619
266316470016778155
Nadia9736490234160293462514651
Hussain16836490234148298393489627679839
Department973863014981156232313348384495569643679
of1689863014975112
Physiology1837863014959129188233252327347422503563
College9731007014989164183203277358433
of14431007014975111
Medicine159110070149110184264284353373446521
and21481007014981155236
Health24201007014974148229248285354
Sciences28111007014954123142217290359433478
Dissertation9721358017098132193255344389431524566599689773
Title97215530122426696120184
The20081555012043104169
role2204155501203096116181
of2413155501206596
glutamate2537155501206787148182251344413446511
signaling3076155501203959126187256276296357424
pathway35281555012068136170231314382436
in3992155501202081
diabetic4100155501206989157225290324344409
neuropathy45371555012061126187217282350419453513567
Faculty9721708012248114178238262292350
Advisor13501708012274140196220264328360
Professor2008171001205989154186251290328394424
Thomas24601710012042103169263331370
E.2857171001205482
Adrian29661710012074143173193261322
Defense9721863012270134162226286330394
Date13941863012270136166230
3120081865012055111
May21471865012091160213
201523881865012055111166222
Abstract9722178012274140184214246312376406
The200821850963483135
majority2165218509691146162215239255282325
of251221850966994
diabetics262821850967187142196248275291343374
develop3024218509671123168220236288343
neuropathy,3389218509665117166190242296351378427470492
which3903218509683132148199248
can4173218509668123172
be4367218509671123
debilitating,4512218509671123178194210226253307334350399453475
but5009218509671120147
the517821850964492144
underlying5345218509665113168220244260303319368422
pathophysiological5789218509671125153201254308357400431447499515568622638689744760
mechanisms2008228109675127179228282331347378453484
are250622810965478130
poorly2649228109655107160184200243
understood.290522810964997152204228259286339391446468
Diabetic338622810966076131185237264280332
neuropathy3731228109649101150174226281335362411454
progresses419822810965579131185209261292323375406
in46262281096756
adistal4695228109655123139170197252268
toproximal497622810962880148172224262278353408424
manner.5413228109675130179228280304320
Previous574622810964872123168184236285316
studies607522810963158107162178230261
have6349228109649104148200
shown200823770963180132199248
that227823770962776131158
glutamate,245823770965470119146200275330357409431
the291123770962877129
most3062237709675128159186
common3270237709652104179254307356
excitatory364823770965290142158185240267320344386
neurotransmitter,4057237709649101149173225253277331380411486502529556608633646
plays472623770965470125168199
a4947237709655
role50242377096257793145
in519123770961665
the527823770962776128
pathogenesis5429237709654109136185237291343392444475491522
of597323770965378
neuropathy.6073237709649101150174226281335362411454476
The200824730963483135
reason216524730962880135166218267
why2458247309667115158
the263824730963280132
role27932473096288096148
of296324730965782
glutamate307124730965470118146200275330357409
in350224730962069
nociception3593247309653106157173225277332359375427476
becomes4095247309655107159211286338369
a4490247309655
problem457124730965579131186202254329
in492224730962069
diabetes501724730965571125180232259311342
and5385247309655104159
the556624730963180132
mechanisms5724247309675127179228282331347378453484
that623124730963180134161
are641924730965478130
involved200825690961665109162178222274329
are235925690966084136
unknown.2517256909654103143192244311359382
Based2921256909651106137189244
on3187256909658106
the331625690963281133
preliminary347125690966084136152168243259308362387429
data,3923256909660115142196218
the416425690963281133
hypothesis431925690965497152204231280332363379410
was4757256909666121152
that493125690963382136163
glutamate511725690965975124151205280335362414
pathways5553256909660115142191257312355386
are596125690966084136
likely61192569096223878130146189
to633025690963285
be6437256909660112
involved200826650961665109162178222274329
in235926650962169
diabetic245526650965571126180232259275327
neuropathy2804266509654106155179231285340367416459
particularly3290266509654109133160176228276292347371387430
neuropathic3742266509654106154178230285340367416432483
pain.4252266509655109125174196
Pathways4471266509652106133182249303346377
were4875266509667119143194
investigated509226650962069113165196224240293348375427482
to559626650963284
look570326650962073125165
for589026650963083107
changes6019266509656105160209262314345
that638726650963180135162
might200827610967591145194221
reflect22512761096287999118170222249
neuropathic2522276109653105153178230284339366415431482
pain3030276109655110126174
