stilbenes and Status-Epilepticus

Resveratrol (RESV; 3,5,4'-tri-hydroxy stilbene), a naturally occurring phytoalexin, is found at a high concentration in the skin of red grapes and red wine. RESV mediates a wide-range of biological activities, which comprise an increased life span, anti-ischemic, anti-cancer, antiviral, anti-aging and anti-inflammatory properties. Studies in several animal prototypes of brain injury suggest that RESV is an effective neuroprotective compound. Ability to enter the brain after a peripheral administration and no adverse effects on the brain or body are other features that are appealing for using this compound as a therapy for brain injury or neurodegenerative diseases. The goal of this review is to discuss the promise of RESV for treating acute seizures, preventing the acute seizure or status epilepticus induced development of chronic epilepsy, and easing the chronic epilepsy typified by spontaneous recurrent seizures and cognitive dysfunction. First, the various beneficial effects of RESV on the normal brain are discussed to provide a rationale for considering RESV treatment in the management of acute seizures and epilepsy. Next, the detrimental effects of acute seizures or status epilepticus on the hippocampus and the implications of post-status epilepticus changes in the hippocampus towards the occurrence of chronic epilepsy and cognitive dysfunction are summarized. The final segment evaluates studies that have used RESV as a neuroprotective compound against seizures, and proposes studies that are critically needed prior to the clinical application of RESV as a prophylaxis against the development of chronic epilepsy and cognitive dysfunction after an episode of status epilepticus or head injury.

Topics: Animals; Epilepsy; Hippocampus; Humans; Resveratrol; Seizures; Status Epilepticus; Stilbenes

Antiepileptic drug therapy, though beneficial for restraining seizures, cannot thwart status epilepticus (SE) induced neurodegeneration or down-stream detrimental changes. We investigated the efficacy of resveratrol (RESV) for preventing SE-induced neurodegeneration, abnormal neurogenesis, oxidative stress and inflammation in the hippocampus. We induced SE in young rats and treated with either vehicle or RESV, commencing an hour after SE induction and continuing every hour for three-hours on SE day and twice daily thereafter for 3 days. Seizures were terminated in both groups two-hours after SE with a diazepam injection. In contrast to the vehicle-treated group, the hippocampus of animals receiving RESV during and after SE presented no loss of glutamatergic neurons in hippocampal cell layers, diminished loss of inhibitory interneurons expressing parvalbumin, somatostatin and neuropeptide Y in the dentate gyrus, reduced aberrant neurogenesis with preservation of reelin + interneurons, lowered concentration of oxidative stress byproduct malondialdehyde and pro-inflammatory cytokine tumor necrosis factor-alpha, normalized expression of oxidative stress responsive genes and diminished numbers of activated microglia. Thus, 4 days of RESV treatment after SE is efficacious for thwarting glutamatergic neuron degeneration, alleviating interneuron loss and abnormal neurogenesis, and suppressing oxidative stress and inflammation. These results have implications for restraining SE-induced chronic temporal lobe epilepsy.

Topics: Animals; Behavior, Animal; Cell Adhesion Molecules, Neuronal; Cell Death; Cognition; Extracellular Matrix Proteins; GABAergic Neurons; Gene Expression Regulation; Hippocampus; Inflammation; Interneurons; Longevity; Male; Microglia; Nerve Degeneration; Nerve Tissue Proteins; Neurogenesis; Neuropeptide Y; Oxidative Stress; Parvalbumins; Rats, Inbred F344; Reelin Protein; Resveratrol; Seizures; Serine Endopeptidases; Somatostatin; Status Epilepticus; Stilbenes; Tumor Necrosis Factor-alpha

In adult rats, trans-resveratrol attenuates kainic acid (KA)-induced convulsions and the associated hippocampal neurotoxicity. Increased neuronal survival was correlated with reduced lipid peroxidation. Since free radical generation after KA is age dependent and does not correlate with the onset of seizure-induced injury, the present study investigated whether daily trans-resveratrol treatment in development could protect the juvenile hippocampus from seizures and onset of damage at postnatal (P) day 21. Rat pups were treated with daily injections of trans-resveratrol under three dosage regimens (1-15 mg/kg and 20-50mg/kg). Weight, electroencephalography (EEG), histology, and N-methyl-d-aspartate (NMDA) receptor expression were determined. Malondialdehyde (MDA) concentration was assessed from separate animals. trans-Resveratrol did not interfere with growth or attenuate KA-induced EEG seizures. However, modest protection was afforded in the CA1, the subregion most sensitive to injury at this age. The CA3 and entorhinal amygdala cortex (AMG/EC) were not spared. Changes in NR1 subunit or NR1 C2 splice variant expression were also not prevented. Baseline MDA concentrations of hippocampal subfields were low at P14, P21, and P60 and high in aged adults. Glutamate (100 μM) to stimulate peroxidation products was significant at young ages but was much greater at older ages. After KA, elevated MDA levels were observed at 24h but only in adult preparations. Thus, while antioxidant therapy with trans-resveratrol may be considered as an adjunctive therapy to hinder epileptic activity and neurodegeneration at adult ages, it had only modest effects at young ages when production of free radicals within limbic structures is limited in this experimental model of seizures.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Body Weight; Brain Waves; Cell Count; Disease Models, Animal; Electroencephalography; Excitatory Amino Acid Agonists; Female; Gene Expression Regulation, Developmental; Hippocampus; Kainic Acid; Lipid Peroxidation; Male; Malondialdehyde; Neuroprotective Agents; Phosphopyruvate Hydratase; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Resveratrol; Status Epilepticus; Stilbenes

Resveratrol is indicated to be involved in neuroprotection and anti-inflammation in epileptic rats. The molecular mechanism is still not fully understood. In this study, we investigated the role of resveratrol in nuclear factor-kappa B associated inflammatory responses induced by status epilepticus. Our data showed that seizures activated mammalian target of rapamycin (mTOR), increased the activity of nuclear factor-kappa B and promoted the expressions of inflammatory molecules including inducible nitric oxide synthase, cyclooxygenase-2 and interleukin-1β. Futhermore, resveratrol significantly inhibited the activation of nuclear factor-kappa B and the production of proinflammatory molecules via mTOR pathway. Additionally, we also proved that the inhibition of mTOR signal by resveratrol was mostly attributed to AMP-activated kinase (AMPK) activation. Altogether, our results suggest that resveratrol suppresses inflammatory responses induced by seizures partially via AMPK/mTOR pathway.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Hippocampus; Inflammation; Male; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Status Epilepticus; Stilbenes; TOR Serine-Threonine Kinases