Thus, lithium has been demonstrated to protect, against the deleterious effects of glutamate, NM.DA receptor activation, aging, serum/NGF deprivation, ouabain, thapsigargin (which mobilizes intracellular methlphenylpyridinium (MPP+), Ca2+), and p-amyloid in vitro.149 More importantly, lithium’s neurotrophic and cytoprotective effects have also been demonstrated in rodent, brain in vivo. Thus, lithium treatment has been shown to attenuate the biochemical deficits produced by kainic acid infusion, ibotcnic acid infusion, and forebrain cholinergic system lesions,149,154,155 Inhibitors,research,lifescience,medical to exert dramatic protective effects against middle cerebral artery occlusion,156 and to enhance hippocampal

neurogenesis in the adult rodent hippocampus.157 The potential therapeutic relevance of these preclinical findings in discussed below. Human evidence for the neurotrophic effects of mood stabilizers While the body of preclinical data demonstrating neurotrophic and neuroprotective

effects of lithium is striking, considerable caution must, clearly be exercised in extrapolating Inhibitors,research,lifescience,medical to the clinical situation with humans. In view of lithium and VPA’s robust effects on the levels of the cytoprotective protein bcl-2 in the FC, Drevets and associates28 reanalyzed older data demonstrating Inhibitors,research,lifescience,medical approximately 40% reductions in subgenual PFC volumes in familial mood disorder subjects. Consistent, with neurotrophic/neuroprotective effects of lithium and VPA, they found that the patients Inhibitors,research,lifescience,medical treated with kinase inhibitor Brefeldin A chronic lithium or VPA exhibited subgenual PFC volumes, which were significantly higher than the volumes in non-lithiumtreated or VPA-treated patients, and not. significantly

different from controls.158 Although the results of the study by Drevets158 suggest that mood stabilizers may have provided neuroprotective effects during naturalistic use, considerable caution is warranted in view of the small sample size and crosssectional nature of the study. To investigate Inhibitors,research,lifescience,medical the potential neurotrophic effects of lithium in humans more definitively, a. longitudinal clinical study was recently undertaken using proton magnetic resonance spectroscopy (MRS) to quantify N-acctylaspartate (NAA, a putative marker of neuronal viability) levels. It was found that chronic lithium administration at therapeutic doses increases NAA concentration in the human brain in vivo.159 ‘ITtiesc findings provide intriguing indirect, support, for the contention that, similar to the findings Drug_discovery observed in the rodent brain and in human neuronal cells in culture, chronic lithium increases neuronal viability/function in the human brain. Furthermore, a striking approximately 0.97 correlation between lithiuminduced NAA increases and regional voxel gray matter content, was observed,159 thereby providing evidence for colocalization with the region -specific bcl-2 increases observed in the rodent, brain cortices (eg, gray versus white matter).