The Molecular Neurobiology Section has continued to investigate the molecular and cellular actions of mood stabilizing drugs used to treat bipolar disorder, a common and devastating disease affecting about 3-4% of the population in the US. Two most commonly used mood stabilizers are lithium and valproate (VPA), the latter is also an anticonvulsant drug. Using a technique that can block or inactivate both isoforms of glycogen synthase kinase-3 (GSK-3), we have shown that both GSK-3alpha and beta isoforms are important targets for lithium to display protective effects against glutamate-induced excitotoxicity in nerve cells termed neurons. Glutamate excitotoxicity has been implicated in a number of neuropsychiatric and neurological diseases including depression, Alzheimers disease, Huntingtons disease, among others.? In this fiscal year, we also reported that lithium could suppress the expression of plasminogen activator inhibitor type-1 (PAI-1) through a complex mechanism. PAI-1 is a major inhibitor of tissue-type plasminogen activator (tPA). Conversely, tPA protein was increased by lithium and this tPA up-regulation had a critical role in protecting neurons from apoptosis, also referred to as program cell death, resulting from insults such as endoplasmic reticulum (ER) stress. ER stress has been found to be associated with bipolar disorder. This new finding may have strong implications in the therapeutic effect of lithium in treating bipolar disorder.? On the other hand, VPA can directly inhibit histone deacetylases (HDACs) and this action is known to have impact on gene expression by changing the structure of the DNA-protein complex called chromatin. We have found a new target gene affected by VPA through inhibition of HDACs. This protein is alpha-synuclein. In contrast to the previous belief that alpha-synuclein is harmful to neurons and could be involved in the occurrence of neurodegenerative diseases such as Alzheimers disease, we provided evidence that endogenous alpha-synuclein increased by VPA treatment could actually protect neurons from being killed by glutamate toxicity. This paradoxical finding may help to develop new drugs for treating certain forms of mental illnesses.? Brain-derived neurotrophic factor (BDNF) can provide nutrients to neurons so that they have normal development and function, and are more resistant to attack by exogenous insults. Abnormal BDNF has also been linked to mental illnesses such as depression and schizophrenia. We found that both lithium and VPA treatment induced BDNF protein. These effects were due to actions of lithium and VPA on GSK-3 and HDACs, respectively, to increase the efficiency of a specific type of BDNF messenger RNA to be made. It should be pointed out that we have preliminary data indicating that tPA amounts were increased in the brain of mice chronically treated with lithium or VPA. Because tPA may be involved in the maturation of BDNF from its precursor, these effects are also of high significance.? Clinically, lithium and VPA are often used together, because not all bipolar patients respond well to treatment with either drug alone, and combined use of both drugs can improve the treatment benefits. In agreement with these clinical observations, we found that under certain experimental conditions, neither lithium nor VPA was able to protect neurons from glutamate-induced insult; however, when lithium and VPA were used together, complete protection was observed. We also provided evidence that this synergistic protection of neurons is due to potentiation of the inhibition of GSK-3 activity. This clinically important finding has been reported this year in a prestigious journal, the Journal of Neuroscience.? It is increasingly recognized that inflammation in the brain can cause severe damage, and is involved not only in brain injury but also in neuropsychiatric diseases such as depression. Very interestingly, we found that the mood stabilizer VPA has highly significant anti-inflammatory effects. We showed this using a stroke model in rats and a culture that contained a mixture of neurons and glia, which are cells that support neuronal cells. We showed that VPA acted on one type of glial cell called microglia to prevent them from being over-activated such that inflammation was inhibited. At present, there is no effective drug that can control brain inflammation. Our finding raises the possibility that VPA can be developed as a new anti-inflammatory drug for a variety of pathological conditions. Our results also point out that not only neurons, but also glia are important targets of mood stabilizers.? Huntingtons disease (HD) is not only a movement disorder, but a neuropsychiatric disease because patients show learning disability and depression before movement abnormality is detected. HD is fatal with no medicine proven to be significantly effective for this disease at the present time. Because HD is a genetic disorder caused by an over repetition of an amino acid, glutamine, in a diseased protein called huntingtin, we have used two genetic mouse models, namely YAC128 and N171-82Q, to test the effectiveness of lithium and VPA cotreatment. Our preliminary results showed that this cotreatment reduced the anxiety behavior in YAC128, while improving memory, motor coordination and prolonged survival time in N171-82Q mice. These exciting results are clinically important, and will be presented this December in the Annual Meeting of the American College of Neuropsychopharmacology (ACNP).
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