Support of retinal ganglion cell survival and axon regeneration by lithium through a Bcl-2-dependent mechanism.
OBJECTIVE
To explore whether lithium, a long-standing mood-stabilizing drug, can be used to induce expression of Bcl-2 and support the survival and regeneration of axons of retinal ganglion cells (RGCs).


METHODS
Levels of expression of Bcl-2 in the retina were assessed with quantitative reverse transcription-polymerase chain reaction. To determine whether lithium directly supports the survival of and axon-regenerative functions of RGCs, various amounts of lithium were added to cultures of isolated RGCs. Anti-Thy1.2 antibodies-conjugated to magnetic beads were used to isolate the RGCs. In addition, retina-brain slice cocultures were prepared from tissues of Bcl-2-deficient or Bcl-2-transgenic mice and treated with various amounts of lithium. The effects of the expression of Bcl-2 on lithium-mediated functions were then analyzed.


RESULTS
Normal mouse retina expressed very low levels of Bcl-2 after birth. Addition of lithium in the culture increased mRNA levels of Bcl-2 in retinas of postnatal mice in a dose-dependent manner. Moreover, lithium promoted not only the survival of RGCs but also the regeneration of their axons. Depleting or forcing the expression of Bcl-2 in RGCs eliminated the effects of lithium.


CONCLUSIONS
Lithium supports both the survival and regeneration of RGC axons through a Bcl-2-dependent mechanism. This suggests that lithium may be used to treat glaucoma, optic nerve neuritis, the degeneration of RGCs and their nerve fibers, and other brain and spinal cord disorders involving nerve damage and neuronal cell loss. To achieve full regeneration of the severed optic nerve, it may be essential to combine lithium therapy with other drugs that mediate induction of a permissive environment in the mature central nervous system.
Huang
Xizhong
X
Schepens Eye Research Institute and Program in Neuroscience, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA.
Wu
Da-Yu
DY
Chen
Guang
G
Manji
Husseini
H
Chen
Dong Feng
DF
D000818:Animals; D001369:Axons / Q000502:physiology*; D001921:Brain / Q000166:cytology; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D018021:Lithium Chloride / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018021:Lithium Chloride