Abstract
In previous studies, we found regional differences in the induction of antioxidative molecules in astrocytes against oxidative stress, postulating that region-specific features of astrocytes lead region-specific vulnerability of neurons. We examined region-specific astrocytic features against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) as an oxidative stress using co-culture of mesencephalic neurons and mesencephalic or striatal astrocytes in the present study. The 6-OHDA-induced reduction of mesencephalic dopamine neurons was inhibited by co-culturing with astrocytes. The co-culture of midbrain neurons with striatal astrocytes was more resistant to 6-OHDA than that with mesencephalic astrocytes. Furthermore, glia conditioned medium from 6-OHDA-treated striatal astrocytes showed a greater protective effect on the 6-OHDA-induced neurotoxicity and oxidative stress than that from mesencephalic astrocytes. The cDNA microarray analysis showed that the number of altered genes in both mesencephalic and striatal astrocytes was fewer than that changed in either astrocyte. The 6-OHDA treatment, apparently up-regulated expressions of Nrf2 and some anti-oxidative or Nrf2-regulating phase II, III detoxifying molecules related to glutathione synthesis and export in the striatal astrocytes but not mesencephalic astrocytes. There is a profound regional difference of gene expression in astrocytes induced by 6-OHDA. These results suggest that protective features of astrocytes against oxidative stress are more prominent in striatal astrocytes, possibly by secreting humoral factors in striatal astrocytes.
Highlights
It is well known that astrocytes are abundant glial cells and play an important role in the maintenance of the neuronal homeostasis, such as regulating cerebral blood flow and maintaining synaptic function
We previously found regional differences in the induction of antioxidative molecules in astrocytes against oxidative stress in dopaminergic neurodegeneration in the model of Parkinson s disease, and suggested a possibility that region-specific features of astrocytes lead region-specific vulnerability of neurons
We examined region-specific astrocytic features against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) as dopaminergic oxidative stress using co-cultures of mesencephalic neurons and mesencephalic or striatal astrocytes
Summary
It is well known that astrocytes are abundant glial cells and play an important role in the maintenance of the neuronal homeostasis, such as regulating cerebral blood flow and maintaining synaptic function. Nrf, inactivated by its suppressor protein ubiquitin ligase Keap in the normal condition, is activated by conformational change and detachment of Keap in response to ROS or electrophiles, and translocated into the nucleus binding to antioxidant responsive element (ARE) to promote gene expression of various phase II detoxifying and antioxidative molecules, such as GSH-related enzymes (GCL, GSH S-transferase (GST), GSH peroxidase (Gpx)), quinone oxidoreductase (NQO-1), superoxide dismutase (SOD), catalase, hemeoxigenase-1 (HO-1), xCT, and MT [3,9,10,11] Both GSH and MT can prevent dopamine (DA) quinone-induced neurotoxicity as a dopaminergic neuron-specific oxidative stress by competitively binding to DA quinones [12,13,14]. Tehneunmubmerbeorfomf emseesnecnecpehpahliacliTc HTH-p-opsoitsiivtieveddopopamaminineregrgicicnneeuuroronnsswwaassddeeccrreeaasseedd ttoo aapppprrooxxiimmaattee 7700%% ooffcocnotnrtorloal ftaefrtetrreatrtemaetmntewntithw6it-hOH6-DOAH(D1A2.5(μ12M.5) aμloMn)e.aTlohneed. eTcrheeasdeeicnredaospeaminindeorgpiacmnienuerrognisc inneduurocends biynd6-uOceHdDAbywa6s-OinHhDibAitedwbays thinehpibreit-etrdeatbmyenttheof cporne-ttrroelaGtmCeMntanodf 6-cOonHtrDoAl -GGCCMM fraonmd s6t-rOiaHtaDl Aas-GtroCcMytefsr,obmutsntroiat tbayl tahsetropcryet-einsc, ubbuattionnotwbiyth tehietheprreG-iCnMcubfraotimonmwesitehnceeipthhearlicGaCsMtrocfyrotems (mFiegsuenrece2pBh)a.liFcurathsterromcyotrees, o(nFliyguprere-t2rBe)a.tmFeunrtthweritmhoGreC, Monflryompr6e--OtrHeaDtmAe-tnrteatwedithmeGseCnMcephfraolmic a6s-OtroHcDytAes-t(rMeaitde-d6-mOHesDenAc-eGpChaMli)csahsotwroecdytaesdr(aMmida-t6ic-OreHdDucAti-oGnCoMf T) Hsh-poowseitdivae ddorapmamatiincerregdicuncetiuornonosf wTHith-pooustiatinvye addodpitaimonianle6r-gOicHnDeAurtorneastmweitnhto, ubut tapnrye-atrdedaittmioennatlw6i-tOhHGDCAM tfrreoamtm6-eOntH, DbuAt-tprerea-tterdeasttrmiaetnatl awsittrhocGyCteMs (Sfrtor-m6-O6-HODHAD-AG-CtrMea)teddidstnroiatt.al astrocytes (Str-6-OHDA-GCM) did not
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