Neuroprotective Effects of Lacosamide and Memantine on Hyperoxic Brain Injury in Rats

Polat, İpek; Mıçılı, Serap Cilaker; Çalışır, Meryem; Bayram, Erhan; Yış, Uluç; Ayanoğlu, Müge; Okur, Derya; Edem, Pınar; Paketçi, Cem; Tugyan, Kazim; Yılmaz, Osman; Kurul, Semra Hız

doi:10.1007/s11064-020-03056-5

Cited by 13 publications

(2 citation statements)

References 26 publications

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“…Also, whether lacosamide and other anticonvulsive drugs increase other forms of cell death 50,51 is unknown and requires further study. However, our results are compatible with the lack of increased apoptosis observed in the parietal cortex of newborn rats exposed to hyperoxia in vivo 52 . Also, in adult mice, lacosamide decreased neurodegeneration in a closed head injury model 53 and reduced pyknosis in the pilocarpine model 36 .…”

Section: Discussionsupporting

confidence: 89%

“…However, our results are compatible with the lack of increased apoptosis observed in the parietal cortex of newborn rats exposed to hyperoxia in vivo. 52 Also, in adult mice, lacosamide decreased neurodegeneration in a closed head injury model 53 and reduced pyknosis in the pilocarpine model. 36 Thus, there is considerable evidence that lacosamide does not increase apoptosis in different models.…”

Section: Discussionmentioning

confidence: 96%

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Lacosamide decreases neonatal seizures without increasing apoptosis

et al. 2022

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Objective Many seizing neonates fail to respond to first‐line anticonvulsant medications. Phenobarbital, an allosteric modulator of γ‐aminobutyric acid type A (GABAA) receptors, has low efficacy in treating neonatal seizures and causes neuronal apoptosis. Nonetheless, it is one of the most used anticonvulsants in this age group. In neonatal mice, phenobarbital's poor effectiveness is due in part to high intraneuronal chloride concentration, which causes GABA to exert depolarizing actions. Therefore, another approach to treat neonatal seizures could be to use anticonvulsants that do not rely on GABAergic modulation. We evaluated whether lacosamide decreases seizures in neonatal mice and whether it increases apoptosis in vitro and in vivo. Methods In vitro, we measured the effect of different lacosamide concentrations on seizure‐like activity induced by the pro‐convulsant drug 4‐aminopyridine in neocortical brain slices (layer IV/V) from neonatal (postnatal day 8–11) and adult (1–1.6 months old) C57BL/6J mice. In vivo, we recorded the effect of different lacosamide concentrations on neonatal behavioral seizures induced by kainic acid. We studied neocortical apoptosis in vitro and in vivo, measuring terminal deoxynucleotidyl transferase (TdT) dUTP nick‐end labeling signal and cleaved‐caspase 3. Results Lacosamide reduced epileptiform activity in neocortical brain slices of neonates and adults in a concentration‐dependent manner. In vivo, lacosamide reduced the duration and number of behavioral seizures. Lacosamide did not increase total or neuronal apoptosis in the neocortex in vitro or in vivo. Significance Lacosamide reduces neocortical seizure‐like activity in neonatal mice in vitro and in vivo without an acute increase in apoptosis. Our results support the use of lacosamide to treat neonatal seizures, with the advantage of not increasing apoptosis acutely.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 96%

Lacosamide decreases neonatal seizures without increasing apoptosis

et al. 2022

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Oxygen toxicity: cellular mechanisms in normobaric hyperoxia

et al. 2022

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In clinical settings, oxygen therapy is administered to preterm neonates and to adults with acute and chronic conditions such as COVID-19, pulmonary fibrosis, sepsis, cardiac arrest, carbon monoxide poisoning, and acute heart failure. In non-clinical settings, divers and astronauts may also receive supplemental oxygen. In addition, under current standard cell culture practices, cells are maintained in atmospheric oxygen, which is several times higher than what most cells experience in vivo. In all the above scenarios, the elevated oxygen levels (hyperoxia) can lead to increased production of reactive oxygen species from mitochondria, NADPH oxidases, and other sources. This can cause cell dysfunction or death. Acute hyperoxia injury impairs various cellular functions, manifesting ultimately as physiological deficits. Chronic hyperoxia, particularly in the neonate, can disrupt development, leading to permanent deficiencies. In this review, we discuss the cellular activities and pathways affected by hyperoxia, as well as strategies that have been developed to ameliorate injury. Graphical abstract • Hyperoxia promotes overproduction of reactive oxygen species (ROS). • Hyperoxia dysregulates a variety of signaling pathways, such as the Nrf2, NF-κB and MAPK pathways. • Hyperoxia causes cell death by multiple pathways. • Antioxidants, particularly, mitochondria-targeted antioxidants, have shown promising results as therapeutic agents against oxygen toxicity in animal models.

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