and3230276109655104158
fit34112761096234269
with350627610966783110159
previously369127610965478130174190243291322338381
established409827610965283110165220236252283331383438
pharmacological4562276109655104158182260314366418434487541557608663679
evidence.526727610965296112167219268320372394
The568327610963886138
aim584727610965571146
of601927610965277
this61192761096307995126
project627127610965579131147199251278
was2008285709666121152
to218228570963083
identify228728570961974126174201217243285
changes2597285709652101156204258310341
in296128570961867
expression305328570965291145169221252283299351400
of347828570965378
genes3581285709654106154206237
and3843285709655104159
their402428570963079131147171
protein422028570965478130158210226274
products451928570965579131186235286313344
that488628570963078133160
are507128570965579131
involved522428570961967112164180224276331
in557728570961968
glutamate567028570965470119146200275330357409
signalling610128570963450104153208224240256304358
in648128570961968
diabetes.200829530965571125180232259311342364
This239429530963786102133
will25512953096668298114
help2688295309651103119173
to288329530963082
further298729530962876100127176228252
the326229530962978130
understanding341429530965199154206230261288343392447463511565
of400429530965277
the410329530963078130
mechanisms4258295309675127179227282331347378453484
of476629530965378
diabetic486829530965571126180232259275327
neuropathy.5217295309651103152176228283337364413456478
In571729530962169
diabetic581129530965571125180232259275327
rats,616029530962681108139161
there634329530963078130154206
were2008304909666118143194
consistent2224304909652104153184200231258310359386
changes2632304909652100155204258310341
in299530490961664
expression,308130490965291145169221252283299351400422
particularly3525304909655109134161177228277293348372388431
in397830490961564
the406430490962776128
lumbar421430490961664139194249273
and4509304909654103158
sacral468930490963185137161216232
dorsal4943304909654107131162217233
root519830490962476128155
ganglia5375304909654108157211227243298
of569530490965277
the579430490962776128
spinal594430490963185101150205221
cord6186304909652105129183
and6391304909654103158
in200831450961665
the209531450962776128
sympathetic224531450963174149203258285334386413429481
ganglia.2748314509653108157211227243297319
The309031450963382134
changes3246314509652101155204258310341
were3609314509666118143194
consistent3825314509652104153184200231258310359386
between4233314509655107134200252304353
the460831450962776128
different47583145096557196121173197249298325
groups510531450965478130178233264
of539131450965277
animals5490314509655104120195249265296
as580831450965586
well5916314509667119135151
as608931450965485
between6196314509655107134200252304353
adjacent2008324109655109126180232284333360
groups239032410966286138187242273
of268532410966085
ganglia.2793324109662116165219235251306328
The314332410964291143
most3316324109675128159186
prominent352432410966387139214230279331379407
changes3953324109660108163212266318349
in432432410962473
both4419324109663115142191
the463232410963684136
GK4799324109669117
groups493832410966286138187241272
included523232410962573125141190245297351
marked5614324109675129154194246301
upregulation5937324109656111135187241289305360387403455504
of646332410966186
Gria4200833370967094110164209
(ionotropic223933370963652104153206233257309363379431
AMPA2699333709659133180233
receptor),295433370963182134186241268320344374396
downregulation3372333709661114180229253305359407423478505521574622
of401633370965984
Grik3412933370967094110150194
and4346333709661110164
Grik4453933370967094110150194
(both475533370963691143171219
ionotropic,499733370962274123176203227279333349401423
kainite5442333709647102118167183210262
receptors)572633370963082134186240268320344375405
and6153333709661110164
Grin1634633370967094110159203
and2008343309655103158
Grin2A219734330967094110158203262
(both248134330963893145172221
ionotropic,272434330962577126178205229281336352404426
NMDA3172343309668141201260
receptors),345434330963384136188243270322346377407429
activation3905343309663115142158202257284300352401
of432834330966186
all44363433096648096
of455434330966186
which4670343309667116132183232
has4924343309657112143
been5089343309663115167216
shown532734330964089141207256
to560534330963688
induce571534330962574128177229281
hyperalgesia;6018343309657100155207231285301355407438454509531
downregulation2008352909655107174222247298352401417471498514567616
of264635290966187
Slc1a6275535290964965117161216260
(excitatory303735290963991129181197224279306358382425
amino3484352909664139155204257
acid3763352909664115131186
transporter397135290963761116164195250302326354406430
