Valproate-Induced Liver Injury: Modulation by the Omega-3 Fatty Acid DHA Proposes a Novel Anticonvulsant Regimen

Abstract

BackgroundThe polyunsaturated, ω-3 fatty acid, docosahexaenoic acid (DHA), claims diverse cytoprotective potentials, although via largely undefined triggers. Thus, we currently first tested the ability of DHA to ameliorate valproate (VPA)-evoked hepatotoxicity, to modulate its anticonvulsant effects, then sought the cellular and molecular basis of such actions. Lastly, we also verified whether DHA may kinetically alter plasma levels/clearance rate of VPA.Methods and ResultsVPA (500 mg/kg orally for 14 days in rats) evoked prominent hepatotoxicity that appeared as a marked rise (2- to 4-fold) in serum hepatic enzymes (γ-glutamyl transferase [γ-GT], alanine aminotransferase [ALT], and alkaline phosphatase [ALP]), increased hepatic lipid peroxide (LPO) and tumor necrosis factor-alpha (TNFα) levels, as well as myeloperoxidase (MPO) activity (3- to 5-fold), lowering of serum albumin (40 %), and depletion of liver reduced-glutathione (GSH, 35 %). Likewise, histopathologic examination revealed hepatocellular degeneration, replacement by inflammatory cells, focal pericentral necrosis, and micro/macrovesicular steatosis. Concurrent treatment with DHA (250 mg/kg) markedly blunted the elevated levels of liver enzymes, lipid peroxides, TNFα, and MPO activity, while raising serum albumin and hepatic GSH levels. DHA also alleviated most of the cytologic insults linked to VPA. Besides, in a pentylenetetrazole (PTZ) mouse convulsion model, DHA (250 mg/kg) markedly increased the latency in convulsion evoked by VPA, beyond their individual responses. Lastly, pharmacokinetic studies revealed that joint DHA administration did not alter serum VPA concentrations.ConclusionsDHA substantially ameliorated liver injury induced by VPA, while also markedly boosted its pharmacologic effects. DHA manipulated definite cellular machinery to curb liver oxidative stress and inflammation, without affecting VPA plasma levels. Collectively, these protective and synergy profiles for DHA propose a superior VPA-drug combination regimen.

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“…injected with SVP (500 mg/kg) while the normal control group received the vehicle (2.5 ml/kg) for 1 week. The choice of SVP dose has taken into consideration the previous investigations that revealed SVP‐induced remarkable hepatotoxic injury in rodents . The groups were administrated as follows:…”

Study on the influence of caffeic acid against sodium valproate–induced nephrotoxicity in rats

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Drug‐induced liver injury in a chronic hepatitis C patient treated by peginterferon, ribavirin and simeprevir

“…The key CYP‐mediated branch of the VPA pathway is the generation of the metabolite 4‐ene‐VPA by CYP2C9 and CYP2A6, but not CYP3A4 . The feature of VPA‐induced hepatitis is focal pericentric necrosis and periportal microvesicular fatty liver with an elevation of serum ammonia levels because of the inhibition of β‐oxidation by those metabolites . However, these typical features of VPA‐induced hepatitis were not observed in this case.…”