Ceftriaxone Treatment Preserves Cortical Inhibitory Interneuron Function via Transient Salvage of GLT-1 in a Rat Traumatic Brain Injury Model

Hameed, Mustafa Q.; Hsieh, Tsung‐Hsun; Morales-Quezada, León; Lee, Henry H.C.; Damar, Ugur; MacMullin, Paul; Hensch, Takao K.; Rotenberg, Alexander

doi:10.1093/cercor/bhy328

Cited by 32 publications

(29 citation statements)

References 99 publications

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“…Glutamate transport thus constitutes a powerful antiexcitotoxic mechanism in the brain. Rat TBI models show a large, transient posttraumatic decline in GLT‐1 mRNA and protein levels and transporter function that starts within 24 hours of injury and normalizes by 6 weeks after injury . Possible explanations for these changes include increased endocytosis due to glutamate‐induced clustering, caspase‐3–mediated proteolysis of existing protein, and diminished de novo gene transcription …”

Section: Ceftriaxonementioning

confidence: 99%

“…Progressively worsening oxidative stress, coupled with the breakdown of the protective perineuronal net surrounding these cells, leads to their gradual loss, whereas excitatory neurons remain largely unaffected . Preferential loss of these inhibitory interneurons results in a progressive loss of GABAergic intracortical inhibition and may contribute to epileptogenesis …”

Section: Ceftriaxonementioning

confidence: 99%

“…In vivo ceftriaxone results in a threefold increase in GLT‐1 protein expression in healthy rodent brains 5‐7 days after start of treatment . The GLT‐1 normalization after TBI may result from increase by ceftriaxone of the glutamate transporter gene SLC1A2 expression, which is reduced after TBI …”

Section: Ceftriaxonementioning

confidence: 99%

“…Although GLT‐1 upregulation does not seem to last long after cessation of treatment, ceftriaxone's stabilization of GLT‐1 levels in the acute and subacute posttraumatic period partially protects against delayed excitotoxic damage to the vulnerable GABAergic inhibitory interneuron system and preserves both intracortical inhibition (as measured by transcranial magnetic stimulation) and cortical Parvalbumin expression up to 6 weeks after TBI …”

Section: Ceftriaxonementioning

confidence: 99%

“…Rat TBI models show a large, transient posttraumatic decline in GLT-1 mRNA and protein levels and transporter function that starts within 24 hours of injury and normalizes by 6 weeks after injury. [163][164][165][166] Possible explanations for these changes include increased endocytosis due to glutamate-induced clustering, 167 caspase-3-mediated proteolysis of existing protein, 168 and diminished de novo gene transcription. 169,170 Excessive glutamate leakage from injured neurons together with transiently deranged synaptic glutamate clearance results in increased extracellular glutamate, which persists for days after trauma in humans as well as rodents.…”

Section: Ceftriaxonementioning

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: Ceftriaxonementioning

confidence: 99%

Section: Ceftriaxonementioning

confidence: 99%

Section: Ceftriaxonementioning

confidence: 99%

Section: Ceftriaxonementioning

confidence: 99%

Section: Ceftriaxonementioning

confidence: 99%

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

et al. 2020

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Depressed glutamate transporter 1 expression in a mouse model of Dravet syndrome

Hameed,

Hui,

Lin

et al. 2023

Ann Clin Transl Neurol

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Dravet syndrome (DS) is a monogenic, often refractory, epilepsy resultant from SCN1A haploinsufficiency in humans. A novel therapeutic target in DS that can be engaged in isolation or as adjunctive therapy is highly desirable. Here, we demonstrate reduced expression of the rodent glutamate transporter type 1 (GLT‐1) in a DS mouse model, and in wild type mouse strains where Scn1a haploinsufficiency is most likely to cause epilepsy, indicating that GLT‐1 depression may play a role in DS seizures. As GLT‐1 can be upregulated by common and safe FDA‐approved medications, this strategy may be an attractive, viable, and novel avenue for DS treatment.

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Enhancement of Glutamate Uptake as Novel Antiseizure Approach: Preclinical Proof of Concept

Kamiński,

Socała,

Abram

et al. 2024

Annals of Neurology

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ObjectiveExcitotoxicity is a common hallmark of epilepsy and other neurological diseases associated with elevated extracellular glutamate levels. Thus, here, we studied the protective effects of (R)‐AS‐1, a positive allosteric modulator (PAM) of glutamate uptake in epilepsy models.Methods(R)‐AS‐1 was evaluated in a range of acute and chronic seizure models, while its adverse effect profile was assessed in a panel of standard tests in rodents. The effect of (R)‐AS‐1 on glutamate uptake was assessed in COS‐7 cells expressing the transporter. WAY 213613, a selective competitive EAAT2 inhibitor, was used to probe the reversal of the enhanced glutamate uptake in the same transporter expression system. Confocal microscopy and Western blotting analyses were used to study a potential influence of (R)‐AS‐1 on GLT‐1 expression in mice.Results(R)‐AS‐1 showed robust protection in a panel of animal models of seizures and epilepsy, including the maximal electroshock‐ and 6 Hz‐induced seizures, corneal kindling, mesial temporal lobe epilepsy, lamotrigine‐resistant amygdala kindling, as well as seizures induced by pilocarpine or Theiler's murine encephalomyelitis virus. Importantly, (R)‐AS‐1 displayed a favorable adverse effect profile in the rotarod, the minimal motor impairment, and the Irwin tests. (R)‐AS‐1 enhanced glutamate uptake in vitro and this effect was abolished by WAY 213613, while no influence on GLT‐1 expression in vivo was observed after repeated treatment.InterpretationCollectively, our results show that (R)‐AS‐1 has favorable tolerability and provides robust preclinical efficacy against seizures. Thus, allosteric enhancement of EAAT2 function could offer a novel therapeutic strategy for treatment of epilepsy and potentially other neurological disorders associated with glutamate excitotoxicity. ANN NEUROL 2024

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Ceftriaxone Treatment Preserves Cortical Inhibitory Interneuron Function via Transient Salvage of GLT-1 in a Rat Traumatic Brain Injury Model

Cited by 32 publications

References 99 publications

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

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

Depressed glutamate transporter 1 expression in a mouse model of Dravet syndrome

Enhancement of Glutamate Uptake as Novel Antiseizure Approach: Preclinical Proof of Concept

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