4)442335290965383
and4528352909664113168
upregulation4718352909658112136188242290306361388404457505
of524635290966186
Slc1a1535535290964965116161215260
(excitatory563735290963991129181197224279306358382425
amino6084352909664139155204256
acid6363352909663115131186
transporter200836250962751106155186240293317344396420
3),24503625096447496
both2568362509654107134182
of277236250965378
which2872362509666115131183231
mediate3125362509675127182198253280332
neural3479362509649101149173228244
reuptake374536250962475124179206260301353
of411936250965378
glutamate421936250965470118145200275330357409
from465036250962549101176
the484836250962776128
synaptic499836250963173122177231259275326
cleft;534636250965268120145172194
and5562362509655104158
upregulation5742362509649103127179233282298352379395448497
of626036250965378
Gclc6360362509670121137189
(glutathione20083721096308399148175230257306322374423475
synthase),250537210963678127154203258289341370393
which2924372109667115131183232
reflects317837210962980100119171223250281
a3486372109654
response356337210962880111165218267298350
to393537210963184
protect404537210965579131158210262289
against4361372109654108163179228259286
oxidative466937210965795111166221248264308360
damage.5056372109655109184239293345367
Despite2008381709660112143197213240292
many2332381709675129178221
theories257538170963785137190214230282313
existing2910381709661100116147174190239292
about3225381709663118170219246
the349338170963785137
pathogenesis3653381709663118145194246300352401453484500531
of420638170966287
diabetic431538170966480135189241268284336
neuropathy,4673381709658110159183235290344371420463485
there518038170963786138162213
is541538170962657
no5494381709658110
unifying5627381709657106122147190206255309
hypothesis.5958381709658101155208235284336367383414436
It641638170962755
is649338170962556
possible2008391309655107138169185240256308
that233839130963988143170
changes2530391309664113168217271323354
in290639130962877
glutamate300539130966783131158213288343370422
signalling344939130964359113162217233249265314367
can3839391309664119167
contribute4028391309665117166193217233288336363415
to446639130963992
these458039130963988140171223
other482539130966592141193217
mechanisms5077391309675127179228282331347378453484
and5583391309667116171
possibly5776391309667120151182198252268311
unify6109391309662110126152194
these632639130963988140171223
different20084009096557196121173197249298325
theories.235540090962372124176201217269300322
A2695400909659
better2772400909655107134161213237
understanding302740090964998153205229260287341390445461510564
of360940090965277
the370940090962372124
role38554009096207288140
that401740090962372127154
glutamate418940090965470118146200275330357409
plays461640090965571125168199
in483840090961260
development4917400909654106151203219271326401453502529
of546440090965277
diabetic556040090965470125180232259275326
neuropathy5905400909649101149173225280334362410453
may6377400909675129172
pave2008410509655109154206
the223641050963382134
way2399410509667121164
for258541050963284108
future271641050963180107156180231
therapeutic297041050963382134158213267319368395411463
intervention.34554105096237299151175219271320347363415464486
Keywords:2008429509750101147211262288341376398
Diabetes,242942970966076130185237264316347369
Diabetic282042970966076130185237264280332
Neuropathy,3174429709659111160184236291345372421464486
Glutamate368242970967086135162216291346373425
Signalling,412942970964056110159214230246262310364386
Dorsal4537429709660112136168222238
Root4797429709649101154181
Ganglia,5000429709670124173227243259314336
Sympathetic535842970964083158212267294343395422438490
Ganglia.5870429709670124173227243259314336
Research9284447017081171232322414459549633
Relevance16004447017081171204294372465549638728
and23674447017093177269
Potential26754447017079168210300384426459552585
Impact33004447017039170263355445487
Neuropathy928464409659111160184236291345372421464
affects141646440965580105157209236267
more1707464409675128152203
than193346440962977132181
50%213646440964691153
of231346440965277
diabetics241446440965571126180232259275327358
but2796464409655104131
the294946440962978130
underlying310346440964897152204228244287303352406
pathophysiological3533464409654109136185237292341384415431483499551605621673728744
mechanism4301464409675127179227282331347378453
remains477646440962678153207223272303
poorly5103464409655107160184200243
understood.537046440964897152204228259286339391446468
The586046440963685137
symptoms601946440963376151206233285360391
and6434464409655104159
signs92847400963147101150181
can1125474009652106155
range130247400961873122176228
frommildly15524740096194395170261277293348364407
