Long-term administration of estrogen or tamoxifen to ovariectomized rats affords neuroprotection to hippocampal neurons by modulating the expression of Bcl-2 and Bax.
Recently we reported that chronic treatment with 17beta-estradiol (E2) or tamoxifen (TAM) regulates the ovariectomy-induced downregulation of the key molecules linked to hippocampal synaptic plasticity and signal transduction pathway. We now report modulation of the antiapoptotic (Bcl-2) and proapoptotic (Bax) proteins in the hippocampus of both the ovariectomized (OVX) rats as well as those given E2 or TAM subcutaneously as a daily dose for four weeks post-ovariectomy. Forty bilaterally OVX animals were divided into four groups of 10 each, namely i) OVX+E2 (0.1 mg/kg body weight), ii) OVX+TAM (0.05 mg/kg body weight), iii) OVX+vehicle (0.1 ml of sesame oil) and iv) OVX controls. An additional group of 10 animals constituted the ovary intact controls. Following culmination of treatment regimen, brain tissues of five animals from each group were processed for immunohistochemical staining of Bcl-2 and Bax on perfusion fixed cryo-sections. The remaining animals in each group were utilized for protein and Western blot analyses using unfixed hippocampal tissue. The results revealed that chronic administration of both E2 and TAM prevented the ovariectomy-induced downregulation of Bcl-2 and upregulation of Bax expression while restoring the Bcl-2/Bax ratio as observed in the ovary intact rats. Furthermore, TUNEL assay demonstrated a decline in the percentage of TUNEL positive cells in E2 or TAM treated groups. Confocal microscope studies of ERalpha and the apoptotic markers revealed that these two proteins co-reside in the same ERalpha positive hippocampal neurons. Thus, long-term E2 or TAM therapy modulates the apoptotic proteins and affords neuroprotection to the hippocampal neurons. Furthermore the estrogen-like effects of TAM point towards its potential as a beneficial therapeutic agent for neurodegenerative disorders, particularly in the postmenopausal women.
Sharma
K
K
Department of Anatomy, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029, India.
Mehra
Raj D
RD
D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018696:Neuroprotective Agents; D010052:Ovariectomy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D013629:Tamoxifen / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis*
D004965:Estrogen Antagonists; D004967:Estrogens; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D013629:Tamoxifen