Resveratrol Treatment after Status Epilepticus Restrains Neurodegeneration and Abnormal Neurogenesis with Suppression of Oxidative Stress and Inflammation

Abstract

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.

Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus

“…Protracted and orchestrated hyperactivity of multiple populations of neurons typically lead to continuous seizures or SE, which cause excitotoxic neurodegeneration and neuroinflammation associated with an increase in the concentration of multiple proinflammatory cytokines and activation of microglia (5,35,36). In this study, IN treatment with A1-exosomes 2 h after SE resulted in their targeting into the hippocampus within 6 h of administration, which seemed to provide considerable protection to glutamatergic neurons and GABAergic interneurons in the hippocampus.…”

“…The antiinflammatory effects of A1-exosome treatment were also accompanied by robust neuroprotection, epitomized by diminished loss of neurons in the DH and the CA1 pyramidal cell layer, two regions in the hippocampus that typically display increased vulnerability to SE-induced neuronal death (5,40,41). Moreover, IN administration of A1-exosomes after SE promoted preservation of subclasses of GABAergic interneurons, particularly those expressing PV and SS.…”

“…We investigated whether IN administration of A1-exosomes after SE would result in targeting of these exosomes into the hippocampus, the region exhibiting intense hyperactivity of neurons, increased oxidative stress, and inflammation with infiltration of peripheral monocytes during and/or after SE (5,12). We administered PKH26-labeled A1-exosomes via IN route (15 μg, ∼7.5 × 10 9 ) immediately after the termination of 2 h of SE by an injection of diazepam.…”

“…It can produce substantial neurodegeneration, blood-brain barrier disruption, and inflammation in the hippocampus if not extinguished quickly by antiepileptic drug (AED) treatment (3)(4)(5). An episode of extended SE is sufficient to cause chronic hippocampus dysfunction, exemplified by persistent inflammation with activation of microglia and monocyte infiltration, loss of sizable fractions of several subclasses of inhibitory interneurons, aberrant and waned neurogenesis, hippocampus-dependent cognitive and memory impairments, and chronic epilepsy (5)(6)(7)(8)(9)(10)(11)(12). Numerous situations such as head trauma, stroke, Alzheimer's disease, brain tumor, and encephalitis can engender SE.…”

Antioxidant treatment after epileptogenesis onset prevents comorbidities in rats sensitized by a past stressful event

“…Thus, in the SDL group, SE will occur in a context of oxidative stress. Because there is a tight relationship between ROS accumulation and epilepsy, we reasoned that SE should amplify oxidative stress in the SDL group, and tested whether the antioxidant treatment would prevent excessive ROS accumulation. We first assessed the antioxidant/detoxifying systems in animals 6 weeks after SE (Figure C).…”