THE ANTI-APOPTOTIC
EFFECT AND THERAPEUTIC POTENTIAL OF MOOD STABILIZERS FOR GLUTAMATE-RELATED
NEURODEGENERATIVE DISEASES
Chuang
D-M, Ren M, Senatorov VV, Leng Y Yasuda S
Molecular
Neurobiology Section, Mood and Anxiety Disorders Program, National Institute of
Mental Health, NIH, Bethesda, MD 20892-1363, USA
Long term
treatment with lithium, the primary drug used to treat bipolar mood disorder,
robustly protects against glutamate-induced, NMDA receptor-mediated
excitotoxicity in primary cultures of rat brain neurons. The Neuroprotective
effects of lithium in these CNS neurons are accompanied by a reduction in NMDA
receptor-mediated calcium influx, up-regulation of anti-apoptotic Bcl-2 protein,
down-regulation of pro-apoptotic p53 and Bax proteins, and activation of the
cell survival phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signaling
pathway. In addition, lithium antagonizes glutamate-induced activation of
c-Jun-N-terminal kinas (JNK), p38 kinase andAP-1 binding, and suppresses
glutamate-induced loss of Phosphorylated CREB due to activation of protein
phosphatase-1. Evidence has also been obtained that lithium induces BDNF and
activates its receptor TrkB in cortical neurons, and this BDNF/TrkB signaling
activation is imperative for the Neuroprotective effects of this drug. We have
shown that valproic acid (VPA), another major mood stabilizer, also protects
cultured CNS neurons from glutamate excitotoxicity. VPA neuroprotection is
mimicked by inhibitors of histone deacetylase (HDAC), a newly identified target
of VPA, and is correlated with hyperacetylation of histone. Both VPA and
lithium increase the exon III promoter activity of the BDNF gene. Under
conditions where VPA or lithium alone provides only limited neuroprotection,
synergistic protective effects can be obtained by the co-presence of both drugs.
In a rat
stroke model, we found that post-insult treatments with therapeutic doses of
lithium or VPA markedly reduce ischemia-induced brain infarction and
neurological deficits. These Neuroprotective effects are associated with a
suppression of caspase-3 activation and an induction of heat shock protein 70
(HSP70). In a rat excitotoxicity model of Huntington’s disease (HD) in which an
excitotoxin, Quinolinic acid (QA), was infused into the striatum, we found that
either long- or short-term pretreatment with lithium reduces QA-induced DNA
damage, caspase-3 activation and loss of striatal neurons, and this
neuroprotection is associated with an increase in the number of Bcl-2-expressing
neurons and the levels of Bcl-2 proteins in these cells. Lithium also induces
cell proliferation near the site of QA infusion with a concomitant loss of
proliferating cells in the subventricular zone. Some of these proliferating
cells show the phenotypes of neurons or astroglia. This finding is corroborated
with our in vitro results that lithium stimulates the proliferation of
neuroblasts in primary cultures of CNS neurons. Taken together, our results
suggest that lithium and VPA, either alone or in combination, might have utility
in the treatment of neurodegenerative diseases particularly those linked to
excitotoxicity.