α2δ-1 Signaling Drives Cell Death, Synaptogenesis, Circuit Reorganization, and Gabapentin-Mediated Neuroprotection in a Model of Insult-Induced Cortical Malformation

Lau, Lauren A.; Noubary, Farzad; Wang, Dongqing; Dulla, Chris G.

doi:10.1523/eneuro.0316-17.2017

Cited by 24 publications

(23 citation statements)

References 60 publications

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“…Following injury or prolonged epileptiform activity, activated astrocytes release synaptogenic thrombospondins (TSPs) that bind to α2δ‐1 receptors, contributing to excitatory synaptogenesis . Genetically induced increases and decreases in α2δ‐1 expression are associated with enhanced or decreased epileptogenesis. Gabapentinoids interfere with binding of TSPs to α2δ‐1 during development and after injury, resulting in a reduction of excitatory synaptogenesis .…”

Section: Gabapentinoids As Repurposed Antiepileptogenic Drugsmentioning

confidence: 99%

“…Brief (4‐8 days) GBP treatment (400 mg/kg/d) beginning 1 day after SE reduced gliosis, inflammation, and hippocampal neuronal loss, increased seizure threshold, and reduced evoked seizure severity . GBP also has similar protective effects in brain ischemic injury, following direct cortical trauma, and with cortical freeze lesions . Progressive increases in excitatory connectivity and epileptogenesis, shown using laser scanning photostimulation of caged glutamate 2 weeks following neocortical trauma in the “undercut” model, are markedly reduced by even a brief 3‐day GBP treatment after injury (100 mg/kg ip 3×/d) .…”

Section: Gabapentinoids As Repurposed Antiepileptogenic Drugsmentioning

confidence: 99%

“…207 GBP also has similar protective effects in brain ischemic injury, 208 following direct cortical trauma, 199,209 and with cortical freeze lesions. 201,202,210 Progressive increases in excitatory connectivity and epileptogenesis, shown using laser scanning photostimulation of caged glutamate 2 weeks following neocortical trauma in the "undercut" model, are markedly reduced by even a brief 3-day GBP treatment after injury (100 mg/kg ip 3×/d). 209 Recent results show long-lasting dose-dependent antiepileptogenic effects of PGB (50 or 100 mg/kg ip beginning at P7 ×3 weeks) in juvenile α2δ-1-overexpressing mice that persist for at least 3 months after the end of treatment (W. Zhang and D.A.…”

Section: As Repurposed Antiepileptogenic Drugsmentioning

confidence: 99%

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Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

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Section: Gabapentinoids As Repurposed Antiepileptogenic Drugsmentioning

confidence: 99%

Section: Gabapentinoids As Repurposed Antiepileptogenic Drugsmentioning

confidence: 99%

Section: As Repurposed Antiepileptogenic Drugsmentioning

confidence: 99%

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Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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“…In each of these studies, the drugs gabapentin or pregabalin normalize pathologically elevated rates of mEPSCs in rat or mouse neuronal tissue with synapses in spinal cord dorsal horn (Patel et al, 2000;Li et al, 2014b;Matsuzawa et al, 2014;Zhou and Luo, 2014;Zhou and Luo, 2015;Park et al, 2016;Alles et al, 2017;Chen et al, 2018;Chen et al, 2019;Deng et al, 2019). Gabapentinoids reduced the rate of mEPSCs between glutamatergic neurons in rat entorhinal cortex (Cunningham et al, 2004), in neocortex neurons after cortical freeze lesions (Andresen et al, 2014;Lau et al, 2017), between neocortex and striatal neurons (Zhou et al, 2018), at glutamate neurons in hypothalamus of spontaneously hypertensive rats (Ma et al, 2018), at the mouse calyx of Held (Di Guilmi et al, 2011) and in cortico-striatal synapses after prolonged prior stimulation of striatum (Nagai et al, 2019). Therefore, the most widely replicated effects of gabapentin and pregabalin at the cellular level are decreases in the rate of mEPSCs at excitatory synapses, particularly at synapses with pathologically enhanced activity.…”

Section: Downloaded Frommentioning

confidence: 99%

“…The idea that a thrombospondin/2-1 interactions might underlie gabapentinoid drug actions other than analgesia in chronic pain also has been studied. Repeated prophylactic gabapentin JPET # 266056 page 22 treatment in models of post-traumatic epilepsy (Li et al, 2012;Andresen et al, 2014;Lau et al, 2017;Takahashi et al, 2018) prevented the stabilization of abnormal new synapses in neocortex, presumably by blocking the action of astrocyte-derived thrombospondin.…”

Section: Jpet # 266056 Page 21mentioning

confidence: 99%

Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins

Taylor¹,

Harris²

2020

The Journal of Pharmacology and Experimental Therapeutics

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The gabapentinoid drugs gabapentin and pregabalin (Neurontin® and Lyrica®) are mainstay treatments for neuropathic pain and for preventing focal seizures. Both drugs have similar effects to each other in animal models and clinically. Studies have shown that a protein first identified as an auxiliary subunit of voltage-gated calcium channels (the alpha2-delta subunit, 2-1 or CaVa2d1) is the high-affinity binding site for gabapentin and pregabalin, and is required for the efficacy of these drugs. The 2-1 protein is required for the ability of gabapentin and pregabalin to reduce neurotransmitter release in neuronal tissue, consistent with a therapeutic mechanism of action via voltage-gated calcium channels. However, recent studies have revealed that 2-1 interacts with several proteins in addition to voltage-gated calcium channels, and these additional proteins could be involved in gabapentinoid pharmacology. Furthermore, gabapentin and pregabalin have been shown to modify the action of a subset of NMDAsensitive glutamate receptors, neurexin-1, and thrombospondin proteins by binding to 2-1. Thus, these effects may contribute substantially to gabapentinoid therapeutic mechanism of action. Significance Statement It is widely believed that gabapentin and pregabalin act by modestly reducing the membrane localization and activation of voltage-gated calcium channels at synaptic endings in spinal cord and neocortex via binding to the 2-1 protein. However, recent findings show that the 2-1 protein also interacts with NMDA-sensitive glutamate receptors, neurexin-1, thrombospondins (adhesion molecules), and other presynaptic proteins. These newly discovered interactions, in addition to actions at calcium channels, may be important mediators of gabapentin and pregabalin therapeutic effects.

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The Presynaptic α2δ Protein Family and Their Therapeutic Potential

Ablinger,

Eibl,

Roznovcova

et al. 2024

Ion Channels as Targets in Drug Discovery

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α2δ-1 Signaling Drives Cell Death, Synaptogenesis, Circuit Reorganization, and Gabapentin-Mediated Neuroprotection in a Model of Insult-Induced Cortical Malformation

Abstract: Visual Abstract

Cited by 24 publications

References 60 publications

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins

The Presynaptic α2δ Protein Family and Their Therapeutic Potential

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