Hyperthermia‐induced seizures followed by repetitive stress are associated with age‐dependent changes in specific aspects of the mouse stress system

Abstract

Stress is among the most frequently self-reported factors provoking epileptic seizures in children and adults. It is still unclear, however, why some people display stress-sensitive seizures and others do not. Recently, we showed that young epilepsy patients with stress-sensitive seizures exhibit a dysregulated hypothalamic-pituitaryadrenal (HPA)-axis. Most likely, this dysregulation gradually develops, and is triggered by stressors occurring early in life (early-life stress [ELS]). ELS may be particularly impactful when overlapping with the period of epileptogenesis. To examine this in a controlled and prospective manner, the present study investigated the effect of repetitive variable stressors or control treatment between postnatal day (PND) 12 and 24 in male mice exposed on PND10 to hyperthermia (HT)-induced prolonged seizures (control: normothermia). A number of peripheral and central indices of HPAaxis activity were evaluated at pre-adolescent and young adult age (ie, at PND25 and 90, respectively). At PND25 but not at PND90, body weight gain and absolute as well as relative (to body weight) thymus weight were reduced by ELS (vs control), whereas relative adrenal weight was enhanced, confirming the effectiveness of the stress treatment. Basal and stress-induced corticosterone levels were unaffected, though, by ELS at both ages. HT by itself did not affect any of these peripheral markers of HPA-axis activity, nor did it interact with ELS. However, centrally we did observe age-specific interaction effects of HT and ELS with regard to hippocampal glucocorticoid receptor mRNA expression, neurogenesis with the immature neurone marker doublecortin and the number of hilar (ectopic) granule cells using Prox1 staining. This 2 of 15 | UMEOKA Et Al. | INTRODUC TI ONApproximately 50% of all children and adults with epilepsy acknowledge stress as a seizure-provoking factor, 1,2 ranking stress among the most frequently self-reported precipitants of seizures. 2-10 Why some individuals show stress-sensitivity in seizure activity and others do not still remains unclear. One explanation could be that the former as opposed to the latter group responds differently to stress as, for example, reflected by aberrant hypothalamic-pituitary-adrenal (HPA) activation or downstream targets after stress. In accordance, recent evidence obtained in a cohort of children and adolescents (6-17 years of age) with epilepsy indicated that those with stress-sensitive compared to individuals with stress-insensitive seizures or healthy controls show a blunted cortisol response to experimentally induced stress. 11Possibly, this renders hormonal negative-feedback actions on the brain less adequate, which could result in increased levels of proexcitatory central stress hormones such as corticotrophin-releasing hormone. 12 Which elements of the stress system become aberrant at specific developmental stages is not easy to investigate in humans with stress-sensitive seizures because this would require prospective longitudinal investigation of both centr...

Biomarkers in Stress Related Diseases/Disorders: Diagnostic, Prognostic, and Therapeutic Values

“…Deciphering the interaction of different immune cytokines with neuronal circuits of stress is critical to delineate the physiological and psychological stress responses and the prognosis of illness (Godoy et al, 2018). It is proved, experimentally, that hyperthermia and early life stresses in the murine model resulted in deregulation of hypothalamic-pituitary-adrenal (HPA) axis, skewing of hippocampal glucocorticoid receptor mRNA expression and defective neurogenesis indicated by the immature neuron marker doublecortin in an age-dependent manner (Umeoka et al, 2019). Advances in proteomic research have come up with various potential proteins as a panel of biomarkers for diagnosis and therapy related to immunity, blood coagulation, management of oxidative stress, energy metabolism, etc.…”

Simple Febrile Seizures: A Benign Phenomena?

“…Such animal studies have shown that hyperthermia-induced seizures occurring early in life may dysregulate central components in an agedependent manner, conferring higher vulnerability of this cohort to develop epilepsy. 18 Based on the current literature, an imbalance between proinflammatory and anti-inflammatory cytokines might play a role in the pathogenesis of febrile seizures. Sahin et al reviewed the effect of interleukin 12 (IL-12) a proinflammatory cytokine, IL-10 an anti-inflammatory cytokine, and interferon B and demonstrated reduced cerebrospinal fluid levels of IL-10 in febrile seizure patients in response to inflammatory conditions.…”

Clinical Correlation of Altered Molecular Signatures in Epileptic Human Hippocampus and Amygdala

“…In addition to receptors and ion channels, dysregulation of glial functions, such as malfunction and/or downregulation of glutamate transporters, is involved in the generation of epileptic seizures and pathological changes of MTLE [ 22 , 23 ]. Both experimental and clinical investigations suggest that several factors, such as the frequency [ 24 ] and intensity [ 25 ] of seizures, prolonged seizures [ 26 ], anticonvulsants [ 27 , 28 ], age of onset [ 29 , 30 ], and psychiatric/cognitive abnormalities [ 31 ], could affect the histological and molecular architecture of the epileptic brain. The expression levels of various genes of both the human epileptic hippocampus and amygdala were investigated.…”