Neuroprotective effects of ceftriaxone treatment on cognitive and neuronal deficits in a rat model of accelerated senescence

Tikhonova, Maria A.; Ho, Shih Chun; Akopyan, Anna A.; Kolosova, N. G.; Weng, Jun; Meng, Wan Yun; Lin, Chih Li; Amstislavskaya, Tamara G.; Ho, Ying-Jui

doi:10.1016/j.bbr.2017.05.002

Cited by 34 publications

(33 citation statements)

References 79 publications

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“…166,181 Ceftriaxone is a safe and commonly used β-lactam antibiotic approved by the FDA, with good BBB permeability and documented neuroprotective potential. [182][183][184][185][186] It is also a potent stimulator of GLT-1 expression at CNS concentrations that are achievable in humans at doses used to treat bacterial meningitis (100 mg/kg/d, maximum dose = 4 g/d). [187][188][189] Ceftriaxone increases EAAT2 expression via the NFκB signaling pathway.…”

Section: Ceftriaxonementioning

confidence: 99%

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%

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

et al. 2020

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“…A 50 mg/kg doses of CEF also expressively amplified the immunoreactivity of TH in the striatum. Tikhonova et al, 2017 Genetic murine model: on two different genotypes rats genotype.…”

Section: Zhang Et Al 2015mentioning

confidence: 99%

“…Furthermore, CEF amplified the gene expression of Mme and Ide (genes that encode enzymes involved in Aβ degradation) as well as the expression of EPO gene (a gene that encodes erythropoietin correlated to endothelial function and removal of Aβ) (Tikhonova et al, 2018). CEF-treated animals also showed improvements in memory impairments and restoration of cognitive function and neuronal density (Tikhonova et al, 2017). CEF also attenuated increased levels of acetylcholine esterase enzyme and oxidative stress (Akina et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Repurposing of the β-Lactam Antibiotic, Ceftriaxone for Neurological Disorders: A Review

2019

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To date, there is no cure or disease-modifying agents available for most well-known neurological disorders. Current therapy is typically focused on relieving symptoms and supportive care in improving the quality of life of affected patients. Furthermore, the traditional de novo drug discovery technique is more challenging, particularly for neurological disorders. Therefore, the repurposing of existing drugs for these conditions is believed to be an efficient and dynamic approach that can substantially reduce the investments spent on drug development. Currently, there is emerging evidence that suggests the potential effect of a beta-lactam antibiotic, ceftriaxone (CEF), to alleviate the symptoms of different experimentally-induced neurological disorders: Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, epileptic-seizure, brain ischemia, traumatic brain injuries, and neuropathic pain. CEF also affects the markers of oxidative status and neuroinflammation, glutamatergic systems as well as various aggregated toxic proteins involved in the pathogenesis of different neurological disorders. Moreover, it was found that CEF administration to drug dependent animal models improved the withdrawal symptoms upon drug discontinuation. Thus, this review aimed to describe the effects of CEF against multiple models of neurological illnesses, drug dependency, and withdrawal. It also emphasizes the possible mechanisms of neuroprotective actions of CEF with respective neurological maladies.

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“…Ceftriaxone is a promising candidate antiepileptogenic therapy with documented neuroprotective potential (Cui et al 2014;Jagadapillai et al 2014;Zumkehr et al 2015;Krzyzanowska et al 2017;Tikhonova et al 2017). It may help minimize secondary glutamate excitotoxity by virtue of being a potent stimulator of promoting GLT-1 (EAAT2) expression at concentrations that are achievable in rodents at approximately 200 mg/kg IP, and in the human central nervous system at doses commonly used to treat bacterial meningitis (100 mg/kg/day IV; Max: 4 g/24 h) (Rothstein et al 2005;Lee et al 2008;Lewerenz et al 2009).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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Traumatic brain injury (TBI) results in a decrease in glutamate transporter-1 (GLT-1) expression, the major mechanism for glutamate removal from synapses. Coupled with an increase in glutamate release from dead and dying neurons, this causes an increase in extracellular glutamate. The ensuing glutamate excitotoxicity disproportionately damages vulnerable GABAergic parvalbumin-positive inhibitory interneurons, resulting in a progressively worsening cortical excitatory:inhibitory imbalance due to a loss of GABAergic inhibitory tone, as evidenced by chronic post-traumatic symptoms such as epilepsy, and supported by neuropathologic findings. This loss of intracortical inhibition can be measured and followed noninvasively using long-interval paired-pulse transcranial magnetic stimulation with mechanomyography (LI-ppTMS-MMG). Ceftriaxone, a β-lactam antibiotic, is a potent stimulator of the expression of rodent GLT-1 and would presumably decrease excitotoxic damage to GABAergic interneurons. It may thus be a viable antiepileptogenic intervention. Using a rat fluid percussion injury TBI model, we utilized LI-ppTMS-MMG, quantitative PCR, and immunohistochemistry to test whether ceftriaxone treatment preserves intracortical inhibition and cortical parvalbumin-positive inhibitory interneuron function after TBI in rat motor cortex. We show that neocortical GLT-1 gene and protein expression are significantly reduced 1 week after TBI, and this transient loss is mitigated by ceftriaxone. Importantly, whereas intracortical inhibition declines progressively after TBI, 1 week of post-TBI ceftriaxone treatment attenuates the loss of inhibition compared to saline-treated controls. This finding is accompanied by significantly higher parvalbumin gene and protein expression in ceftriaxone-treated injured rats. Our results highlight prospects for ceftriaxone as an intervention after TBI to prevent cortical inhibitory interneuron dysfunction, partly by preserving GLT-1 expression.

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Neuroprotective effects of ceftriaxone treatment on cognitive and neuronal deficits in a rat model of accelerated senescence

Cited by 34 publications

References 79 publications

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

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

Repurposing of the β-Lactam Antibiotic, Ceftriaxone for Neurological Disorders: A Review

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

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