Lithium inhibits aluminum-induced apoptosis in rabbit hippocampus, by preventing cytochrome c translocation, Bcl-2 decrease, Bax elevation and caspase-3 activation.
A variety of studies on neuronal death models suggest that lithium has neuroprotective properties. In the present investigation, we have examined the effect of chronic lithium treatment on hippocampus, as monitored by changes at the subcellular level of apoptosis-regulatory proteins which have been induced by the neurotoxin, aluminum maltolate. Intracisternal administration of aluminum into rabbit brain induces cytochrome c release, decreases levels of the anti-apoptotic proteins Bcl-2 and Bcl-X(L), increases levels of the pro-apoptotic Bax, activates caspase-3, and causes DNA fragmentation as measured by the TUNEL assay. Pretreatment for 14 days with 7 mm of lithium carbonate in drinking water prevents aluminum-induced translocation of cytochrome c, and up-regulates Bcl-2 and Bcl-X(L,) down-regulates Bax, abolishes caspase-3 activity and reduces DNA damage. The regulatory effect of lithium on the apoptosis-controlling proteins occurs in both the mitochondria and endoplasmic reticulum. We propose that the neuroprotective effect of lithium involves the modulation of apoptosis-regulatory proteins present in the subcellular organelles of rabbit brain.
Ghribi
Othman
O
Department of Pathology, Health Sciences Center, University of Virginia, Charlottesville, VA 22908-0214, USA.
Herman
Mary M
MM
Spaulding
Natalie K
NK
Savory
John
J
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D003720:Densitometry; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D008094:Lithium / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism; D011753:Pyrones / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011817:Rabbits; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D003574:Cytochrome c Group; D009942:Organometallic Compounds; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011753:Pyrones; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C067527:aluminum maltolate; D008094:Lithium; D053148:Caspase 3; D020169:Caspases