We have used various experimental model systems to test the hypothesis that glycogen synthase kinase-3 (GSK-3) and histone deacetylases (HDACs) are initial targets of lithium and valproic acid (VPA), respectively, that trigger diverse neurobiological events including neuroprotective and neurotrophic effects, anti-inflammatory effects, antidepressant effects, promotion of stem cell migration, regulation of microRNA expression, and modulation of behavioral phenotypes. Our studies identified a number of novel signaling pathways and neuroprotective and neurotrophic genes targeted by lithium and VPA, and underlying mechanisms were elucidated in both in vitro and in vivo experimental settings. Studies on the effects of mood stabilizers in the rat ischemic stoke model and animal models of Huntingtons disease (HD) were markedly expanded. The results of these studies identified previously unknown neurobiological actions induced by these mood stabilizers. In primary brain neurons, we identified a previously unknown function of fibroblast growth factor-21 (FGF-21), namely its ability to mediate the synergistic neuroprotective effects of lithium and VPA against glutamate excitotoxicity (Leng et al. Mol Psychiatry, advance online). Until now, FGF-21 has been thought to be expressed only in the peripheral systems, notably the liver, has a prominent role in regulating glucose and fatty acid metabolism, and is a putative therapeutic target for diabetes and obesity. Our results demonstrated for the first time that FGF-21 can be markedly induced in primary brain neurons and intact brain of rodents following co-treatment with lithium and VPA. More importantly, FGF-21 mediates, at least in part, the synergistic neuroprotection induced by lithium-VPA co-treatment. FGF-21s neuroprotection involves Akt-1 activation and GSK-3 inhibition;interestingly, both events also reciprocally regulate FGF-21 induction. Our recent results showed that FGF-21 RNA and protein levels were robustly decreased in the brains of ischemic rats (Wang, Z et al., in preparation) and ALS mice (Wang J et al., in preparation), suggesting that this growth factor is a novel target for therapeutic intervention of brain disorders. We expanded our studies using middle cerebral artery occlusion (MCAO) in rats as a model of focal cerebral ischemia, and made a number of original findings. Similar to the effects of lithium, we found that post-insult treatment with VPA reduced infarct volume and improved behavioral outcomes in rats that underwent MCAO. For the first time, we demonstrated that VPA robustly reduced blood-brain barrier (BBB) disruption induced by MCAO, and that this reduction was largely due to decreases in ischemia-induced matrix metalloproteinase 9 (MMP-9) overexpression and tight junction degradation (Wang et al., JCBFM, 2011). We also showed that long-term VPA treatment enhanced post-ischemic angiogenesis by upregulating hypoxia inducible factor-1alpha (HIF-1alpha ) and its downstream targets, pro-angiogenic vascular endothelial growth factor (VEGF) and MMP-2/9 (Wang et al., Stroke, 2012). In addition, tail-vein injection of mesenchymal stem cells (MSCs) into MCAO rats was found to be highly beneficial when these MSCs were primed with both lithium and VPA to induce MMP-9 and CXC chemokine receptor 4 (CXCR4), respectively, thereby promoting MSC migration to the infarct region (Tsai et al., Neuropsychopharm,, 2011;Stroke, 2012). Furthermore, we reported that HDAC inhibition by a VPA analog, sodium butyrate, enhanced post-MCAO-induced neurogenesis and oligodendrogenesis in multiple ischemic brain regions, and this effect required activation of BDNF-TrkB signaling (Kim et al., J Neurochem, 2009;AJTR, 2014). Finally, our very recent work reported microRNA (miRNA) regulation following ischemic stroke (e.g. miR-446f, miR-446h, miR-155, miR-1224, and miR-297a) and their potential for underlying the benefits of post-insult VPA treatment (e.g. miR-885-3p and miR-331) in a rat model of cerebral ischemia (Hunsberger et al., 2012), suggesting that miRNAs may underlie disease processes that contribute to numerous neurological disorders. Additionally, we found miR34a to be involved in regulating the life and death of neuronal cells in an in vitro study (Hunsberger et al., AJTR, 2013). In a pilot clinical study in collaboration with Dr. Giia-Sheun Peng of Tri-Service General Hospital in Taiwan, we found that three-month treatment with VPA commencing 3-24 hours after stroke markedly reduced neurological deficits, compared with the vehicle-treated control (Lee et al., CNS Neurosci &Thera, resubmitted). In a most recent study, we treated MCAO rats with a specific HDAC6 isoform inhibitor, tubastatin A, and found remarkable neuroprotective effects and behavioral improvements with a time window of at least 24 hours after insult (Wang Z et al., in preparation). The beneficial effects of tubastatin A were associated with tubulin hyperacetylation, and may involve neuroprotection against excitotoxicity and amelioration of defective mitochondrial transport. HD is an inherited, fatal neurodegenerative/neuropsychiatric disorder with no available treatment to halt symptom progression. We assessed the therapeutic potential of dietary treatment with lithium and/or VPA in two transgenic mouse models of HD, N171-82Q and YAC128. We detected hyperactivity of GSK-3 and HDACs in the brains of untreated HD mice, and found that daily dietary co-treatment with lithium and VPA more effectively alleviated impaired locomotion and depressive-like behaviors than mono-treatment in both mouse models of HD, and significantly prolonged the lifespan of N171-82Q mice (Chiu et al., Neuropsychophar, 2011;Sheuing et al., Int J Biol Sci, 2014). Levels of BDNF and HSP70 in the brains of both strains were also more consistently elevated by lithium-VPA co-treatment. Recently, we observed that long-term administration of a BDNF TrkB receptor agonist, LM22A, elicited behavioral benefits in N171-82Q mice (Chiu et al., SFN abstract, 2013), further supporting the roles of BDNF/TrkB signaling in HD pathology and therapy. In another ongoing study using N171-82Q mice, we found that intranasal delivery of mouse MSCs preconditioned with both lithium and VPA ameliorated behavioral deficits (Linares et al., SFN abstract, 2013), suggesting a novel avenue for HD therapeutic intervention. We have also completed projects related to the neurobiology of lithium and VPA: (1) We studied the regulation of miRNAs by mood stabilizers in order to identify novel miRNA-mediated signatures and mechanisms in patient-derived lymphoblastoid cell lines (LCLs) from BD patients who were lithium responders and non-responders. Several prominent miRNAs notably Let-7 were identified by microarray and their interactions with target mRNAs in LCLs have been studied by GRANITE (Hunsberger et al., Translational Psychiatry, resubmitted). (2) Pre- or post-treatment with lithium was shown to potentiate the rapid antidepressant effects of ketamine in chronically stressed mice by robustly reducing ketamine dose requirement and prolonging its antidepressant duration (Chiu et al., IJNN, submitted). This potentiation is associated with enhanced activation of the BDNF and mTOR signaling pathways. In summary, our recent work has markedly increased our understanding of the molecular and cellular actions of mood stabilizers, and substantially advanced our knowledge of their effects in a number of experimental models of neurodegenerative and neuropsychiatric diseases. With the completion of a number of ongoing projects, we expect to provide further mechanistic insights and set the stage for clinical investigations into the use of mood stabilizers to intervene in certain CNS disorders.
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