GABAergic interneurons in epilepsy: More than a simple change in inhibition

Marafiga, Joseane Righes; Pasquetti, Mayara Vendramin; Calcagnotto, María Elisa

doi:10.1016/j.yebeh.2020.106935

Cited by 58 publications

(30 citation statements)

References 141 publications

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“…Similarly, the ion channels are also reported to be dysfunctional in epilepsy-inducing seizures [35]. Zingerone has prevented the ion channel disruptions, as previously reported by Hosseini and Mirazi [33]. However, the exact mentioned mechanism by which zingerone acts in the present model of epilepsy is not clear and needs further study.…”

Section: Discussionsupporting

confidence: 70%

“…The effect of zingerone in altering epileptogenesis could be attributed to its role in decreasing stimulatory neural transmission, elevating GABAergic activity, and perturbing ionchannel activity, as reported previously [28][29][30][31][32]. In the case of epileptogenesis, there are reports of decreased GABAergic activity of neurons leading to seizures [33]. Zingerone has been previously reported in the seizure model of mice to enhance the GABAergic activity by an increase in the Ca ++ influx through ionophores of presynaptic 5HT3 receptors causing an anticonvulsant effect [34].…”

Section: Discussionmentioning

confidence: 55%

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Zingerone Targets Status Epilepticus by Blocking Hippocampal Neurodegeneration via Regulation of Redox Imbalance, Inflammation and Apoptosis

et al. 2021

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Epilepsy is an intricate neurological disease where the neurons are severely affected, leading to the mortality of millions worldwide. Status epilepticus (SE), induced by lithium chloride (LiCl) and pilocarpine, is the most accepted model for epilepsy. The current work aims to unravel the mechanisms underlying the anti-epileptic efficacy of zingerone (an active ingredient of ginger), which has beneficial pharmacological activities on seizure-induced behavioral, histological, neurochemical, and molecular patterns in mice. Zingerone restored cognitive function by diminishing seizure activity, escape latency, and subsequent hippocampal damage manifested in histology. Seizures are associated with local inflammation, redox imbalance, and neural loss, confirmed by the present study of SE, and was attenuated by zingerone treatment. Nuclear factor-kappa B and its downstream signaling molecules (TNF-α, IL-1β, IL-6, NO, MPO) were activated in the LiCl-and-pilocarpine-induced group leading to inflammatory signaling, which was substantially ameliorated by zingerone treatment. The intrinsic apoptotic process was triggered subsequent to SE, as demonstrated by augmentation of cleaved caspase-3, downregulation of Bcl-2. However, zingerone treatment downregulated caspase-3 and upregulated Bcl-2, increasing cell survival and decreasing hippocampal neural death, deciphering involvement of apoptosis in SE. Therefore, zingerone plays an essential role in neuroprotection, probably by precluding oxidative stress, inflammation, and obstructing the mitochondrial pathway of apoptosis.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 55%

Zingerone Targets Status Epilepticus by Blocking Hippocampal Neurodegeneration via Regulation of Redox Imbalance, Inflammation and Apoptosis

et al. 2021

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“…GABAergic interneurons exhibit a remarkable diversity in morphology, electrical discharge properties, and molecular marker expression patterns (61,62). We identified PVALB + interneurons as a key player in epileptogenesis, as the deletion of 4E-BP2 in PVALB + interneurons but not in other subtypes, is sufficient to promote epileptogenesis.…”

Section: Discussionmentioning

confidence: 94%

4E-BP2–dependent translation in parvalbumin neurons controls epileptic seizure threshold

