Author/Editor     Glavan, Gordana; Živin, Marko
Title     The influence of intermittent l-DOPA treatment on striatal molecular markers in hemiparkinsonian rats
Translated title     Vpliv intermitentnega dajanja l-DOPA na striatne molekulske označevalce pri hemiparkinsonskih podganah
Type     članek
Source     Zdrav Vestn
Vol. and No.     Letnik 77, št. Suppl 2
Publication year     2008
Volume     str. II-27-33
Language     eng
Abstract     Motor complications after chronic l-DOPA treatment in patients with Parkinson’s disease may be caused by the fluctuations of l-DOPA availability in the brain that provokes the sensitization of striatal output neurons of dopamine-depleted striatum. The aim of this study was to analyze the effects of intermittent l-DOPA/carbidopa treatment schedule (injection of l-DOPA/carbidopa every fourth day, 6-treatments) on the development of locomotor sensitization of hemiparkinsonian rats to l-DOPA, and on the development of dopaminergic sensitization of striatal output neurons of the indirect and direct pathways. The development of locomotor sensitization was verified by the increased intensity of contralateral turning behavior after the last l-DOPA injection. It is well known that PPT mRNA is expressed predominantly by the neurons of the direct pathway, PENK mRNA by the neurons of the indirect pathway, while GAD67 mRNA is expressed in the neurons of both pathways. Dopaminergic sensitization of striatal output neurons of dopaminedepleted striatum was thus assessed by the analysis of changes of striatal preprotachykinin (PPT), proenkephalin (PENK) and GAD 67 mRNA levels 4 and 12 hours after the last l-DOPA injection. We found, that chronic dopamine depletion by itself down-regulates the expression of striatal PPT mRNA and up-regulates GAD67 and PENK mRNAs. These changes of basal expression were not reversed by the intermittent l-DOPA/carbidopa treatment. However, in dopamine-depleted striatum, the intermittent treatment with l-DOPA induced increased responsiveness of striatal PPT and GAD67, but not PENK mRNA expression, to l-DOPA. Our results are in agreement with the hypothesis, that intermittent l-DOPA treatment induces locomotor sensitization that may be linked to the increased dopaminergic responsiveness of striatonigral neurons of the direct pathway, within dopamine-depleted striatum.
Summary     Zapleti kroničnega zdravljenja Parkinsonove bolezni z l-DOPA v obliki motenj gibanja (diskinezij) so morda povezani s posledicami nihanja koncentracije tega zdravila v možganih, ki ob pomanjkanju dopamina v striatumu, povzroči dopaminergično senzitizacijo projekcijskih striatalnih nevronov. Namen raziskave je bil preučiti učinek protokola intermitentnega dajanja l-DOPA/karbidopa hemiparkinsonskim podganam (injekcija l-DOPA/karbidopa vsak četrti dan, 6-krat), na razvoj lokomotorne senzitizacije na l-DOPA ter na razvoj dopaminergične senzitizacije projekcijskih nevronov posredne in neposredne poti. Lokomotorno senzitizacijo poskusnih podgan, ki smo jim dajali l-DOPA po intermitentnem protokolu, smo dokazali s povečanjem intenzitete kontralateralnega kroženja po zadnji injekciji l-DOPA glede na intenziteto kroženja kontrolnih podgan. Znano je, da se PPT mRNK v striatumu izraža predvsem v nevronih neposredne poti, GAD67 mRNK pa v nevronih neposredne in posredne poti. Zato smo dopaminergično senzitizacijo striatalnih nevronov ugotavljali z analizo sprememb ravni izražanja mRNK preprotahikinina (PPT), glutamat-dekarboksilaze z molekulsko težo 67 kDa (GAD67) in proenkefalina (PENK) v denerviranem striatumu 4 in 12 ur po zadnji injekciji l-DOPA. Ugotovili smo, da kronično pomanjkanje dopamina v striatumu povzroči zmanjšanje bazalnega izražanja PPT mRNK ter povečanje bazalnega izražanja GAD67 in PENK mRNK v striatumu. Intermitentno dajanje l-DOPA/karbidopa ni zmanjšalo odklonov bazalnega izražanja omenjenih mRNK v primerjavi z intaktnim striatumom, temveč je povzročilo povečano odzivnost izražanja PPT in GAD67 mRNK na l-DOPA. Rezultati naše raziskave so skladni s hipotezo, da lahko z intermitentnim dajanjem l-DOPA hemiparkinsonskim podganam povzročimo lokomotorno senzitizacijo na l-DOPA, ki bi lahko bila povezana s povečano dopaminergično odzivnostjo striatonigralnih nevronov neposredne poti v striatumu, ki mu primanjkuje dopamin.
Descriptors     PARKINSON DISEASE
LEVODOPA
DYSKINESIA, DRUG-INDUCED
TACHYKININS
ENKEPHALINS
GLUTAMATE DECARBOXYLASE
RNA, MESSENGER
IN SITU HYBRIDIZATION
OLIGONUCLEOTIDE PROBES
RATS, WISTAR