Valproic acid preserves motoneurons following contusion in organotypic spinal cord slice culture

Pandamooz, Sareh; Salehi, Mohammad Saied; Nabiuni, Mohammad; Dargahi, Leila

doi:10.1080/10790268.2016.1213518

Cited by 9 publications

(5 citation statements)

References 29 publications

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“…More recently, short-term (24–72 hour) postnatal valproate exposure was associated with wide spread cell death in the brain of mice, including effects observed in the cerebellum and hippocampus [15, 20, 21], suggesting potential wide spread effects on neural development. Interestingly, valproate treatment in adults with spinal muscular atrophy have shown that valproate treatment increases muscle strength and function by increasing survival motor neuron protein [33], as well as preserving motor neurons following injury in in vitro models [34]. Thus, valproate may have complex effects on neural centers involved in motor coordination, with the selectivity and direction of these effects depending upon the timing of drug exposures.…”

Section: Discussionmentioning

confidence: 99%

Effect of early postnatal exposure to valproate on neurobehavioral development and regional BDNF expression in two strains of mice

Bath

Pimentel

2017

Epilepsy & Behavior

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Valproic Acid (Valproate) has been used for over 30 years as a first line treatment for epilepsy. In recent years, prenatal exposure to valproate has been associated with teratogenic effects, limiting its use in women that are pregnant or of childbearing age. However, despite its potential detrimental effects on development, valproate continues to be prescribed at high rates in pediatric populations in some countries. Animal models allow us to test hypotheses regarding the potential effects of postnatal valproate exposure on neurobehavioral development, as well as identify potential mechanisms mediating observed effects. Here, we test the effect of early postnatal (P4-P11) valproate exposure (100mg/kg and 200mg/kg) on motor and affective development in two strains of mice, SVE129 and C57Bl/6N. We also assessed the effect of early valproate exposure on regional BDNF protein levels, a potential target of valproate, and mediator of neurodevelopmental outcomes. We found that early life valproate led to significant motor impairments in both SVE129 and C57Bl/6N mice. Both lines of mice showed significant delays in weight gain, as well as impairments in the righting reflex (P7–8), wire hang (P17), open field (P12 and P21), and rotarod (P25 and P45) tasks. Interestingly, some of the early locomotor effects were strain and dose dependent. We observed no effects of valproate on early markers of anxiety-like behavior. Importantly, early life valproate had significant effects on regional BDNF expression, leading to a near 50% decrease in BDNF levels in the cerebellum of both strains of mice, while not impacting hippocampus BDNF protein levels. These observations indicate that postnatal exposure to valproate may have significant, and region specific effects, on neural and behavioral development, with specific consequences for cerebellar development and motor function.

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Section: Discussionmentioning

confidence: 99%

Effect of early postnatal exposure to valproate on neurobehavioral development and regional BDNF expression in two strains of mice

Bath

Pimentel

2017

Epilepsy & Behavior

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“…Its pharmacological effects involve diverse mechanisms that affect the transmission of nerve signals in vitro and in vivo . VPA is neuroprotective in some neurological diseases 2 , 3 . VPA was also found to decrease the excitation of neurons by N-methyl-D-aspartic acid (NMDA), inhibit voltage-gated sodium (Nav) channels, and modify the firing of neuronal cells 4 .…”

Section: Introductionmentioning

confidence: 99%

Valproate reduces neuroinflammation and neuronal death in a rat chronic constriction injury model

