Scriptaid, a Novel Histone Deacetylase Inhibitor, Protects Against Traumatic Brain Injury via Modulation of PTEN and AKT Pathway

Wang, Guohua; Jiang, Xiaoyan; Pu, Hongjian; Zhang, Wenting; Chen, An; Hu, Xiaoming; Liou, Anthony Kian-Fong; Leak, Rehana K.; Gao, Yanqin; Chen, Jun

doi:10.1007/s13311-012-0157-2

Cited by 92 publications

(81 citation statements)

References 68 publications

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“…Some HDAC inhibitors preferentially promote the transcription of neuroprotective genes. We recently reported that Scriptaid, a novel inhibitor of class I/II HDACs, protects gray matter against experimental TBI (10). These findings are consistent with reports indicating that other HDAC inhibitors can attenuate gray matter injury in TBI models (11)(12)(13)(14).…”

supporting

confidence: 89%

“…Nonetheless, it is known that oligodendrocytes are especially vulnerable to mechanical trauma (10,26,27), and that neuroinflammation may exacerbate WMI following TBI (15,21). The present study improves our understanding of white matter pathophysiology by showing that microglia/macrophages exert protective or destructive effects on oligodendrocytes depending on M2 or M1 polarization status, respectively.…”

Section: Discussionmentioning

confidence: 50%

“…This study used the well-established CCI model of TBI in mice (10,21). Scriptaid was injected at 3.5 mg/kg at 2 h after TBI, and this was repeated daily for the next 2 d. Animals were assigned at random to groups, and all measurements were performed by investigators blinded to the experimental group assignments.…”

Section: Methodsmentioning

confidence: 99%

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HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis

Wang

Shi

Jiang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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313

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Severe traumatic brain injury (TBI) elicits destruction of both gray and white matter, which is exacerbated by secondary proinflammatory responses. Although white matter injury (WMI) is strongly correlated with poor neurological status, the maintenance of white matter integrity is poorly understood, and no current therapies protect both gray and white matter. One candidate approach that may fulfill this role is inhibition of class I/II histone deacetylases (HDACs). Here we demonstrate that the HDAC inhibitor Scriptaid protects white matter up to 35 d after TBI, as shown by reductions in abnormally dephosphorylated neurofilament protein, increases in myelin basic protein, anatomic preservation of myelinated axons, and improved nerve conduction. Furthermore, Scriptaid shifted microglia/ macrophage polarization toward the protective M2 phenotype and mitigated inflammation. In primary cocultures of microglia and oligodendrocytes, Scriptaid increased expression of microglial glycogen synthase kinase 3 beta (GSK3β), which phosphorylated and inactivated phosphatase and tensin homologue (PTEN), thereby enhancing phosphatidylinositide 3-kinases (PI3K)/Akt signaling and polarizing microglia toward M2. The increase in GSK3β in microglia and their phenotypic switch to M2 was associated with increased preservation of neighboring oligodendrocytes. These findings are consistent with recent findings that microglial phenotypic switching modulates white matter repair and axonal remyelination and highlight a previously unexplored role for HDAC activity in this process. Furthermore, the functions of GSK3β may be more subtle than previously thought, in that GSK3β can modulate microglial functions via the PTEN/PI3K/Akt signaling pathway and preserve white matter homeostasis. Thus, inhibition of HDACs in microglia is a potential future therapy in TBI and other neurological conditions with white matter destruction.T raumatic brain injury (TBI) often leads to catastrophic neurological disabilities and sometimes ends in death (1). TBI results not only in gray matter damage, but also in severe white matter injury (WMI), thereby disrupting signal transmission and eliciting poor functional outcomes (2, 3). WMI in TBI patients is strongly correlated with neurological deficits, and diffusion tensor imaging of white matter offers prognostic value for neurological status (2-4). At present, there are no satisfactory therapies to protect TBI patients against either gray matter injury or WMI. Furthermore, most preclinical TBI studies greatly emphasize gray matter over white matter, which may contribute to the many disappointing results in clinical trials to date (5).Previous studies have shown that histone deacetylase (HDAC) inhibitors mitigate WMI after ischemia (6, 7). HDACs allow DNA to be wrapped more tightly around histones, thereby blocking gene transcription and acting in opposition to histone acetyltransferases that promote gene transcription (8, 9). Some HDAC inhibitors preferentially promote the transcription of neuroprotective genes. We...

