Preclinical toxicology of the anticonvulsant calcium valproate

Walker, Robin M.; Smith, Graham; Barsoum, N. J.; Macallum, Grace E.

doi:10.1016/0300-483x(90)90038-i

Cited by 42 publications

(31 citation statements)

References 43 publications

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“…Consistent with previous work, 9 VPA administration by itself failed to induce pancreatic injury; in the setting of injury, however, VPA delayed recovery. This is also the first demonstration of the practical application of a newly developed digital image analysis tool that uses machine-learning algorithms to reliably quantify acinar content from standard H&E-stained pancreatic sections.…”

Section: Discussionsupporting

confidence: 89%

“…7,8 However, long-term administration of VPA (for 1 year) to mice and dogs had no effect on the pancreas, and in rats, there were only subtle microscopic findings of pancreatic lobular atrophy and vacuolization. 9 Short-term exposure to VPA by itself failed to induce any pancreatic changes in these animals. It is unclear whether VPA in combination with other inducers would predispose to pancreatitis.…”

mentioning

confidence: 83%

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Valproic Acid Limits Pancreatic Recovery after Pancreatitis by Inhibiting Histone Deacetylases and Preventing Acinar Redifferentiation Programs

Eisses

Criscimanna

Dionise

et al. 2015

The American Journal of Pathology

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The mechanisms by which drugs induce pancreatitis are unknown. A definite cause of pancreatitis is due to the antiepileptic drug valproic acid (VPA). On the basis of three crucial observationsdthat VPA inhibits histone deacetylases (HDACs), HDACs mediate pancreas development, and aspects of pancreas development are recapitulated during recovery of the pancreas after injurydwe hypothesized that VPA does not cause injury on its own, but it predisposes patients to pancreatitis by inhibiting HDACs and provoking an imbalance in pancreatic recovery. In an experimental model of pancreatic injury, we found that VPA delayed recovery of the pancreas and reduced acinar cell proliferation. In addition, pancreatic expression of class I HDACs (which are the primary VPA targets) increased in the midphase of pancreatic recovery. VPA administration inhibited pancreatic HDAC activity and led to the persistence of acinar-to-ductal metaplastic complexes, with prolonged Sox9 expression and sustained b-catenin nuclear activation, findings that characterize a delay in regenerative reprogramming. These effects were not observed with valpromide, an analog of VPA that lacks HDAC inhibition. This is the first report, to our knowledge, that VPA shifts the balance toward pancreatic injury and pancreatitis through HDAC inhibition. The work also identifies a new paradigm for therapies that could exploit epigenetic reprogramming to enhance pancreatic recovery and disorders of pancreatic injury. We have recently gained a greater appreciation that the pancreas has a tremendous ability to recover and regenerate after injury.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 83%

Valproic Acid Limits Pancreatic Recovery after Pancreatitis by Inhibiting Histone Deacetylases and Preventing Acinar Redifferentiation Programs

Eisses

Criscimanna

Dionise

et al. 2015

The American Journal of Pathology

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“…However, the use of such high doses in mice has been justified, since it reproduced the plasma concentrations that are normally measured in patients treated with therapeutic doses of VPA [8, 38, 39]. Furthermore, VPA had previously failed to induce any changes in the body weights of Swiss CF1 mice despite the use of even higher dose of valproate (800 mg/kg) that was used over a period of 2 or 13 weeks [40]. Similarly, VPA had no effects on body weight or food intake in albino CD rats when various doses were used (up to 1,600 mg/kg) over a 2-week period, and when rats were treated chronically (13 or 52 weeks) they even had a tendency to lose weight [40].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, VPA had previously failed to induce any changes in the body weights of Swiss CF1 mice despite the use of even higher dose of valproate (800 mg/kg) that was used over a period of 2 or 13 weeks [40]. Similarly, VPA had no effects on body weight or food intake in albino CD rats when various doses were used (up to 1,600 mg/kg) over a 2-week period, and when rats were treated chronically (13 or 52 weeks) they even had a tendency to lose weight [40]. Clearly, rodents are much more resistant to the metabolic effects associated with VPA treatment than humans.…”

Section: Discussionmentioning

confidence: 99%

Valproic Acid and CEBPα-Mediated Regulation of Adipokine Gene Expression in Hypothalamic Neurons and 3T3-L1 Adipocytes

