Combined cell grafting and VPA administration facilitates neural repair through axonal regeneration and synaptogenesis in traumatic brain injury

Liu, Sujuan; Tian, Haili; Niu, Yanmei; Yu, Chunxia; Xie, Lingjian; Jin, Zhe; Niu, Wenyan; Ren, Jing; Li, Fu; Liu, Yang

doi:10.3724/abbs.2022123

“…Many medications are currently available to modulate cerebral excitation, several of which have been studied in TBI [ 72 , 73 ]. As part of a pharmacologic treatment protocol, combinations of anti-excitatory medications, including valproic acid, ketamine, perampanel, MK801, felbamate, and levetiracetam, have shown promise in reducing blood–brain barrier (BBB) disruption, expression of pro-inflammatory genes and cytokines, lesion volume, neuronal death, and functional deficits in preclinical TBI models [ 18 , 23 , 24 , 44 , 56 ]. Valproic acid inhibits sodium channels involved in excitatory neurotransmission, as well as increasing levels of the inhibitory neurotransmitter GABA in the CNS, making it useful in targeting the hyperacute post-synaptic excitation [ 74 ].…”

Section: Resultsmentioning

confidence: 99%

Multi-Mechanistic Approaches to the Treatment of Traumatic Brain Injury: A Review

Lynch

¹

,

Narayan

²

,

Li

³

2023

JCM

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Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Despite extensive research efforts, the majority of trialed monotherapies to date have failed to demonstrate significant benefit. It has been suggested that this is due to the complex pathophysiology of TBI, which may possibly be addressed by a combination of therapeutic interventions. In this article, we have reviewed combinations of different pharmacologic treatments, combinations of non-pharmacologic interventions, and combined pharmacologic and non-pharmacologic interventions for TBI. Both preclinical and clinical studies have been included. While promising results have been found in animal models, clinical trials of combination therapies have not yet shown clear benefit. This may possibly be due to their application without consideration of the evolving pathophysiology of TBI. Improvements of this paradigm may come from novel interventions guided by multimodal neuromonitoring and multimodal imaging techniques, as well as the application of multi-targeted non-pharmacologic and endogenous therapies. There also needs to be a greater representation of female subjects in preclinical and clinical studies.

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“…For example, it has been known that VPA promotes hippocampal neurogenesis and cell proliferation via the Wnt/β-catenin signaling pathway in the transgenic mouse model of Alzheimer’s diseases [ 65 ], Parkinson’s disease [ 66 ], and amyotrophic lateral sclerosis [ 66 , 67 ]. In addition, VPA has been reported to induce synaptogenesis, axonal regeneration, and synaptic plasticity in the mice model of traumatic brain injury [ 68 ]. Several studies have been reported that Wnt regulators have been used as potential drugs for cancer treatment [ 1 , 16 , 69 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of HDAC inhibitors on neuroblastoma SH-SY5Y cell differentiation into mature neurons via the Wnt signaling pathway

Choi

¹

,

Hwang

²

,

Mahesh

³

et al. 2023

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Histone deacetylase (HDAC) inhibitors affect cell homeostasis, gene expression, and cell cycle progression and promote cell terminal differentiation or apoptosis. However, the effect of HDAC inhibition on SH-SY5Y cells, which are neuroblastoma cells capable of differentiating into neurons under specific conditions, such as in the presence of retinoic acid (RA), is unknown. In this study, we hypothesized that HDAC inhibitors induced the neuronal differentiation of SH-SY5Y cells. To test this hypothesis, we used phase contrast microscopy, immunocytochemistry (ICC), qPCR, and western blotting analysis. MS-275 and valproic acid (VPA), two HDAC inhibitors, were selected to evaluate neuronal differentiation. It was confirmed that cells treated with MS-275 or VPA differentiated into mature neurons, which were distinguished by bipolar or multipolar morphologies with elongated branches. In addition, the mRNA expression of neuronal markers (Tuj1 and NEFH) and the oligodendrocyte marker (CNP) was significantly increased with MS-275 or VPA treatment compared to that with RA treatment. In addition, the protein expression of the other neuronal markers, Tuj1 and NeuN, was highly increased with HDAC inhibitor treatments compared to that with RA treatment. Furthermore, we confirmed that noncanonical Wnt signaling was upregulated by HDAC inhibitors via MAPK signaling and the Wnt/JNK pathway. Therefore, both MS-275 and VPA promoted the differentiation of SH-SY5Y cells into mature neurons via the Wnt signaling pathway.

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“…Many medications are currently available to modulate cerebral excitation, several of which have been studied in TBI [29,30]. As part of a pharmacologic treatment protocol, combinations of antiexcitatory medications including valproic acid, ketamine, perampanel, MK801, felbamate and levetiracetam have shown promise in reducing blood-brain barrier (BBB) disruption, expression of pro-inflammatory genes and cytokines, lesion volume, neuronal death and functional deficits in preclinical TBI models [31][32][33][34][35]. Valproic acid inhibits sodium channels involved in excitatory neurotransmission, as well as increasing levels of the inhibitory neurotransmitter GABA in the CNS, making it useful in targeting the hyperacute post-synaptic excitation [36].…”

Section: Anti-excitatory Treatmentsmentioning

confidence: 99%

Multi-mechanistic Approaches to the Treatment of Traumatic Brain Injury: A Review

Lynch¹,

Narayan²,

Li³

2023

Preprint

3

0

View full text Add to dashboard Cite

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Despite extensive research efforts, the majority of trialed monotherapies to date have failed to demonstrate significant benefit. It has been suggested that this is due to the complex pathophysiology of TBI, which may possibly be addressed by a combination of therapeutic interventions. In this article, we have reviewed combinations of different pharmacologic treatments, combinations of non-pharmacologic interventions, and combined pharmacologic and non-pharmacologic interventions for TBI. Both preclinical and clinical studies have been included. While promising results have been found in animal models, clinical trials of combination therapies have not yet shown clear benefit. This may possibly be due to their application without consideration of the evolving pathophysiology of TBI. Improvements of this paradigm may come from novel interventions guided by multimodal neuromonitoring and multimodal imaging techniques, as well as the application of multi-targeted non-pharmacologic and endogenous therapies. There also needs to be a greater representation of female subjects in preclinical and clinical studies.

show abstract

Combined cell grafting and VPA administration facilitates neural repair through axonal regeneration and synaptogenesis in traumatic brain injury

Cited by 4 publications

References 50 publications

Multi-Mechanistic Approaches to the Treatment of Traumatic Brain Injury: A Review

Multi-Mechanistic Approaches to the Treatment of Traumatic Brain Injury: A Review

Effects of HDAC inhibitors on neuroblastoma SH-SY5Y cell differentiation into mature neurons via the Wnt signaling pathway

Multi-mechanistic Approaches to the Treatment of Traumatic Brain Injury: A Review

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