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supporting

confidence: 89%

Section: Discussionmentioning

confidence: 50%

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HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis

Wang

Shi

Jiang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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313

292

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“…10,35,36 However, long-term dietary supplementation with o-3 PUFAs did not significantly prevent o-3 PUFAs protects against TBI H Pu et al tissue loss at the impact region. Nonetheless, o-3 PUFAs completely abolished neuronal loss in the CA3 region of the hippocampus.…”

Section: Oligodendrocyte Protection Is Mediated Via Direct Effect Andmentioning

confidence: 99%

Omega-3 Polyunsaturated Fatty Acid Supplementation Improves Neurologic Recovery and Attenuates White Matter Injury after Experimental Traumatic Brain Injury

Guo

Zhang

et al. 2013

J Cereb Blood Flow Metab

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100

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Dietary supplementation with omega-3 (o-3) fatty acids is a safe, economical mean of preventive medicine that has shown protection against several neurologic disorders. The present study tested the hypothesis that this method is protective against controlled cortical impact (CCI). Indeed, mice fed with o-3 polyunsaturated fatty acid (PUFA)-enriched diet for 2 months exhibited attenuated short and long-term behavioral deficits due to CCI. Although o-3 PUFAs did not decrease cortical lesion volume, these fatty acids did protect against hippocampal neuronal loss after CCI and reduced pro-inflammatory response. Interestingly, o-3 PUFAs prevented the loss of myelin basic protein (MPB), preserved the integrity of the myelin sheath, and maintained the nerve fiber conductivity in the CCI model. o-3 PUFAs also directly protected oligodendrocyte cultures from excitotoxicity and blunted the microglial activation-induced death of oligodendrocytes in microglia/oligodendrocyte cocultures. In sum, o-3 PUFAs elicit multifaceted protection against behavioral dysfunction, hippocampal neuronal loss, inflammation, and loss of myelination and impulse conductivity. The present report is the first demonstration that o-3 PUFAs protect against white matter injury in vivo and in vitro. The protective impact of o-3 PUFAs supports the clinical use of this dietary supplement as a prophylaxis against traumatic brain injury and other nervous system disorders.

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“…The Morris water maze was performed 22-27 days after tGCI, as previously described (64). Briefly, an 11 cm-diameter platform was submerged in a pool of opaque water.…”

Section: Morris Water Mazementioning

confidence: 99%

Apurinic/Apyrimidinic Endonuclease 1 Upregulation Reduces Oxidative DNA Damage and Protects Hippocampal Neurons from Ischemic Injury

Leak

Li²,

Zhang³

et al. 2015

Antioxidants & Redox Signaling

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Aims: Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme that participates in base-excision repair of oxidative DNA damage and in the redox activation of transcription factors. We tested the hypothesis that APE1 upregulation protects neuronal structure and function against transient global cerebral ischemia (tGCI). Results: Upregulation of APE1 by low-dose proton irradiation (PI) or by transgene overexpression protected hippocampal CA1 neurons against tGCI-induced cell loss and reduced apurinic/apyrimidinic sites and DNA fragmentation. Conversely, APE1 knockdown attenuated the protection afforded by PI and ischemic preconditioning. APE1 overexpression inhibited the DNA damage response, as evidenced by lower phospho-histone H2A and p53-upregulated modulator of apoptosis levels. APE1 overexpression also partially rescued dendritic spines and attenuated the decrease in field excitatory postsynaptic potentials in hippocampal CA1. Presynaptic and postsynaptic markers were reduced after tGCI, and this effect was blunted in APE1 transgenics. The Morris water maze test revealed that APE1 protected against learning and memory deficits for at least 27 days post-injury. Animals expressing DNA repair-disabled mutant APE1 (D210A) exhibited more DNA damage than wild-type controls and were not protected against tGCI-induced cell loss. Innovation: This is the first study that thoroughly characterizes structural and functional protection against ischemia after APE1 upregulation by measuring synaptic markers, electrophysiological function, and long-term neurological deficits in vivo. Furthermore, disabling the DNA repair activity of APE1 was found to abrogate its protective impact. Conclusion: APE1 upregulation, either endogenously or through transgene overexpression, protects DNA, neuronal structures, synaptic function, and behavioral output from ischemic injury. Antioxid. Redox Signal. 22,[135][136][137][138][139][140][141][142][143][144][145][146][147][148]

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Scriptaid, a Novel Histone Deacetylase Inhibitor, Protects Against Traumatic Brain Injury via Modulation of PTEN and AKT Pathway

Cited by 92 publications

References 68 publications

HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis

HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis

Omega-3 Polyunsaturated Fatty Acid Supplementation Improves Neurologic Recovery and Attenuates White Matter Injury after Experimental Traumatic Brain Injury

Apurinic/Apyrimidinic Endonuclease 1 Upregulation Reduces Oxidative DNA Damage and Protects Hippocampal Neurons from Ischemic Injury

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