| Parkinson’s disease (PD) is one of the most common progressiveneurodegenerative movement disorders associated with the loss of dopamine (DA)neurons in the substantia nigra (SN), affecting approximately2%of the populationover the age of65years. PD is characterized by motor symptomatology that is statictremor, rigidity, slowness of movement (bradykinesia), the inability to move(akinesia) and postural instability, The clinical spectrum of the disorder is moreextensive covering a wide range of non-motor symptoms including cognitive andbehavioural symptoms, autonomic dysfunction, sensory symptoms and fatigue. Thedisorder affects several regions of the brain, including the SN that controls balanceand movement. PD may also affect regions of the brain that regulate involuntaryfunctions such as blood pressure and heart activity. The pathological hallmarks andbiochemical changes of PD are the loss of nigrostriatal dopaminergic neurons, thereduction of DA content in the striatum, accumulation of brain iron and the proteindeposits called Lewy bodies appear in dead or dying dopamine-producing neurons.Until now, the aetiology of the degeneration of the SN remains unclear. Lines ofevidence have revealed that the pathogenesis of degeneration in PD is associatedwith multiple genetic susceptibilities, environmental factors, oxidative damage processes, excitotoxicity and energy defects. L-dopamine (L-DOPA), a precursor ofDA, is considered to be the ‘gold standard’ treatment for PD. However, there aresymptoms of the disease that are not satisfactorily controlled or do not respond toL-DOPA, Chronic L-DOPA treatment is frequently associated with the developmentof motor complications. However, cuurent therapy for PD is limited to thesymptomatic relief of patients, having failed to prevent or inhibit the process ofneurodegeneration so far. Hence, many studies are focused on searching for newpotential therapeutic targets and agents for PD such as iron chelators, however, someof these drugs can not cross the blood-brain barrier, which limited the clinical uses.A selective significant increase in iron occurs in the substantia nigra parscompacta of Parkinsonian subjects, and in6-OHDA treated rats and monkeys, whichhas been implicated in the biochemical pathology of PD. Chelation of the overloadiron may prevent formation of cytotoxic oxygen free radicals in the SN and reducedopaminegic neurodegeneration. Iron chelators, such as dexrazoxane, have beenshown to reduce iron overload-induced brain damage in the cardiovascular system.In Some studies have focused on the neuroprotective effects of iron chelators whichindicate a new therapeutic strategy in the treatment of PD. Our study investigated theneuroprotective pontential of the Food and Drug Administration (FDA) permittedcadioprotective iron chelator, dexrazoxane, injected intraperitoneally in peripheraladministration to6-OHDA lesioned rats. In physiological conditions, dex can notcross BBB, but it has not been reported in any paper whether dex could enter thebrain when BBB was broken down in PD.Dex, belonging to a class of bis (2,6-dioxopiperazines), has been proven effectiveboth in patients and animal models for reduction of doxorubicin (DOX)-inducedcardiotoxicity without affecting the antitumor activity. Dex was also used clinicallyas an antidote for alleviating tissue damage due to accidental anthracycline extravasation. Dex could permeate the cell membrane and hydrolyze to itsrings-opened metal-ion-binding metabolite (ADR-925) with a structure similar toEDTA. ADR-925could remove iron or bind free iron to decrease ROS formation.The present study is the first to show neuroprotection with a FDA permittedcadioprotective iron chelator, The latter can have implications for the treatment ofPD where abnormal iron accumulation in the brain is thought to be associated withthe degenerative processes Our study have expanded the range of clinical use of Dex,suggest that Dex would cross the BBB to permeate into brain and become the newpotential therapeutic targets for PD.AIM: In this study, we will investigate whether Dexrazoxane could cross the BBBin PD, further study to investigate the effects of iron chelator on motor,neuropathological and neurochemical alterations in unilateral6-OHDA lesioned PDmodel rats after peripheral administration and the underlying mechanisms.METHODS:(1) Establishing unilateral6-OHDA lesioned of striatum PD modelrats: Injection of6-OHDA into left striatum of rats employing stereotaxic apparatus.Four weeks later, APOmorphine-induced rotation behaviour and catalepsy test wastested to select successful PD model rats.(2) Successful model rats were divided intofive groups: model group, L-DOPA group, Dex1.5mg/kg/day group, Dex5mg/kg/day group, Dex15mg/kg/day group. The drugs were administered to rats for21days, the rats in sham-operraterd and model groups were injected with the samevolume of saline. At the end of each week, APOmorphine (0.06mg/kg,s.c) wasadministrated to observed changes in the rotation behavioral of6-OHDA rats.(3)blood brain barrier(BBB) integrity was assessed with a one-step immunoblot assayfor HRP IgG in rats.(4)HPLC was used to observe the level of Dex in plasma and brain in6-OHDA lesioned rats.(5) Immunohistochemistry was carried out todetermine the number of TH positive, GFAP positive and OX-42positive cells inSN prepared from the above mentioned rats that treated with drugs for three weeks.(6) Neurotransmitter levels in striatum and midbrain of the above mentioned ratswere measured by high-performance liquid chromatography(HPLC).(7) Perls’ ironstaining was carried out to observe the iron accumulation in SN.(8) The activities ofSOD and GSH-PX in serum and midbrain were evaluated by xanthine oxidase anddithiobis nitrobenzoic acid enzyme enzymatic reaction, respectively. MDA content inserum and midbrain was detected by thiobarbituric acid conversion method.(9)Western blotting was used to investigate the levels of Nuclear factor-κB (NF-κB),Interleukin-1β(IL-1β), Inflammasomes in SN.(10) The leves of IL-1β and TNF-α inplasma were analyzed by ELISA kit, The leves of TNF-α in SN were analyzed bysemi-quantitive reverse transcriptase-polymerase chain reaction (RT-PCR).RESULTS:(1) The IgG accumulation increased significantly in model and Dex rats.(2) After Dex15mg/kg intraperitoneal administration, the plasma concentration reachthe peak at10minutes after injection, meanwhile, the highest Dex concentration inbrain of the model group (Striatum>Midbrain>Cortex) appeared at60min afterinjection.(3) Dex treated rats exhibited significant alleviation of rotation behaviorinduced by Apomorphine.(4) Dex had no influence on extracellular dopamine levelsin the lesioned side of the striatum, meanwhile, Dex decreased glutamate levels inSN of model rats.(5) The number of TH positive cells in lesioned side in SN in Dextreated rats increased significantly compared to model rats and the intact side.(6)The number of GFAP and OX-42positive cells in lesioned side in SN in Dex treatedrats decreased significantly compared to model rats.(7) The number of iron positivecells in lesioned side in SN in Dex treated rats decreased significantly compared to model rats.(8) Dex treated rats exhibited significant alleviation in MDA levels inplasma and SN of model rats, meanwhile, Dex increased the ability of SOD andGSH-Px both in plasma and SN of model rats.(9) Nuclear factor-κB, Interleukin-1βand Inflammasomes express in SN of lesioned side decreased significantly in Dextreated rats.(10) The levels of IL-1β and TNF-α in plasma in SN showed asignificant decrease in Dex treated rats.CONCLUSION: The results suggested that Dex can cross the BBB in6-OHDAlesioned model rats and leak into brain. Dex increase rotation behavior induced byApomorphine and the loss of TH positive cells in SN, indicating the neuroprotectiveeffects of Dex, verifying the mechanism in neuroprotective effects of Dex, whichconceptually support the idea that iron chelator Dex may be a new therapeutic targetfor PD. |
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