Brown¹,

Imran²,

Ur³

et al. 2008

Neuroendocrinology

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Background/Aims: Valproic acid (VPA) is the drug of choice for treating epilepsy, but has the unwanted effects of inducing weight gain and increasing the risk of developing insulin resistance. The mechanism through which these side effects occur is unknown. VPA inhibits histone deacetylase (HDAC), but also decreases the transcriptional activity of CCAAT enhancer binding protein α (CEBPα). Given the possible association between VPA, CEBPα and adipokine gene regulation, we hypothesized that they would alter the expression of resistin (rstn), fasting-induced adipose factor (fiaf) and suppressor of cytokine signaling-3 (socs-3), genes implicated in the development of leptin and insulin resistance. Methods: We investigated the effects of VPA (1 mM; 24 or 48 h) on gene expression using real-time RT-PCR in 3 distinct models: N-1 hypothalamic neurons, 3T3-L1 adipocytes and male CD-1 mice. Subsequently, cells were treated with 5 nM of the more specific HDAC inhibitor trichostatin A (TSA). CEBPα expression was also modified in N-1 neurons using either RNA interference (RNAi) or an overexpression vector to evaluate its effects on target gene expression. Results: In N-1 neurons, VPA induced significant increases in CEBPα and socs-3, but inhibited rstn and fiaf gene expression. In contrast, TSA induced rstn and socs-3, but inhibited fiaf. VPA also induced the expression of CEBPαin 3T3-L1 adipocytes, but had no effect on other target genes, and TSA suppressed fiaf and socs-3.Subsequently, CEBPα was overexpressed (24 h) or silenced using RNAi (24 and 48 h) in N-1 neurons. The silencing of CEBPα led to significant decreases in rstn mRNA, but increased fiaf and socs-3 expression, whereas its overexpression had the opposite effect. When male CD-1 mice were treated with either a single (100 mg/kg; 24 h), or multiple (200 mg/kg; 72 h) daily injections of VPA, no changes in body weight or gene expression were detected in either hypothalamic or adipose tissues. Conclusions: In summary, these experiments reveal a potentially important role for CEBPα in the regulation of hypothalamic gene expression in N-1 neurons and suggest that it might modulate central energy metabolism. Although VPA also modified hypothalamic gene expression in vitro, it remains to be determined whether it has similar effects in vivo.

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“…9 These findings indicate that this level of valproate supplementation is subsymptomatic, which is consistent with previous preclinical analysis of valproate toxicity in rodents. 36 When dietary levels of sodium valproate were increased to 1250 mg/kg chow, corresponding plasma valproate levels increased to 131.4 Ϯ 10.1 mol/L. This level of supplementation did correspond to a significant decrease in plasma glucose levels in STZ-treated apoE Ϫ/Ϫ mice (from 23.2 Ϯ 5.6 to 13.1 Ϯ 2.0 mmol/L, P Ͻ 0.05).…”

Section: Effect Of Hyperglycemia and Dietary Valproate Supplementatiomentioning

confidence: 93%

Valproate Attenuates Accelerated Atherosclerosis in Hyperglycemic ApoE-Deficient Mice

Bowes

Khan

Shi

et al. 2009

The American Journal of Pathology

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We have previously shown that glucosamine promotes endoplasmic reticulum (ER) stress in vascular cells leading to both inflammation and lipid accumulation-the hallmark features of atherosclerosis. Pretreatment with glycogen synthase kinase (GSK)-3 inhibitors protects cultured cells from ER stress-induced dysfunction. Here we evaluate the potential role of GSK-3 on the pro-atherogenic effects of hyperglycemia and ER stress. We show that GSK-3-deficient mouse embryonic fibroblasts do not accumulate unesterified cholesterol under conditions of ER stress. Furthermore, GSK-3 inhibitors, including valproate, attenuate ER stress-induced unesterified cholesterol accumulation in wild-type mouse embryonic fibroblasts. In vivo we show that hyperglycemic apoE-deficient mice have accelerated atherogenesis at the aortic root compared with normoglycemic control mice. Mice fed a diet supplemented with 625 mg/kg valproate have significantly reduced lesion volume relative to nonsupplemented controls. Valproate supplementation has no apparent effect on the plasma levels of either glucose or lipids or on the expression of diagnostic markers of ER stress in the lesion. Significant reductions were observed in total hepatic lipids (>50.4%) and hepatic GSK-3␤ activity (>55.8%) in mice fed the valproate diet.

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Preclinical toxicology of the anticonvulsant calcium valproate

Cited by 42 publications

References 43 publications

Valproic Acid Limits Pancreatic Recovery after Pancreatitis by Inhibiting Histone Deacetylases and Preventing Acinar Redifferentiation Programs

Valproic Acid Limits Pancreatic Recovery after Pancreatitis by Inhibiting Histone Deacetylases and Preventing Acinar Redifferentiation Programs

Valproic Acid and CEBPα-Mediated Regulation of Adipokine Gene Expression in Hypothalamic Neurons and 3T3-L1 Adipocytes

Valproate Attenuates Accelerated Atherosclerosis in Hyperglycemic ApoE-Deficient Mice

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