Retracted: Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy

Abstract

Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients. There are no treatments for modifying the disease-preventing seizure onset, reducing severity or improving prognosis. Among the potential molecular targets for attaining these unmet therapeutic needs, we focused on oxidative stress since it is a pathophysiological process commonly occurring in experimental epileptogenesis and observed in human epilepsy. Using a rat model of acquired epilepsy induced by electrical status epilepticus, we show that oxidative stress occurs in both neurons and astrocytes during epileptogenesis, as assessed by measuring biochemical and histological markers. This evidence was validated in the hippocampus of humans who died following status epilepticus. Oxidative stress was reduced in animals undergoing epileptogenesis by a transient treatment with N-acetylcysteine and sulforaphane, which act to increase glutathione levels through complementary mechanisms. These antioxidant drugs are already used in humans for other therapeutic indications. This drug combination transiently administered for 2 weeks during epileptogenesis inhibited oxidative stress more efficiently than either drug alone. The drug combination significantly delayed the onset of epilepsy, blocked disease progression between 2 and 5 months post-status epilepticus and drastically reduced the frequency of spontaneous seizures measured at 5 months without modifying the average seizure duration or the incidence of epilepsy in animals. Treatment also decreased hippocampal neuron loss and rescued cognitive deficits. Oxidative stress during epileptogenesis was associated with de novo brain and blood generation of disulfide high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms. Drug-induced reduction of oxidative stress prevented disulfide HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Our data show that targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes. This intervention may be considered for patients exposed to potential epileptogenic insults.

A combination of NMDA and AMPA receptor antagonists retards granule cell dispersion and epileptogenesis in a model of acquired epilepsy

“…Only few previous studies have evaluated rationally chosen drug combinations for antiepileptogenic effects and most of these studies used antiinflammatory or antioxidant drug combinations 52 – 56 . Prompted by previous studies that showed synergistic anticonvulsant interactions of NMDA and AMPA receptor antagonists in the kindling model of TLE (see Introduction), we evaluated whether such combination provides antiepileptogenic or disease-modifying effects in the intrahippocampal kainate model of TLE.…”

Metabolic Dysfunction and Oxidative Stress in Epilepsy

“…In fact, treatment with various compounds that act to decrease oxidative stress (antioxidants, NADPH oxidase inhibitors, etc.) have been demonstrated to protect against seizure-induced neuronal death [ 24 , 99 , 100 , 101 , 105 , 106 ]. Neuronal death, particularly in the hippocampus, is a common feature of acquired epilepsy and is thought to contribute to cognitive dysfunction [ 107 ].…”

Metabolic and Homeostatic Changes in Seizures and Acquired Epilepsy—Mitochondria, Calcium Dynamics and Reactive Oxygen Species

“…Sulforaphane also suppressed the progression of amygdala kindling, and also ameliorated the cognitive impairment induced by epileptic seizure [ 142 ]. An interesting approach was chosen in a recent study by Pauletti and colleagues [ 143 ] where they combined the Nrf2 inducer sulforaphane with N -acetylcysteine treatment with the rationale that these mechanisms are complementary in increasing glutathione levels, as glutathione is one of the main intracellular antioxidants and thus one of the most potent ROS scavengers within the brain. Sulforaphane at high doses (>100 mg/kg) was shown to lead to sedation, hypothermia, impairment of motor coordination, decrease in skeletal muscle strength, and deaths in addition to offsite effects such as leucopenia [ 144 ].…”

“…Nrf2 activation boosts ROS scavengers, but was more recently found to have an effect on ROS producing enzymes such as the NADPH oxidase. Further characterization of this interaction will help to design ideal drug targets and allow for combinations of approaches such as have been recently advocated [ 143 ] to combat seizure induced ROS. These are one of the main events leading to cell death and continuous seizures during seizure activity and thus contribute to epilepsy and epilepsy comorbidities.…”