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

Hypoxic encephalopathy of the newborn is a major cause of long-term neurological sequelae. We have previously shown that CEP-701 (lestaurtinib), a drug with an established safety profile in children, attenuates short-term hyperexcitability and tropomyosin-related kinase B (TrkB) receptor activation in a well-established rat model of early life hypoxic seizures (HS). Here, we investigated the potential long-term neuroprotective effects of a post-HS transient CEP-701 treatment. Following exposure to global hypoxia, 10 day old male Sprague-Dawley pups received CEP-701 or its vehicle and were sequentially subjected to the light-dark box test (LDT), forced swim test (FST), open field test (OFT), Morris water maze (MWM), and the modified active avoidance (MAAV) test between postnatal days 24 and 44 (P24-44). Spontaneous seizure activity was assessed by epidural cortical electroencephalography (EEG) between P50 and 100. Neuronal density and glial fibrillary acidic protein (GFAP) levels were evaluated on histological sections in the hippocampus, amygdala, and prefrontal cortex at P100. Vehicle-treated hypoxic rats exhibited significantly increased immobility in the FST compared with controls, and post-HS CEP-701 administration reversed this HS-induced depressive-like behavior (p < 0.05). In the MAAV test, CEP-701-treated hypoxic rats were slower at learning both context-cued and tone-signaled shock-avoidance behaviors (p < 0.05). All other behavioral outcomes were comparable, and no recurrent seizures, neuronal loss, or increase in GFAP levels were detected in any of the groups. We showed that early life HS predispose to long-lasting depressive-like behaviors, and that these are prevented by CEP-701, likely via TrkB modulation. Future mechanistically more specific studies will further investigate the potential role of TrkB signaling pathway modulation in achieving neuroprotection against neonatal HS, without causing neurodevelopmental adverse effects.

Prevalence of Insomnia among Pancreatic Cancer Patients following Pancreaticoduodenectomy.

INTRODUCTION: Sleep disturbances are more common in cancer patients than in the general population; however, there is limited research pertaining to the occurrence of such disturbances that subsequently impact patients' quality of life. The aim of our study is to describe the prevalence of insomnia among pancreatic cancer patients who have recently undergone recent pancreaticoduodenectomy. METHODS: We performed a 6-year (2014-2020) retrospective cohort analysis of all adult patients aged 18 and above with pancreatic cancer who underwent pancreaticoduodenectomy at our institution. Insomnia was characterized using the Pittsburgh Sleep Quality Index (PSQI). Symptoms of insomnia and the impact caused by these symptoms on daily lives were assessed with the Insomnia Severity Index (ISI), and patients were divided into mild insomnia (ISI 8-14) or moderate to severe insomnia (ISI ≥ 15). RESULTS: Out of forty patients with pancreatic cancer that have undergone pancreaticoduodenectomy, 19 (47.2%) reported that their sleep disturbances had a significant effect on their quality of life. A total of 22 (55.0%) patients reported insomnia, with 63.2% reporting mild insomnia. Chemotherapy was found to significantly increase the risk of moderate to severe insomnia. The mean ISI score was 7.2 ± 6.9, and the mean PSQI score was 7.0 ± 5.1. ISI and PSQI showed a strong positive correlation (r = 0.78, p < 0.01). CONCLUSION: Sleep disturbances such as insomnia following pancreatic cancer surgery are highly prevalent. Treating physicians and surgeons should recognize and routinely screen for sleep disorders through the management of a multidisciplinary team in order to alleviate some of the burden on the patients' mental well-being.

Overview on Emotional Behavioral Testing in Rodent Models of Pediatric Epilepsy.

Psychiatric and cognitive disturbances are the most common comorbidities of epileptic disorders in children. The successful treatment of these comorbidities faces many challenges including their etiologically heterogonous nature. Translational neurobehavioral research in age-tailored and clinically relevant rodent seizure models offers a controlled setting to investigate emotional and cognitive behavioral disturbances, their causative factors, and potentially novel treatment interventions. In this review, we propose a conceptual framework that provides a nonsubjective approach to rodent emotional behavioral testing with a focus on the clinically relevant outcome of behavioral response adaptability. We also describe the battery of neurobehavioral tests that we tailored to seizure models with prominent amygdalo-hippocampal involvement, including testing panels for anxiety-like, exploratory, and hyperactive behaviors (the open-field and light-dark box tests), depressive-like behaviors (the forced swim test), and visuospatial navigation (Morris water maze). The review also discusses the modifications we introduced to active avoidance testing in order to simultaneously test auditory and hippocampal-dependent emotionally relevant learning and memory. When interpreting the significance and clinical relevance of the behavioral responses obtained from a given testing panel, it is important to avoid a holistic disease-based approach as a specific panel may not necessarily mirror a disease entity. The analysis of measurable behavioral responses has to be performed in the context of outcomes obtained from multiple related and complementary neurobehavioral testing panels. Behavioral testing is also complemented by mechanistic electrophysiological and molecular investigations.