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. We also reported that lithium suppressed 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 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 and bipolar disorder. 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. Heat shock protein 70 (HSP70) is a crucial neuroprotective protein with multiple functions including anti-inflammatory effects. We found HSP70 expression was highly elevated in the brain of rats subjected to stroke and treated with VPA. This HSP70 induction likely contributes to the neuroprotective and anti-inflammatory effects of this drug in the animal stroke model. Our most recent study using isolated cortical neurons from rat brain suggests that VPA-induced HSP70 expression involves inhibition of class I HDACs to enhance the acetylation of the transcription factor Sp1 and its binding to the promoter of HSP70 gene. We also investigated the effects of sodium butyrate, a VPA analog with efficacy to inhibit HDACs and display anti-depressant-like effects, in the rat stroke model. Similar to VPA, post-insult treatment with sodium butyrate enhanced neurogenesis (new birth of neurons) in a number of brain regions including the injured cortex and striatum. Additionally, oligodendrogenesis (new birth of oligodendrocytes) was found to be enhanced by treatment with sodium butyrate. These butyrate-induced effects on neurogenesis and oligodendrogenesis in the brain of ischemic rats are dependent on the activity of the BDNF-TrkB signaling pathway. 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 results showed that lithium-VPA cotreatment reduced hypolocomotor activity and normalized anxiety-like behaviors in YAC128 HD mice. This drug cotreatment also prevented hypolocomotor activity, reduced depression-like behaviors and markedly prolonged life span in N171-82Q HD mice. In all cases, lithium-VPA cotreatment was found to be more effective than either drug alone in inducing these beneficial effects in both transgenic mouse models of HD. These results are consistent with the clinical observations that lithium-VPA cotreatment often produces more efficacious outcome in bipolar patients resistant to treatment with either lithium or VPA alone.

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Project End
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Budget End
Support Year
22
Fiscal Year
2009
Total Cost
$1,285,432
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
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Leng, Yan; Wang, Junyu; Wang, Zhifei et al. (2016) Valproic Acid and Other HDAC Inhibitors Upregulate FGF21 Gene Expression and Promote Process Elongation in Glia by Inhibiting HDAC2 and 3. Int J Neuropsychopharmacol 19:
Linares, Gabriel R; Chiu, Chi-Tso; Scheuing, Lisa et al. (2016) Preconditioning mesenchymal stem cells with the mood stabilizers lithium and valproic acid enhances therapeutic efficacy in a mouse model of Huntington's disease. Exp Neurol 281:81-92
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Leng, Y; Wang, Z; Tsai, L-K et al. (2015) FGF-21, a novel metabolic regulator, has a robust neuroprotective role and is markedly elevated in neurons by mood stabilizers. Mol Psychiatry 20:215-23
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Kim, Hyeon Ju; Chuang, De-Maw (2014) HDAC inhibitors mitigate ischemia-induced oligodendrocyte damage: potential roles of oligodendrogenesis, VEGF, and anti-inflammation. Am J Transl Res 6:206-23
Scheuing, Lisa; Chiu, Chi-Tso; Liao, Hsiao-Mei et al. (2014) Preclinical and clinical investigations of mood stabilizers for Huntington's disease: what have we learned? Int J Biol Sci 10:1024-38
Lee, Jiunn-Tay; Chou, Chung-Hsing; Cho, Nai-Yu et al. (2014) Post-insult valproate treatment potentially improved functional recovery in patients with acute middle cerebral artery infarction. Am J Transl Res 6:820-30
Huang, Fengzhen; Zhang, Li; Long, Zhe et al. (2014) miR-25 alleviates polyQ-mediated cytotoxicity by silencing ATXN3. FEBS Lett 588:4791-8

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