Greetings:

You may have seen this already, but these were new studies for me and
I thought I would pass them along as an FYIs.

Schafer et al. Inhibition of glycogen synthase kinase-3beta is
involved in the resistance to oxidative stress in neuronal HT22 cells.
Brain Res 1005:84-9 (2004). PMID: 15044068.

They found that pharmacological inhibition of GSK-3beta by lithium in
the parental neuronal cells (that are sensitive to oxidative stress)
resulted in an increased tolerance to glutamate and hydrogen peroxide,
"suggesting that GSK-3beta is involved in the control of oxidative
stress resistance in these cells."

I also found this study that is very recent:

Cytoprotection by lithium and valproate varies between cell types and
cellular stresses.
Eur J Pharmacol. 2006 Jun 6;539(1-2):18-26. Epub 2006 Apr 5.
PMID: 16678157

"Our results suggest that lithium and valproate may decrease
vulnerability of human neural, but not glial, cells to cellular injury
evoked by oxidative stress possibly arising from putative
mitochondrial disturbances implicated in bipolar disorder."

[Thanks for the info, Erich. I think that I already saw the first abstract above
and that it was one of those that helped me decide that taking lithium would be
beneficial for me. Although the second paper also suggests clear benefits from
taking lithium, the statement in the abstract: "Thus the cytoprotective effects
of lithium and valproate against H(2)O(2)-induced cell death is likely
independent of GSK-3 inhibition" appears to contradict the conclusion of the
first paper. Since I do not have direct access to the full papers (and do not
currently wish to have the full papers sent to me on a slow dialup), I have
asked Olafur to examine them and resolve this conflict if possible. One
difference may be that the concentration used in the first paper is far higher
than the therapeutically normal plasma concentration of 1 mM used in the second
paper. --Paul]

[Paul is correct, they used 10 times higher concentration of lithium chloride in
the first study than in the second study (10mM compared to 1mM). The high
concentration used in the first study is well over the accepted therapeutic
plasma range for lithium chloride, which is defined as 0,6-1,2mM in the second
study. However the conflict between the two studies does not seem to be
explained by the difference in concentration of lithium used. In the second
study lithium chloride protected SH-SY5Y cells against H2O2 induced cell death.
But as the quote below from the full text explains, two different GSK-3beta
inhibitors did not protect the cells against H2O2 induced cell death, indicating
that GSK-3beta inhibition was not the mechanism responsible for the protective
effect of lithium in this case.

"Inhibition of GSK-3[beta] activity has been implicated in the neuroprotective
actions of lithium and valproate (Li et al., 2002). To determine if the
neuroprotective action of lithium and valproate against cell death induced by
oxidative stress is due to GSK-3[beta] inactivation, we examined the effect of
two structurally dissimilar synthetic GSK-3[beta] inhibitors, kenpaullone and
SB216763 on rotenone- and H2O2-induced cell death. Similar to the effect of
lithium and valproate, kenpaullone (10 [micro]M) and SB 216763 (5 [micro]M)
significantly inhibited rotenone-induced cell death (P < 0.001). However,
neither kenpaullone nor SB216763 attenuated H2O2-evoked cell death."

Note: [beta] has been substituted above for the Greek letter beta which appears
in the paper quote but will not correctly show in the Yahoo message text. For
the same reason [micro] has been substituted above for the Greek letter Mu.

The GSK-3beta inhibitors were tested on the type of cells previously shown to be
protected against H2O2 induced death by lithium (the SH-SY5Y cells).

A possible explanation for the conflict between the two studies is that the
protective effects of lithium in the first study was not caused by GSK-3beta
inhibition. While the authors of the first study found increased tolerance to
H2O2 in cells treated with lithium, they did not test other GSK-3beta inhibitors
for comparison, or do any additional testing to determine whether the effect of
lithium was caused by GSK-3beta inhibition or some other mechanism. Lithium has
many more effects on cells than just inhibiting GSK-3beta some of which might
account for it's protective effect against H2O2 insult in cells. The authors of
the second study mentioned several mechanism that might explain the
cytoprotective effect of lithium. These include blockage of cytochrome c
release, activation of caspase-3 and upregulation of Bcl-2 levels. -°Olafur]