title: 17β-estradiol protects dopaminergic neurons in organotypic slice of mesencephalon by MAPK-mediated activation of anti-apoptosis gene BCL2.
abstract: Both clinical and experimental studies provide growing evidences that marked sex differences in certain neurological disorders or disease models are largely attributed to the neuroprotective effects of estrogen. The purposes of this study were to assess the neuroprotective effect of 17β-estradiol (E2) on dopaminergic neurons against 6-hydroxydopamine (6-OHDA) in organotypic mesencephalic slice culture and to elucidate the possible mechanism underlying neuroprotection. It was found that long-term exposure to E2 exerted marked effects on restoring the number of dopaminergic neurons, maintaining normal morphology of dopaminergic neurons, and preserving their ability to release dopamine at the presence of 6-OHDA. The neuroprotective effect of E2 could be dramatically blocked by an estrogen receptor antagonist ICI 182, 780 (ICI). The expression of GFAP, TLR4, and anti-apoptosis gene BCL2 were elevated at the presence of E2, whereas only BCL2 activation was blocked by ICI, dominantly responsible for E2-induced neuroprotection. Furthermore, activation of BCL2 was speculated to be mainly mediated through mitogen-activated protein kinase (MAPK) pathways, yet phosphatidylinositol-3-kinase signaling contributed largely to GFAP and TLR4 upregulation. Taken together, MAPK pathway-mediated BCL2 expression accounted for one of the key mechanisms involved in E2 neuroprotective effect on dopaminergic neurons against 6-OHDA insult. This finding provides new insight into controversial estrogen replacement therapy.
authors.affiliation: Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Ren
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Li
authors.forename: Yunqian
authors.initials: Y
authors.lastname: Guan
authors.forename: Yu Alex
authors.initials: YA
authors.lastname: Zhang
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D008636:Mesencephalon / Q000166:cytology* / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics
chemical_list: D018663:Adrenergic Agents; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D004958:Estradiol; D016627:Oxidopamine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases