We continued investigating our central hypothesis that glycogen synthase kinase-3 (GSK-3) and histone deacetylases (HDACs) are initial targets of the mood stabilizers lithium and valproic acid (VPA), respectively, to induce a spectrum of neurobiological effects. Our studies identified previously unknown involvement of signaling pathways and neuroprotective and neurotrophic genes affected by lithium and VPA, and underlying biochemical and molecular mechanisms were elucidated in both in vitro and in vivo settings. Of general impact, results of our research support the use of these agents in the development of treatments for brain disorders. We previously reported that combined treatment with lithium and VPA produced synergistic neuroprotective effects in aging primary brain neurons. This research was expanded to investigate the molecular mechanisms of this phenomenon. Microarray analysis found that fibroblast growth factor (FGF-21), a novel metabolic regulator, was dramatically and selectively increased by lithium-VPA co-treatment. Moreover, purified FGF-21 completely protected neurons from glutamate-induced excitotoxicity, and this was associated with increased Akt-1 and inhibition of GSK-3 activities (Leng et al., Mol Psychiatry in revision, 2013). Our pioneer research suggests that FGF-21 is an innovative gene for neuroprotection in brain disorders. Another mood stabilizer, lamotrigine, was also found to be neuroprotective against glutamate excitotoxicity by induction of Bcl-2 and the remodeling of chromatin (Leng et al., Intl J Neuropsychopharm, 2013). We have also made recent findings that VPA through HDAC inhibition, attenuates ischemia-induced blood-brain barrier (BBB) disruption, enhances postischemic angiogenesis, and promotes functional recovery in a rat cerebral artery occlusion (MCAO) model of ischemic stroke (reviewed in Chiu et al., Pharm Rev, 2013;Fesseler et al., 2013). In one MCAO project investigating the neuroprotective effects of tubastatin A (TubA), a novel specific HDAC6 inhibitor, we discovered that post-ischemic TubA treatment robustly reduced brain infarction and facilitated functional recovery. These findings were confirmed by experiments showing that ischemia reduced levels of acetylated α-tubulin, and TubA significantly restored α-tubulin acetylation levels (Wang et al., Neurosci Meeting abstr 55.08, 2013). These findings support the notion that HDAC6 is a promising target for the treatment of ischemic stroke and the clinical utility of TubA for this brain disorder. Additionally, through the profiling of brain cytoarchitectural alterations after ischemia and drug treatment, we found significant changes in cellular population, composition, distribution, and states of differentiation and proliferation. Our preliminary results show that lithium treatment robustly ameliorates the cytoarchitectural changes after ischemic injury. In other experiments using rat MCAO, we profiled microRNAs (miRNAs), small non-protein coding RNAs, in the ischemic cortex which were upregulated 24 hours following MCAO and VPA treatment. Two promising post-insult VPA-regulated candidates detected were miR-331 and miR-885-3p. miR-331 was also regulated by VPA pre-treatment in rat cortical neuronal cultures subjected to oxygen-glucose deprivation. The predicted targets of these miRNAs identified networks involved in cell death and nervous system development. These predicted networks also showed significant associations with neurodegenerative diseases (Hunsberger et al., 2012). Using primary brain neurons, we determined the potential role for miRNAs in neuroprotection following neuronal death. Combined treatment with lithium and VPA provided near-complete protection from glutamate toxicity in these neurons, and numerous miRNAs were found to be regulated including miR-34a. We then verified the apoptotic actions of miR-34a. It was observed that the pathways associated with mood stabilizer-regulated miRNAs are strongly associated with pathways implicated in neuropsychiatric diseases such as schizophrenia (Hunsberger et al., 2013). We have recently shown that therapeutic doses of either lithium or VPA have neuroprotective and anti-inflammatory effects as well as behavioral benefits in a mouse model of traumatic brain injury (TBI) (Yu et al, J Neurotrauma 29: 362-374 &2342-2351, 2012). Our current studies evaluated effects of combined treatment with subeffective doses of lithium and VPA after TBI. We found that post-trauma treatment with combined subeffective doses significantly reduced lesion volume, attenuated BBB disruption and improved motor coordination. Acetylation of histone H3, an index of HDAC inhibition, was robustly increased by co-treatment and may be considered as part of the biochemical mechanism involved (Yu et al., J Neurosurgery Advance Online, 2013). Our results suggest that using a combination of these