irritating1981474009610345874101156183199248302
to230547400962174
debilitating,2395474009654106161177193209236291318334383437459
depending2870474009655107161213262317333382436
on3322474009652101
the344547400962170122
system35894740096256899126178253
of385847400965378
the395847400962170122
body4096474009655107162205
affected.431747400965580105157209236288343365
Glutamate469847400967086134162216291346373425
is514547400961041
the520847400962270122
most5346474009676128159186
common5548474009652104179254307356
type592647400962164118170
of611347400965277
excitatory620647400965291142158185240267320344387
neurotransmitter928483609649101149174226253277331380411486502529557609633
in15834836096957
themammalian166348360962068120210265340415470486502556605
nervous2283483609649101125170222271302
system.260048360963174105132184259281
Its29034836096113869
receptors299448360961769121173227254307331362
are337148360965579130
broadly351648360965579131186241257300
classified383148360965167122153184200220239291346
as419248360965586
slowactingmetabotropic42934836096314799166235287314330379433523575602657711764791815867921937989
and5297483609655104159
fast547848360961872103130
acting5624483609654106133149198252
ionotropic.58984836096961110162189214266320336388410
Studies632348360964067116171187239270
show92849320963180132199
that114949320963584139166
disturbance133749320966379111138186210265320368420472
in183149320962574
neural1927493209657109158182236252
glutamate220249320966278126154208283338365417
signalling264149320964056110158213229245261310364
plays302749320966379133176207
a3257493209663
role334249320963285101153
in351749320962473
the361249320963685137
pathogenesis3771493209663117144193246300352400452483499530
of432449320966086
several443249320963991136188212266282
neurodegenerative4736493209658110158182234289341395447496548572627654670714766
and5524493209663112167
neuropathic5713493209657109158182234289343370419435487
disorders.622249320966379110163187241293317348371
Several92850280964092136188212267283
glutamate123350280966177125153207282337364416
receptor167150280963183135187241268321345
subtypes203850280963887141168211266318349
are240950280966185137
known256850280964796149215264
to285450280963486
mediate2970502809675127181197252279331
peripheral3323502809662114138154208257309333388404
nociceptive3749502809656108160176228280334361377422474
transmission424550280963458113162193268284315346362414463
while4737502809666115131147199
their495850280963583135151175
respective515650280963182113168220272299315359411
receptor558950280963183135187241268321345
antagonists5956502809661110137192246298347363394421452
can6430502809659114163
alleviate9285124096557187139183199254281333
neuropathic1280512409649101150174226281335362411427479
pain.1779512409654109125174196
Reduction1994512409649101156204256283299352400
in241751240961362
the250151240962573125
local264951240961365117172188
production285751240965478130185234285313329381430
and3306512409655104159
release34875124096217389141196227279
of378551240965378
glutamate388351240965369118145200275330357409
from43145124096224699174
nerve4507512409649101125169221
terminals475151240962476100177193242297313344
also511551240965470101154
alleviates52885124096557187139183199254281333364
allodynia,56725124096557187139194237285301356378
hyperalgesia,607051240964992146198222277293347399430446500523
and928522009655103158
thermal110852200962675127151228283299
sensitivity142952200963082131162178205221265281309351
in180352200961563
diabetic188752200965571126180232260276327
animals2235522009655104120195249265296
and2553522009654103158
shows273352200963079131198229
therapeutic298452200962675127151205260312360388404455
promise.346052200965579131206222253305327
While3808522009677126142158210
glutamate403952200965470118146200275330357409
signalling447052200963046100149203219235251300354
appears4845522009655109164216270294326
to519352200962678
contribute5292522009652104153180204220275323351403
to571752200962678
the581752200962675127
development5965522009655107151203219271326401453502529
of651552200965278
diabetic92853160965571125180232259275327
neuropathy,1279531609649101149174226280335362411454476
the177753160962978130
reason192953160962678132163216264
why2218531609666115158
its23985316096184576
role24965316096267894146
in266453160961867
nociception2755531609649101153169221273328355371423472
becomes3251531609654106158211286338369
a3644531609654
problem372353160965478130185201253328
in407353160961867
diabetes416453160965571125180232259311342
and4530531609655104158
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intervention.9285508096166592144168212264312340355408456478
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