The Section on Molecular Neurobiology continued investigating the neurobiology of mood stabilizing drugs, notably valproic acid (VPA) and lithium. The working hypothesis is that VPA and lithium, by inhibiting their initial targets histone deacetylases (HDACs) and glycogen synthase kinase-3 (GSK-3), respectively, induce transcriptional regulation and elicit neuroprotection, neuro-support, neurogenesis, anti-inflammation, cell migration and behavioral benefits, among others. This current year, extending previous studies, we investigated the induction of heat-shock protein70 (HSP70) in rat cortical neurons. HSP70 is a molecular chaperone capable of assisting the proper folding of proteins, and has neuroprotective and anti-inflammatory properties. We found that VPA treatment up-regulated HSP70 expression, and promoter hyperacetylation and activity (Marinova et al., 2009). Other HDAC inhibitors mimicked the ability of VPA to induce HSP70. VPA treatment increased acetylation of the transcription factor Sp1, and its recruitment to the promoter. Further, VPA-induced neuroprotection against glutamate excitotoxicity was prevented by blocking HSP70 induction. Taken together, the data suggest that Sp1 is likely involved in HSP70 induction by HDAC inhibitors, and induction of HSP70 by VPA in cortical neurons may contribute to its neuroprotective and therapeutic effects. Studies also demonstrated for the first time that HDAC inhibition by VPA and other compounds increased levels of dimethylation and trimethylation of histone H3K4 in rat cortical neurons and astrocytes, suggesting the interplay between histone acetylation and histone methylation (Marinova et al., 2010). These findings have profound implications for the use of HDAC inhibitors to induce neuroprotective proteins in neurodegenerative conditions. New evidence supports that other HDAC inhibitors have antidepressant-like effects in rodents, suggesting that VPA inhibition of HDACs may contribute to both neuroprotection and mood stabilizing effects (Chuang et al., 2009). In collaboration with Dr. Heinz Nau in Germany, we assessed the ability of four VPA derivatives to cause histone hyperacetylation and protect against glutamate-induced excitotoxicity in cultured neurons. We found that two derivatives were far more potent and robust than VPA in inducing histone hyperacetylation and protecting against glutamate excitotoxicity (Leng et al., 2010). These two compounds were also more effective than VPA in increasing HSP70-1a and HSP70-1b mRNA levels. Our results suggest that these two VPA derivatives may ultimately be developed into potent neuroprotective and mood stabilizing drugs. Focal cerebral ischemia induces blood-brain barrier (BBB) disruption, which is a major contributor of stroke pathology. We found that post-ischemic VPA treatment attenuated middle cerebral artery occlusion (MCAO)-induced BBB disruption in rats (Wang et al., 2010). Meanwhile, VPA significantly reduced MCAO-induced elevation of matrix metalloproteinase-9 (MMP-9), and attenuated degradation of tight junction proteins, claudin-5 and ZO-1. Sodium butyrate (SB), another HDAC inhibitor, mimicked these effects of VPA. Our findings suggest that BBB protection by VPA involves HDAC inhibition-mediated suppression of MMP-9 induction and prevention of tight junction degradation. This finding helps in understanding neuroprotective mechanisms of VPA. We also found that postinsult treatment with SB elicited increased cell proliferation, differentiation and migration in the brain ischemic hemisphere (Kim et al., 2009). Some new-born cells act like neuronal precursor cells. We showed that these HDAC inhibition-induced effects depend on the BDNF-TrkB signaling pathway and may contribute to the long-term beneficial effects of HDAC inhibitors in stroke models. GSK-3 is thought to have a central role in mood regulation (Chiu and Chuang, 2010). However, the GSK-3 isoform(s) and brain region(s) involved in regulating these behavioural effects remain elusive. We studied the effects of bilateral intrahippocampal injections of lentivirus-expressing short-hairpin (sh)RNA targeting GSK-3beta, which persistently reduces expression of GSK-3beta, on behavioural performance in mice subjected to chronic stress. Pre-injection of GSK-3beta shRNA significantly decreased immobility time in both forced swim and tail suspension tests (Omata et al., 2010). These results suggest that GSK-3beta shRNA induces antidepressant-like effects in chronically stressed mice. To our knowledge, this is the first demonstration that a single injection of lentivirus-expressing GSK-3 shRNA in the hippocampal dentate gyrus of chronically stressed mice has antidepressant-like effects elicited by gene silencing. In a collaborative study with Carolyn Smith of NIMH, we investigated the role of lithium in a mouse model of Fragile X syndrome in which the FMR1 gene was deleted. Results showed that chronic lithium treatment normalized aberrant dendritic morphology, reduced anxiety levels, deficient social interaction and impaired leaning and memory (Liu et al., 2010). Our previous studies demonstrated that synergistic neuroprotective effects occurred when VPA and lithium were used together. Thus, we investigated the beneficial effects of VPA and lithium co-treatment in two transgenic models of Huntingtons disease (HD). Results showed that VPA and lithium co-treatment suppressed motor deficits and ameliorated psychiatric disturbances in mice (Chiu et al., 2010). Co-treatment also normalized depression-like behavior, improved motor performance and prolonged life span in mice. Importantly, combined treatment was more effective than single drug use. Studies support that HDACs and GSK-3 are initial targets for VPA and lithium to induce these behavioral benefits, while BCl-2, BDNF and its receptor TrkB are important downstream molecules to mediate the neuroprotection. Results strongly suggest a potential utility of lithium and VPA in treating HD, and provide possible molecular mechanisms underlying the effects of this co-treatment. MicroRNAs are 22 nucleotide non-protein coding RNAs that are involved in mRNA translational repression, and are implicated in various diseases ranging from cancer to Alzheimers disease. MicroRNAs also have a role in cell proliferation, synapse formation, and neuroprotection. We investigated microRNAs underlying the neuroprotective effects of VPA and lithium against glutamate excitotoxicity using microRNA microarray. We identified a number of microRNAs regulated under these treatment conditions, and will test the neuroprotective role of select microRNAs in this cellular model and the stroke animal model to determine their therapeutic potential. We hope to identify neuroprotective microRNAs with broad therapeutic potential that may be capable of treating multiple diseases. Mesenchymal stem cells (MSCs) have high potential for the therapy of human diseases. We investigated whether treatment of MSCs with VPA and lithium would enhance cell migration to disease target sites. We found that VPA treatment upregulated CXC chemokine receptor 4 (CXCR4) in MSCs through HDAC inhibition (Tsai et al., 2010). Notably, VPA enhanced stromal cell-derived factor-1a (SDF-1a)-mediated MSC migration. Treatment of MSCs with lithium elevated MMP-9 through GSK-3 inhibition, and potentiated MSC migration across the extracellular matrix. Combining VPA and lithium treatment further increased MSC migration. Overall, VPA and lithium stimulated MSC migration through distinct targets and mediators: HDAC-CXCR4 and GSK-3beta-MMP-9, respectively. Preliminary results showed that I.V. injection of MSCs primed with VPA and lithium enhanced their migration to the brain injured site and improved functional recovery in the rat MCAO model of stroke, suggesting potential utility in human brain disorders.

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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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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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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

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