X-Message-Number: 27429
Date: Wed, 14 Dec 2005 21:33:08 -0800 (PST)
From: Doug Skrecky <>
Subject: GSK-3 inhibitors offer a variety of benefits

[An argument could be made in favor of taking lithium, as a GSK-3
inhibitor for life-extension purposes.]

Nat Med 2005 Dec 11; [Epub ahead of print
Glycogen synthase kinase-3 is an in vivo regulator of h
ematopoietic stem cell repopulation.
  The in vivo regulation of hematopoietic stem cell (HSC)
function is poorly understood. Here, we show that hematopoietic
repopulation can be augmented by administration of a glycogen
synthase kinase-3 (GSK-3) inhibitor to recipient mice transplanted
with mouse or human HSCs. GSK-3 inhibitor treatment improved
neutrophil and megakaryocyte recovery, recipient survival and
resulted in enhanced sustained long-term repopulation. The output
of primitive Lin(-)c-Kit(+)Sca-1(+) cells and progenitors from
HSCs increased upon GSK-3 inhibitor treatment without altering
secondary repopulating ability, suggesting that the HSC pool is
maintained while overall hematopoietic reconstitution is increased.
GSK-3 inhibitors were found to modulate gene targets of Wnt,
Hedgehog and Notch pathways in cells comprising the primitive
hematopoietic compartment without affecting mature cells. Our
study establishes GSK-3 as a specific in vivo modulator of HSC
activity, and suggests that administration of GSK-3 inhibitors may
provide a clinical means to directly enhance the repopulating
capacity of transplanted HSCs.

Circulation. 2005 Aug 30;112(9):1316-22.
Glycogen synthase kinase-3 mediates endothelial cell activation by
tumor necrosis factor-alpha.
  BACKGROUND: Endothelial cell transformation to a thrombogenic
and inflammatory phenotype plays an important role in the
pathogenesis of atherothrombosis, but the responsible signaling
pathways remain to be elucidated. This study was designed to
investigate the regulatory role of glycogen synthase kinase-3
(GSK-3) in tissue factor (TF) and vascular cell adhesion molecule
(VCAM)-1 expression in tumor necrosis factor (TNF)-alpha-stimulated
endothelial cells. METHODS AND RESULTS: In human endothelial cells,
TNF-alpha as well as thrombin induced rapid and transient
dephosphorylation and hence, activation of GSK-3. A GSK-3 inhibitor,
LiCl, suppressed TNF-alpha- and thrombin-induced TF and VCAM-1
expression, whereas NaCl had no effect. A specific GSK-3 inhibitor,
TDZD-8, mimicked the inhibitory effects of lithium. GSK-3
inhibition also significantly suppressed the TNF-alpha-induced
increase in TF activity and VCAM-1 cell-surface expression. The
luciferase reporter system demonstrated that regulation of TF and
VCAM-1 expression by GSK-3 was mediated at the transcriptional
level. The TNF-alpha-induced increase in nuclear factor (NF)-kappaB
DNA-binding activity was significantly suppressed by TDZD-8. TDZD-8
completely prevented the TNF-alpha-induced inhibitor of NF-kappaB
(IkappaB)-alpha degradation but had no effect on IkappaB-kinase-beta
phosphorylation. CONCLUSIONS: GSK-3 regulates TNF-alpha-induced
IkappaB-alpha degradation and NF-kappaB activation independent of
IkappaB-kinase-beta and subsequent induction of TF and VCAM-1
expression in human endothelial cells. This study provides the
experimental basis for a novel strategy of using GSK-3 inhibition
to treat atherothrombotic vascular disease.

Cancer Res. 2005 Apr 1;65(7):2537-41.
Valproic acid stimulates proliferation and self-renewal of
hematopoietic stem cells.
  Histone deacetylase inhibitors have attracted considerable
attention because of their ability to overcome the differentiation
block in leukemic blasts, an effect achieved either alone or in
combination with differentiating agents, such as all-trans
retinoic acid. We have previously reported favorable effects of
the potent histone deacetylase inhibitor valproic acid in
combination with all-trans retinoic acid in patients with
advanced acute myeloid leukemia leading to blast cell reduction
and improvement of hemoglobin. These effects were accompanied by
hypergranulocytosis most likely due to an enhancement of
nonleukemic myelopoiesis and the suppression of malignant
hematopoiesis rather than enforced differentiation of the leukemic
cells. These data prompted us to investigate the effect of
valproic acid on normal hematopoietic stem cells (HSC). Here we
show that valproic acid increases both proliferation and
self-renewal of HSC. It accelerates cell cycle progression of HSC
accompanied by a down-regulation of p21(cip-1/waf-1). Furthermore,
valproic acid inhibits GSK3beta by phosphorylation on Ser9
accompanied by an activation of the Wnt signaling pathway as well
as by an up-regulation of HoxB4, a target gene of Wnt signaling.
Both are known to directly stimulate the proliferation of HSC and
to expand the HSC pool. In summary, we here show that valproic
acid, known to induce differentiation or apoptosis in leukemic
 blasts, stimulates the proliferation of normal HSC, an effect
with a potential effect on its future role in the treatment of
acute myeloid leukemia.

Neuropharmacology. 2005 Mar;48(4):576-83. Epub 2005 Jan 25.
Opposite effects of lithium and valproic acid on trophic factor
deprivation-induced glycogen synthase kinase-3 activation, c-Jun
expression and neuronal cell death.
  Recent studies demonstrate that lithium and valproic acid (VPA),
two commonly used mood-stabilizing drugs, have neuroprotective
effects against a variety of insults. Inhibition of the
proapoptotic enzyme, glycogen synthase kinase-3 (GSK-3), has been
suggested to be the mechanism of action of neuroprotection for
both drugs. In this study, we tested if lithium and VPA could
protect cultured cerebellar granule neurons (CGNs) from
GSK-3-mediated apoptosis induced by trophic factor withdrawal
(serum/potassium deprivation). Both lithium and indirubin, a
specific GSK-3 inhibitor, protected CGNs in a dose-dependent
manner. In contrast, VPA did not provide any neuroprotection and
even potentiated cell death. Immunoblot analysis revealed that
lithium inhibited the trophic factor deprivation-induced
activation of GSK-3 as well as the in vivo phosphorylation of the
microtubule-associated protein Tau on Ser199, a specific target
site for GSK-3. Under these same experimental conditions, however,
VPA neither inhibited GSK-3 activation nor hindered GSK-3 mediated
Tau phosphorylation. Furthermore, in accordance with their effects
on neuronal survival, lithium prevented the induction of c-Jun
expression in trophic factor-deprived CGNs, whereas VPA potentiated
it. Collectively, these results show that VPA is not a universal
inhibitor of neuronal GSK-3, and that instead of being
neuroprotective, VPA can even exacerbate neuronal death under some
conditions.

Farmakol Toksikol. 1986 May-Jun;49(3):69-70.
[Effect of lithium oxybutyrate on the viability of preserved donor
kidney]
  The experiments on 10 dogs showed that replacement of sodium
oxybutyrate for lithium oxybutyrate in the solution for preservation
increases the period of preserving the structural and functional
integrity of the donor kidney, contributes to its survival and
delays the development of the transplant rejection.

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