Lestaurtinib (CEP-701) modulates the effects of early life hypoxic seizures on cognitive and emotional behaviors in immature rats

Medlej, Yasser; Salah, Houssein; Wadi, Lara; Saad, Sarah; Bashir, Bashir; Allam, Jad; Atoui, Zahraa; Darwish, Nora; Karnib, Nabil; Darwish, Hala; Kobeissy, Firas; Wang, Kevin; Hamade, Eva; Obeid, Makram

doi:10.1016/j.yebeh.2019.01.023

Cited by 18 publications

(10 citation statements)

References 54 publications

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“…There are currently 14 ongoing or completed clinical trials using lestaurtinib for the treatment of various cancers including myelofibrosis, leukemia, prostate cancer, and neuroblastoma, and the TrkA pathway is a target for neuroblastoma therapy 55 . Furthermore, the brain-derived neurotrophic factor (BDNF)-TrkB pathway has been implicated in channelopathies 56 , and inhibition of this pathway by lestaurtinib prevents epileptogenesis in immature brains 57 and hyperexcitability-induced emotional and cognitive behavioral dysfunction after hypoxic seizures 58 . These results indicate that this FDA-approved drug might be of interest for CNS activity in diseases characterized by dysfunction of Trk receptor signaling.…”

Section: Discussionmentioning

confidence: 99%

High-throughput screening against protein:protein interaction interfaces reveals anti-cancer therapeutics as potent modulators of the voltage-gated Na+ channel complex

Wadsworth

Folorunso

Nguyen

et al. 2019

Sci Rep

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Multiple voltage-gated Na+ (Nav) channelopathies can be ascribed to subtle changes in the Nav macromolecular complex. Fibroblast growth factor 14 (FGF14) is a functionally relevant component of the Nav1.6 channel complex, a causative link to spinocerebellar ataxia 27 (SCA27) and an emerging risk factor for neuropsychiatric disorders. Yet, how this protein:channel complex is regulated in the cell is still poorly understood. To search for key cellular pathways upstream of the FGF14:Nav1.6 complex, we have developed, miniaturized and optimized an in-cell assay in 384-well plates by stably reconstituting the FGF14:Nav1.6 complex using the split-luciferase complementation assay. We then conducted a high-throughput screening (HTS) of 267 FDA-approved compounds targeting known mediators of cellular signaling. Of the 65 hits initially detected, 24 were excluded based on counter-screening and cellular toxicity. Based on target analysis, potency and dose-response relationships, 5 compounds were subsequently repurchased for validation and confirmed as hits. Among those, the tyrosine kinase inhibitor lestaurtinib was highest ranked, exhibiting submicromolar inhibition of FGF14:Nav1.6 assembly. While providing evidence for a robust in-cell HTS platform that can be adapted to search for any channelopathy-associated regulatory proteins, these results lay the potential groundwork for repurposing cancer drugs for neuropsychopharmacology.

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Section: Discussionmentioning

confidence: 99%

High-throughput screening against protein:protein interaction interfaces reveals anti-cancer therapeutics as potent modulators of the voltage-gated Na+ channel complex

Wadsworth

Folorunso

Nguyen

et al. 2019

Sci Rep

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“…In addition, our system still has the limitation imposed by tethering, and thus, unlike wireless techniques [21], cannot record from freely moving rats undergoing behavioral testing or from pups caged with their mother (younger than 21 postnatal days). Nevertheless, our simple-to-implement key modifications result in a markedly improved traditional hardwired EEG and provide the necessary quality and amount of data required for the long-term study of seizure chronobiology in juvenile and adult rats [22] at a much lower cost than more advanced wireless systems.…”

Section: Discussionmentioning

confidence: 99%

Enhanced setup for wired continuous long-term EEG monitoring in juvenile and adult rats: application for epilepsy and other disorders

