological data indicate that S. aureus, particularly methicillin-resistant
strain of S.aureus (MRSA), are responsible for the most of complicated cases of
Staphylococcusinfectionandareincreasinglyimplicatedasacauseofnosocomial
andcommunityassociatedinfectionsworldwide.
C. perfringens (anaerobic infection) is the causative agent of various diseases
includinggasgangreneandfoodpoisoning.Thebacteriumproducesnumerousextra-
cellulartoxins(7,8).C.perfringensstrain13,theVirs/VirR-twocomponentsystem,
isinvolvedinthecoordinatedregulationofproductionofseveraltoxins; thealpha
toxin (Plc), theta toxin (ProA), and the kappa-toxin (colA). C. perfringens strain
13anditsderivativesweregrownunderanaerobicconditions.Antimicrobialagents
usedinthisstudywereasfollows:cefoxitin,clindomycinhclorclindomycinpo4,
metronidazole, metronidazole for iv injection, potassium penicillin G, penicillin
sodium, rifampin, andtetracyclinehci.AdoseofpenicillinGis198–1500mg/kg,
of clindomycin. Metronidazole and rifampin doses are 8–12mg/kg, clindomycin
PO4 is 2.1 and 8.6mg/kg, and metronidazole is 19 and 75mg/kg. ShimizuT. and
colleagues(9)describedthewholegenomicsequenceofstrain13.Thegenesunique
toC.perfringens arethoseencodingmyoinositolcatabolismproteinsandαandβ
galactosidases, three extracytoplasmic function (ECF) type sigma factors, α man-
nosidasecomponentsforVtypesodiumATPsynthase,selenocysteinesynthaseand
various virulence associated proteins. Gas gangrene caused by C. perfringens is a
fulminantinfection,whichexpeditesprogresstoprofoundshockanddeathwithout
Preface ix
treatment.C.perfringensismorelikelytoberesistanttocllndomycin,chlorampheni-
col,andtetracycline.Inaddition,theantibioticresistancetopenicillin,tetracycline,
cephaloihin,clindomycin,andmetronidazolewasreportedamongclinicalisolatesof
C.perfringens(8).Prophylacticserotherapyorantibiotictherapyisineffectiveand
inthiscase,highdosesofantibioticssuchas20,50,75mg/kgupto86mg/kgevery
4hoursarebeingused.However,incomparable,smallamountsofgalarmin(micro-
gramsrange)anditsanaloguesareusedforthetreatmentofthemultipleinfectious
diseasesincludinggasgangrenecausedbyC.perfringens.
HugeexperimentaldataobtainedrecentlyindicatethePRPs,namelygalarmin,to
bestrong“non-specific”drugfortheprophylaxisandtreatmentofanthrax,gasgan-
grene,tuberculosis,MRSA(septicinfections),andmyocardiuminfarctionsetc.The
physiologyofMycobacterimtuberculosisishighlyaerobicandrequireshighlevels
of oxygen, as it is primarily a pathogen of the mammalian respiratory system. M.
tuberculosisdoesnotretainanybacteriologicalstrainduetohighlipidcontentinits
wallandthusitisneithergrampositive,norgramnegative,butclassifiedasacidfast
gram-positivebacteria.Mycobacteriumoutbreaksareoftencausedbyhypervirulent
strainsofM.tuberculosis.ThegenomeofH37Rvstrainwaspublishedin1948.The
sizeofitis4millionbasepairswith3959genes.Withinthegenometherearealso
6pseudogenesalongwith250genesinvolvedinfattyacidmetabolism.Usually,the
treatmentisgivenforsixtoninemonths,accordingtoatherapyregimenconsisting
oftwomonthstreatmentwithisoniazid, rifampin, pyrazinamide, ethanobutanolor
streptomycinuntilthedrugsensitivityisknown.
Fundamental investigations into the mechanisms of galarmin, Gx-NH , and
2
analogues antibacterial actions indicate that they are different from other known
antibacterialand/orproline-richpolypeptidessuchasRP-39,RP-26,etc.Galarmin
participatesindose-relatedmannerintheformationofHO• radicalsinfenton-like
reactionsandinhibitsCulldichloridecatalyzedH 0 decomposition,thusprevent-
2 2
ingformationofHO•andHOO•radicals(10).Thispeptidealsomanifestsantiradical
activitytowards2.2-diphenyl3.lpicrylhydrazylradicals,dependingontheexistence
ofphenolicOHgroupintyrosineresidueattheendofthemolecule(11).
It was established that galarmin and Gx-NH in low concentrations are scav-
2
engersofHO• radicals(10,11),whereashighconcentrationspromoteHO• radicals
formationinfenton-likereaction(10).Thedatawasobtainedwithgalarmin’spartic-
ipationinoxidativeburstsindose-dependentmannerinneutrophils,monocytes,and
macrophages in normal and inflammatory diseases, such as Bechet’s and Familial
MediterraneanFever(FMF)diseases(12,13).
Being a mediator between the brain neuroendocrine system and bone marrow,
thiscytokinestakepartingenesis,differentiation,andproliferationofthestemcells
inthebonemarrow. Experimentalresultsprovethediscoveryofthenovelclassof
powerfulcompoundsagainstbothaerobicandanaerobicinfectionsthatwillhaveits
impactinpreventingbiologicalterrorism.
Thus, the role of brain immunomodulators and cytokines in the complicated
metabolicandneuroendocrineprocessesshouldbediscussedintheneuroendocrine-
immune network context at health and disease statuses. The elucidation of the
x Preface
molecular mechanisms of PRP-1’s numerous effects on a number of aerobic or
anaerobicinfectionsrepresentsverybiginterest.
The present book contains description of all the main components of the im-
munesystem(cytokines,chemokines,newimmunomodulatorsandanewcytokine,
proline-rich polypeptides) indicating mainly the antibacterial properties of PRPs,
particularlyofgalamin.
Theimportanceofnewbrainimmunomodulatorsandcytokines(mostlyproduced
byneuroendocrinecellsofthehypothalamus)inavarietyofadaptivereactionsofthe
organism,infectiousdiseases,cancer,neurodegenerative,etc.shouldbeemphasized.
However, in this book I focus on the antibacterial properties, mainly proline-rich
polypeptides,thoroughlydiscussingthemostcommonbiochemical,neurohormonal,
andgeneticmechanismsoftheirinfluenceonthemostsevereaerobicandanaerobic
infections.
ProfessorArmenGaloyan,M.D.,Ph.D.