Chu

Cheng

Hsieh

et al. 2018

Sci Rep

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Valproate (VPA) is a well-known drug for treating epilepsy and mania, but its action in neuropathic pain is unclear. We used a chronic constriction injury (CCI) model to explore whether VPA prevents neuropathic pain-mediated inflammation and neuronal death. Rats were treated with or without VPA. CCI + VPA rats were intraperitoneally injected with VPA (300 mg/kg/day) from postoperative day (POD) 1 to 14. We measured paw withdrawal latency (PWL) and paw withdrawal threshold (PWT) 1 day before surgery and 1, 3, 7, 14 days after CCI and harvested the sciatic nerves (SN), spinal cord (SC) and dorsal root ganglia (DRG) on POD 3, 7, and 14. PWL and PWT were reduced in CCI rats, but increased in CCI + VPA rats on POD 7 and POD 14. VPA lowered CCI-induced inflammatory proteins (pNFκB, iNOS and COX-2), pro-apoptotic proteins (pAKT/AKT and pGSK-3β/GSK-3β), proinflammatory cytokines (TNF-α and IL-1β) and nuclear pNFκB activation in the SN, DRG and SC in CCI rats. COX-2 and pGSK-3 proteins were decreased by VPA on immunofluorescence analysis. VPA attenuated CCI-induced thermal and mechanical pain behaviors in rats in correlation with anti-neuroinflammation action involving reduction of pNFκB/iNOS/COX-2 activation and inhibition of pAKT/pGSK-3β-mediated neuronal death from injury to peripheral nerves.

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“…In order to achieve optimum level of regeneration, the cell treatment strategy was combined with VPA administration, a well‐known neuroprotective agent. We defined earlier that adding 5 μM VPA, 1 h after injury in ex vivo spinal cord slice culture can diminish death of majority of cells and preserve neuronal integrity in the first three days post injury . In this regard, 5 μM VPA was applied to attenuate inhospitable context of injury and also provide a better environment for subsequent cell therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Chem. Co., Tehran, Iran and 5 μM concentration was prepared in the complete medium and applied one hour following injury as its effectiveness in the aforementioned injury context was established formerly . The procedure of injured slices treatment was carried out at acute phase and following evaluations were illustrated in Figure B.…”

Section: Methodsmentioning

confidence: 99%

Epidermal neural crest stem cell‐derived glia enhance neurotrophic elements in an ex vivo model of spinal cord injury

Pandamooz

Salehi

Zibaii

et al. 2018

J of Cellular Biochemistry

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Growing evidence that cell-based therapies can improve recovery outcome in spinal cord injury (SCI) models substantiates their application for treatment of human with SCI. To address the effectiveness of these stem cells, potential candidates should be evaluated in proper SCI platform that allows direct real-time monitoring. In this study, the role of epidermal neural crest stem cells (EPI-NCSCs) was elucidated in an ex vivo model of SCI, and valproic acid (VPA) was administered to ameliorate the inhospitable context of injury for grafted EPI-NCSCs. Here the contusion was induced in organotypic spinal cord slice culture at day seven in vitro using a weight drop device and one hour post injury the GFP- expressing EPI-NCSCs were grafted followed by VPA administration. The evaluation of treated slices seven days after injury revealed that grafted stem cells survived on the injured slices and expressed GFAP, whereas they did not express any detectable levels of the neural progenitor marker doublecortin (DCX), which was expressed prior to transplantation. Immunoblotting data demonstrated that the expression of GFAP, BDNF, neurotrophin-3 (NT3), and Bcl2 increased significantly in stem cell treated slices. This study illustrated that the fate of transplanted stem cells has been directed to the glial lineage in the ex vivo context of injury and EPI-NCSCs may ameliorate the SCI condition through releasing neurotrophic factors directly and/or via inducing resident spinal cord cells.

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Valproic acid preserves motoneurons following contusion in organotypic spinal cord slice culture

Cited by 9 publications

References 29 publications

Effect of early postnatal exposure to valproate on neurobehavioral development and regional BDNF expression in two strains of mice

Effect of early postnatal exposure to valproate on neurobehavioral development and regional BDNF expression in two strains of mice

Valproate reduces neuroinflammation and neuronal death in a rat chronic constriction injury model

Epidermal neural crest stem cell‐derived glia enhance neurotrophic elements in an ex vivo model of spinal cord injury

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