Circadian haematotoxicity of the antiepileptic valproic acid in mice

Ben-Cherif, Wafa; Dridi, Ichrak; Hassine, Mohsen; Ben‐Attia, Mossadok; Aouam, Karim; Reinberg, A; Boughattas, Naceur A.

doi:10.1016/j.jab.2013.04.001

Cited by 4 publications

(1 citation statement)

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“…The drug act by suppressing repetitive neuronal firing through inhibition of voltage sensitive sodium channels. Valproate (VPA) has evidence as a neuroprotective at low doses [23,24,25] however at high doses most common toxicities include: hepatotoxicity [26]; haematotoxicity [27]; nephrotoxicity [28]; neurotoxicity [29], bone marrow suppression [26]; teratogenicity and developmental toxicity [30] and Valproate-induced hyperammonemic encephalopathy (VHE) [31].Valproate-induced hyperammonemic encephalopathy (VHE) is an unusual complication characterized by decreasing level of consciousness, focal neurological and cognitive deficits [32], and increased seizure frequency [33]. This is a form of toxicity peculiar to valproate which eventually leads to brain damage [9].Valproate treatment leads to deficiency in carnitine and also results in diminished mitochondrial function with inhibition of the urea cycle in the liver as metabolism of ammonia occurs primarily via the urea cycle.…”

Section: Introductionmentioning

confidence: 99%

Nauclea latifolia stem-bark extract protects the prefrontal cortex from valproic acid - induced oxidative stress in rats: Effect on B-cell lymphoma and neuron specific enolase protein expression

Nwidu

Oboma

2019

GSC Biol. and Pharm. Sci.

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Nauclea latifolia stem-bark (NLS) is widely utilized for broad spectrum pathologies. The study evaluated the protective effects of NLS extract supplemented along with valproic acid on oxidative stress markers, and neuron specific enolase (NSE) and B cell lymphoma 2 (bcl-2) protein expressions in prefrontal cortex of rats. The NLS extract was administered in three doses (50, 100, 200mg/kg) after pre-treatment of the experimental animals with high dose valproic acid (VPA) (500 mg/kg) orally daily by subacute exposure for 28 days. The rats were sacrificed and the prefrontal cortex (PFC) of the brain abstracted and homogenized in ice for biochemical assays to estimate the levels oxidative stress markers; histopathological examination to reveal the histomorphorgical changes and immunohistochemistry to examine effect on NSE andbcl-2protein expressions. The findings revealed significant (P < 0.05 -0.001) elevation of oxidative stress induced by VPA. The NLS extract supplementation mediate significant elevation of the levels of reduced glutathione (P< 0.05 -0.01), antioxidant enzymes [glutathione peroxidase (P< 0.001), superoxide dismutase (P < 0.001), catalase (P< 0.05 -0.01) and glutathione-s-transferase (P < 0.05 -0.01)] and significant decline of lipid peroxidation marker, malondialdehyde, (NLS group vs diseases control group (P < 0.001). The NLS extract studied down-regulated NSE at the prefrontal cortex preventing neuronal damage but no effect on bcl-2 protein expression. We conclude that NLS extract has potential to mitigate VPA induced neurotoxicity by obliterating oxidative stress and down regulating NSE expression, effects demonstrating probable therapeutic role in neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 99%

Nauclea latifolia stem-bark extract protects the prefrontal cortex from valproic acid - induced oxidative stress in rats: Effect on B-cell lymphoma and neuron specific enolase protein expression

Nwidu

Oboma

2019

GSC Biol. and Pharm. Sci.

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Circadian variation in anticonvulsant activity of valproic acid in mice

Khedhaier

Dridi

Aouam

et al. 2017

Biomedicine & Pharmacotherapy

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Circadian variation of cytotoxicity and genotoxicity induced by an immunosuppressive agent “Mycophenolate Mofetil” in rats

Dridi

Grissa

Ezzi

et al. 2016

Chronobiology International

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Immunosuppressive drugs such as Mycophenolate Mofetil (MMF) are used to suppress the immune system activity in transplant patients and reduce the risk of organ rejection. The present study investigates whether the potential cytotoxicity and genotoxicity varied according to MMF dosing-time in Wistar Rat. A potentially toxic MMF dose (300 mg/kg) was acutely administered by the i.p. route in rats at four different circadian stages (1, 7, 13 and 19 hours after light onset, HALO). Rats were sacrificed 3 days following injection, blood and bone marrow were removed for determination of cytotoxicity and genotoxicity analysis. The genotoxic effect of this pro-drug was investigated using the comet assay and the micronucleus test. Hematological changes were also evaluated according to circadian dosing time. MMF treatment induced a significant decrease at 7 HALO in red blood cells, in the hemoglobin rate and in white blood cells. These parameters followed a circadian rhythm in controls or in treated rats with an acrophase located at the end of the light-rest phase. A significant, thrombocytopenia was observed according to MMF circadian dosing time. Furthermore, abnormally shaped red cells, sometimes containing micronuclei, poikilocytotic in red cells and hypersegmented neutrophil nuclei were observed with MMF treatment. The micronucleus test revealed damage to chromosomes in rat bone marrow; the comet assay showed significant DNA damage. This damage varied according to circadian MMF dosing time. The injection of MMF in the middle of the dark-activity phase produced a very mild hematological toxicity and low genotoxicity. Conversely, it induced maximum hematological toxicity and genotoxicity when the administration occurred in the middle of the light-rest phase, which is physiologically analogous to the end of the activity of the diurnal phase in human patients.

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Circadian haematotoxicity of the antiepileptic valproic acid in mice

Cited by 4 publications

References 54 publications

Nauclea latifolia stem-bark extract protects the prefrontal cortex from valproic acid - induced oxidative stress in rats: Effect on B-cell lymphoma and neuron specific enolase protein expression

Nauclea latifolia stem-bark extract protects the prefrontal cortex from valproic acid - induced oxidative stress in rats: Effect on B-cell lymphoma and neuron specific enolase protein expression

Circadian variation in anticonvulsant activity of valproic acid in mice

Circadian variation of cytotoxicity and genotoxicity induced by an immunosuppressive agent “Mycophenolate Mofetil” in rats

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