THE ANTI

Chuang

Molecular

Neurobiology Section, Mood and Anxiety Disorders Program, National Institute of

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,

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