The α2δ Subunit and Absence Epilepsy: Beyond Calcium Channels?

Celli, Roberta; Santolini, Ines; Guiducci, Michela; Luijtelaar, Gilles van; Parisi, Pasquale; Striano, Pasquale; Gradini, Roberto; Battaglia, Giuseppe; Ngomba, Richard Teke; Nicoletti, Ferdinando

doi:10.2174/1570159x15666170309105451

Cited by 19 publications

(12 citation statements)

References 100 publications

(96 reference statements)

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“…These epileptic seizures may present in several ways depending on the area of the brain involved [ 2 ]. According to the International League Against Epilepsy (ILAE) statistics, as of 2013, epilepsy jeopardized approximately 22 million people, accounting for about 116,000 deaths [ 3 , 4 ]. Furthermore, epilepsy became more prevalent as people age, causing a great burden to governments worldwide [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

The Anticonvulsant Effects of Ketogenic Diet on Epileptic Seizures and Potential Mechanisms

Zhang

et al. 2017

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Background:Epilepsy is a syndrome of brain dysfunction induced by the aberrant excitability of certain neurons. Despite advances in surgical technique and anti-epileptic drug in recent years, recurrent epileptic seizures remain intractable and lead to a serious morbidity in the world. The ketogenic diet refers to a high-fat, low-carbohydrate and adequate-protein diet.Currently, its beneficial effects on epileptic seizure reduction have been well established. However, the detailed mechanisms underlying the anti-epileptic effects of ketogenic diet are still poorly understood. In this article, the possible roles of ketogenic diet on epilepsy were discussed.Methods:Data was obtained from the websites including Web of Science, Medline, Pubmed,Scopus, based on these keywords: “Ketogenic diet” and “epilepsy”.Results:As shown in both clinical and basic studies, the therapeutic effects of ketogenic diet might involve neuronal metabolism, neurotransmitter function, neuronal membrane potential and neuron protection against ROS.Conclusion:In this review, we systematically reviewed the effects and possible mechanisms of ketogenic diet on epilepsy, which may optimize the therapeutic strategies against epilepsy.

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Section: Introductionmentioning

confidence: 99%

The Anticonvulsant Effects of Ketogenic Diet on Epileptic Seizures and Potential Mechanisms

Zhang

et al. 2017

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“…Thrombospondin 1 (TSP-1) is an astroglial-derived synaptogenic molecule that showed the ability to induce excitatory synapses [ 17 ] by interacting with the α2δ1 subunit of voltage-sensitive calcium channels [ 18 , 19 ]. TSP-1 expression is augmented in astrocytes following brain injury and seizures [ 20 ] and mice overexpressing the α2δ1 subunit show epileptiform activity [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Early Gabapentin Treatment during the Latency Period Increases Convulsive Threshold, Reduces Microglial Activation and Macrophage Infiltration in the Lithium-Pilocarpine Model of Epilepsy

et al. 2017

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The lithium-pilocarpine model of epilepsy reproduces several features of temporal lobe epilepsy in humans, including the chronological timeline of an initial latency period followed by the development of spontaneous seizures. Epilepsy therapies in humans are implemented, as a rule, after the onset of the spontaneous seizures. We here studied the potential effect on epileptogenesis of starting an early treatment during the latency period, in order to prevent the development of spontaneous seizures. Adult male Wistar rats were treated with 3 mEq/kg LiCl, and 20 h later 30 mg/kg pilocarpine. Once status epilepticus (SE) was achieved, it was allowed to last for 20 min, and then motor seizures were controlled with the administration of 20 mg/kg diazepam. At 1DPSE (DPSE, days post-status epilepticus), animals started to receive 400 mg/kg/day gabapentin or saline for 4 days. At 5DPSE, we observed that SE induced an early profuse microglial and astroglial reactivity, increased synaptogenic trombospondin-1 expression and reduced AQP4 expression in astroglial ending feet. Blood brain barrier (BBB) integrity seemed to be compromised, as infiltrating NG2+ macrophages and facilitated access to the CNS was observed by transplanting eGFP+ blood cells and bone marrow-derived progenitors in the SE animals. The early 4-day gabapentin treatment successfully reduced microglial cell reactivity and blood-borne cell infiltration, without significantly altering the mRNA of proinflammatory cytokines IL-1β and TNFα immediately after the treatment. After 21DSPE, another group of animals that developed SE and received 4 days of gabapentin treatment, were re-exposed to subconvulsive accumulative doses of pilocarpine (10 mg/kg/30 min) and were followed by recording the Racine scale reached. Early 4-day gabapentin treatment reduced the Racine scale reached by the animals, reduced animal mortality, and reduced the number of animals that achieved SE (34% vs. 72%). We conclude that early gabapentin treatment following SE, during the latency period, is able to reduce neuroinflammation and produces a persistent effect that limits seizures and increases convulsive threshold, probably by restricting microglial reactivity and spurious synaptogenesis.

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“…Dysfunctions of voltage-gated calcium channels have been linked to a variety of neurological disorders including Parkinson’s disease, epilepsy, migraine, ataxia, neuropathic pain, and psychiatric disorders [ 3 , 8 , 17 , 43 , 80 , 89 , 105 , 107 , 132 ]. Hence, it is not surprising that likewise α 2 δ proteins have been associated with many of these diseases.…”

Section: α 2 δ Proteins and Neurological Disordersmentioning

confidence: 99%

Neuronal α2δ proteins and brain disorders

Ablinger

Geisler

Stanika

et al. 2020

Pflugers Arch - Eur J Physiol

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α 2 δ proteins are membrane-anchored extracellular glycoproteins which are abundantly expressed in the brain and the peripheral nervous system. They serve as regulatory subunits of voltage-gated calcium channels and, particularly in nerve cells, regulate presynaptic and postsynaptic functions independently from their role as channel subunits. α 2 δ proteins are the targets of the widely prescribed anti-epileptic and anti-allodynic drugs gabapentin and pregabalin, particularly for the treatment of neuropathic pain conditions. Recently, the human genes (CACNA2D1-4) encoding for the four known α 2 δ proteins (isoforms α 2 δ-1 to α 2 δ-4) have been linked to a large variety of neurological and neuropsychiatric disorders including epilepsy, autism spectrum disorders, bipolar disorders, schizophrenia, and depressive disorders. Here, we provide an overview of the hitherto identified disease associations of all known α 2 δ genes, hypothesize on the pathophysiological mechanisms considering their known physiological roles, and discuss the most immanent future research questions. Elucidating their specific physiological and pathophysiological mechanisms may open the way for developing entirely novel therapeutic paradigms for treating brain disorders.

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The α2δ Subunit and Absence Epilepsy: Beyond Calcium Channels?

Cited by 19 publications

References 100 publications

The Anticonvulsant Effects of Ketogenic Diet on Epileptic Seizures and Potential Mechanisms

The Anticonvulsant Effects of Ketogenic Diet on Epileptic Seizures and Potential Mechanisms

Early Gabapentin Treatment during the Latency Period Increases Convulsive Threshold, Reduces Microglial Activation and Macrophage Infiltration in the Lithium-Pilocarpine Model of Epilepsy

Neuronal α2δ proteins and brain disorders

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