et al. 2019

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Background: The electroencephalogram (EEG) is a widely used laboratory technique in rodent models of epilepsy, traumatic brain injury (TBI), and other neurological diseases accompanied by seizures. Obtaining prolonged continuous EEG tracings over weeks to months is essential to adequately answer research questions related to the chronobiology of seizure emergence, and to the effect of potential novel treatment strategies. Current EEG recording methods include wired and the more recent but very costly wireless technologies. Wired continuous long-term EEG in rodents remains the mainstay approach but is often technically challenging due to the notorious frequent EEG cable disconnections from the rodent's head, and to poor signal-to-noise ratio especially when simultaneously monitoring multiple animals. Premature EEG cable disconnections and cable movement-related artifacts result from the animal's natural mobility, and subsequent tension on the EEG wires, as well as from potential vigorous and frequent seizures. These challenges are often accompanied by injuries to the scalp, and result in early terminations of costly experiments. Results: Here we describe an enhanced customized swivel-balance EEG-cage system that allows tension-free rat mobility. The cage setup markedly improves the safety and longevity of current existing wired continuous long-term EEG. Prevention of EEG cable detachments is further enhanced by a special attention to surgical electrode anchoring to the skull. In addition to mechanically preventing premature disconnections, the detailed stepwise approach to the electrical shielding, wiring and grounding required for artifact-free high signal-to-noise ratio recordings is also included. The successful application of our EEG cage system in various rat models of brain insults and epilepsy is described with illustrative high quality tracings of seizures and electrographic patterns obtained during continuous and simultaneous monitoring of multiple rats early and up to 3 months post-brain insult. Conclusion: Our simple-to-implement key modifications to the EEG cage setup allow the safe acquisition of substantial high quality wired EEG data without resorting to the still costly wireless technologies.

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“…The MAAV (P88-94) conditioning test was developed in our laboratory to concurrently assess adaptive avoidance of both context-cued and tone-signaled electrical foot-shocks [ 57 , 58 , 59 , 60 ]. The MAAV shuttle box (Coulbourn Instruments, Allentown, PA, USA) consists of two equal compartments connected via an opening in the middle of the partition wall.…”

Section: Methodsmentioning

confidence: 99%

Potentiating Hemorrhage in a Periadolescent Rat Model of Closed-Head Traumatic Brain Injury Worsens Hyperexcitability but Not Behavioral Deficits

Jalloul

Hajjar

Asdikian

et al. 2021

IJMS

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Post-traumatic epilepsy (PTE) and neurocognitive deficits are devastating sequelae of head injuries that are common in adolescents. Investigating desperately needed treatments is hindered by the difficulties in inducing PTE in rodents and the lack of established immature rat models of pediatric PTE. Hemorrhage is a significant risk factor for PTE, but compared to humans, rats are less prone to bleeding because of their rapid blood coagulation system. In this study, we promoted bleeding in the controlled cortical impact (CCI) closed-head injury model with a 20 min pre-impact 600 IU/kg intraperitoneal heparin injection in postnatal day 35 (P35) periadolescent rats, given the preponderance of such injuries in this age group. Temporo-parietal CCI was performed post-heparin (HTBI group) or post-saline (TBI group). Controls were subjected to sham procedures following heparin or saline administration. Continuous long-term EEG monitoring was performed for 3 months post-CCI. Sensorimotor testing, the Morris water maze, and a modified active avoidance test were conducted between P80 and P100. Glial fibrillary acidic protein (GFAP) levels and neuronal damage were also assessed. Compared to TBI rats, HTBI rats had persistently higher EEG spiking and increased hippocampal GFAP levels (p < 0.05). No sensorimotor deficits were detected in any group. Compared to controls, both HTBI and TBI groups had a long-term hippocampal neuronal loss (p < 0.05), as well as contextual and visuospatial learning deficits (p < 0.05). The hippocampal astrogliosis and EEG spiking detected in all rats subjected to our hemorrhage-promoting procedure suggest the emergence of hyperexcitable networks and pave the way to a periadolescent PTE rat model.

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Lestaurtinib (CEP-701) modulates the effects of early life hypoxic seizures on cognitive and emotional behaviors in immature rats

Cited by 18 publications

References 54 publications

High-throughput screening against protein:protein interaction interfaces reveals anti-cancer therapeutics as potent modulators of the voltage-gated Na+ channel complex

High-throughput screening against protein:protein interaction interfaces reveals anti-cancer therapeutics as potent modulators of the voltage-gated Na+ channel complex

Enhanced setup for wired continuous long-term EEG monitoring in juvenile and adult rats: application for epilepsy and other disorders

Potentiating Hemorrhage in a Periadolescent Rat Model of Closed-Head Traumatic Brain Injury Worsens Hyperexcitability but Not Behavioral Deficits

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