two agents at subtherapeutic doses to treat patients with TBI may also reduce side effects and enhance tolerability. We also previously demonstrated that co-treatment with lithium and VPA produced behavioral benefits in two Huntingtons disease (HD) mouse models and, very importantly, prolonged survival time (Chiu et al., 2011). In addition, GSK-3 and HDAC hyperactivity were consistently suppressed by this combined treatment, which was also associated with upregulation of two important proteins for neuronal growth and protection, brain-derived neurotrophic factor (BDNF) and heat shock protein 70 (HSP70). Lithium and VPA are already FDA-approved medications, and our data provide the rationale and clinical relevance for their combined treatment of HD. Currently, we are assessing the possible therapeutic potential of LM22A-4, a small non-peptide molecule that acts as a direct and specific partial agonist of the BDNF receptor, TrkB, in a transgenic mouse model of HD, by intranasal application which allows drug delivery to the central nervous tissue by bypassing the BBB. HD-associated locomotor impairment, motor coordination and depressive-like behaviors were dramatically improved by LM22A-4 treatment. Since the physiological components largely depend on striatal function, our results suggest that improved motor function in HD mice could be attributable to neuroprotective effects of pharmacologic activation of TrkB by this compound (Chiu et al., Neurosci Meeting abstr 528.04, 2013). In a related study using a mouse stress model of depression, we found that pre- or post-lithium treatment potentiated the antidepressant-like effects of a single acute sub-therapeutic dose of ketamine through increasing p-GSK-3β, and p-P70S6K which is the downstream effector of mTOR. We also investigated the feasibility of stem cell-based therapy for treating neurodegenerative disorders such as Huntingtons disease. Mesenchymal stem cells (MSCs) were preconditioned with lithium and VPA to enhance their biological and functional properties after transplantation in brain via intranasal application. These preconditioned MSCs improved both the speed and distance traveled as well as motor function in HD mice (Linares et al., Neurosci Meeting abstr 433.01, 2013). Our findings suggest that preconditioning MSCs with the mood stabilizers lithium and VPA may have utility in the treatment of HD to reduce the severity of neurological symptoms. In summary, our investigations have substantially contributed to increased knowledge of molecular and cellular actions of mood stabilizers, and resulted in progress into the understanding of their effects in several research models of neurodegenerative and neuropsychiatric diseases. Upon implementation of future studies, we expect to provide further illumination into the biochemical mechanisms, which will pave the way for the use of mood stabilizers in clinical investigations for the treatment of certain brain disorders.

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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
Leeds, Peter R; Yu, Fengshan; Wang, Zhifei et al. (2014) A New Avenue for Lithium: Intervention in Traumatic Brain Injury. ACS Chem Neurosci :
Chiu, Chi-Tso; Wang, Zhifei; Hunsberger, Joshua G et al. (2013) Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder. Pharmacol Rev 65:105-42
Lu, Wen-Hsin; Wang, Chih-Yen; Chen, Po-See et al. (2013) Valproic acid attenuates microgliosis in injured spinal cord and purinergic P2X4 receptor expression in activated microglia. J Neurosci Res 91:694-705
Yu, Fengshan; Wang, Zhifei; Tanaka, Mikiei et al. (2013) Posttrauma cotreatment with lithium and valproate: reduction of lesion volume, attenuation of blood-brain barrier disruption, and improvement in motor coordination in mice with traumatic brain injury. J Neurosurg 119:766-73
Fessler, Emily B; Chibane, Fairouz L; Wang, Zhifei et al. (2013) Potential roles of HDAC inhibitors in mitigating ischemia-induced brain damage and facilitating endogenous regeneration and recovery. Curr Pharm Des 19:5105-20
Leng, Yan; Fessler, Emily Bame; Chuang, De-Maw (2013) Neuroprotective effects of the mood stabilizer lamotrigine against glutamate excitotoxicity: roles of chromatin remodelling and Bcl-2 induction. Int J Neuropsychopharmacol 16:607-20
Hunsberger, Joshua G; Fessler, Emily B; Chibane, Fairouz L et al. (2013) Mood stabilizer-regulated miRNAs in neuropsychiatric and neurodegenerative diseases: identifying associations and functions. Am J Transl Res 5:450-64
Guo, Shuzhen; Arai, Ken; Stins, Monique F et al. (2009) Lithium upregulates vascular endothelial growth factor in brain endothelial cells and astrocytes. Stroke 40:652-5
Kim, Hyeon Ju; Leeds, Peter; Chuang, De-Maw (2009) The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain. J Neurochem 110:1226-40

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