Sharma

Sood

Lou

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals to regulate critical cellular processes such as mRNA translation, lipid biogenesis, and autophagy. Germline and somatic mutations in mTOR and genes upstream of mTORC1, such as PTEN, TSC1/2, AKT3, PIK3CA, and components of GATOR1 and KICSTOR complexes, are associated with various epileptic disorders. Increased mTORC1 activity is linked to the pathophysiology of epilepsy in both humans and animal models, and mTORC1 inhibition suppresses epileptogenesis in humans with tuberous sclerosis and animal models with elevated mTORC1 activity. However, the role of mTORC1-dependent translation and the neuronal cell types mediating the effect of enhanced mTORC1 activity in seizures remain unknown. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2) are translational repressors downstream of mTORC1. Here we show that the ablation of 4E-BP2, but not 4E-BP1, in mice increases the sensitivity to pentylenetetrazole (PTZ)- and kainic acid (KA)–induced seizures. We demonstrate that the deletion of 4E-BP2 in inhibitory, but not excitatory neurons, causes an increase in the susceptibility to PTZ-induced seizures. Moreover, mice lacking 4E-BP2 in parvalbumin, but not somatostatin or VIP inhibitory neurons exhibit a lowered threshold for seizure induction and reduced number of parvalbumin neurons. A mouse model harboring a human PIK3CA mutation that enhances the activity of the PI3K-AKT pathway (Pik3caH1047R-Pvalb) selectively in parvalbumin neurons shows susceptibility to PTZ-induced seizures. Our data identify 4E-BP2 as a regulator of epileptogenesis and highlight the central role of increased mTORC1-dependent translation in parvalbumin neurons in the pathophysiology of epilepsy.

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“…In turn, system Xc − is a glutamate/cysteine antiporter, hence elevated extracellular glutamate concentrations in epilepsy could not only promote excitotoxicity but also facilitate ferroptosis [ 80 ]. While the exact cell-death mechanism of pyknotic neurons in TLE-HS is unclear, previous studies demonstrated that specifically hilar GABAergic neurons, a neuronal subtype whose dysfunction is supposed to play a pro-epileptogenic role in patients with TLE and animal models of acquired epilepsy, seem to be highly sensitive to ferroptosis [ 16 , 32 , 66 , 90 ]. A protective response of the brain might require upregulation of the catalytic subunit of system Xc − , xCT, for sufficient glutathione synthesis.…”

Section: Discussionmentioning

confidence: 99%

Seizure-mediated iron accumulation and dysregulated iron metabolism after status epilepticus and in temporal lobe epilepsy

et al. 2021

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Neuronal dysfunction due to iron accumulation in conjunction with reactive oxygen species (ROS) could represent an important, yet underappreciated, component of the epileptogenic process. However, to date, alterations in iron metabolism in the epileptogenic brain have not been addressed in detail. Iron-related neuropathology and antioxidant metabolic processes were investigated in resected brain tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE-HS), post-mortem brain tissue from patients who died after status epilepticus (SE) as well as brain tissue from the electrically induced SE rat model of TLE. Magnetic susceptibility of the presumed seizure-onset zone from three patients with focal epilepsy was compared during and after seizure activity. Finally, the cellular effects of iron overload were studied in vitro using an acute mouse hippocampal slice preparation and cultured human fetal astrocytes. While iron-accumulating neurons had a pyknotic morphology, astrocytes appeared to acquire iron-sequestrating capacity as indicated by prominent ferritin expression and iron retention in the hippocampus of patients with SE or TLE. Interictal to postictal comparison revealed increased magnetic susceptibility in the seizure-onset zone of epilepsy patients. Post-SE rats had consistently higher hippocampal iron levels during the acute and chronic phase (when spontaneous recurrent seizures are evident). In vitro, in acute slices that were exposed to iron, neurons readily took up iron, which was exacerbated by induced epileptiform activity. Human astrocyte cultures challenged with iron and ROS increased their antioxidant and iron-binding capacity, but simultaneously developed a pro-inflammatory phenotype upon chronic exposure. These data suggest that seizure-mediated, chronic neuronal iron uptake might play a role in neuronal dysfunction/loss in TLE-HS. On the other hand, astrocytes sequester iron, specifically in chronic epilepsy. This function might transform astrocytes into a highly resistant, pro-inflammatory phenotype potentially contributing to pro-epileptogenic inflammatory processes.

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GABAergic interneurons in epilepsy: More than a simple change in inhibition

Cited by 58 publications

References 141 publications

Zingerone Targets Status Epilepticus by Blocking Hippocampal Neurodegeneration via Regulation of Redox Imbalance, Inflammation and Apoptosis

Zingerone Targets Status Epilepticus by Blocking Hippocampal Neurodegeneration via Regulation of Redox Imbalance, Inflammation and Apoptosis

4E-BP2–dependent translation in parvalbumin neurons controls epileptic seizure threshold

Seizure-mediated iron accumulation and dysregulated iron metabolism after status epilepticus and in temporal lobe epilepsy

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