Seizure-induced disinhibition of the HPA axis increases seizure susceptibility

Abstract

Stress is the most commonly reported precipitating factor for seizures. The proconvulsant actions of stress hormones are thought to mediate the effects of stress on seizure susceptibility. Interestingly, epileptic patients have increased basal levels of stress hormones, including corticotropin-releasing hormone (CRH) and corticosterone, which are further increased following seizures. Given the proconvulsant actions of stress hormones, we proposed that seizure-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to future seizure susceptibility. Consistent with this hypothesis, our data demonstrate that pharmacological induction of seizures in mice with kainic acid or pilocarpine increases circulating levels of the stress hormone, corticosterone, and exogenous corticosterone administration is sufficient to increase seizure susceptibility. However, the mechanism(s) whereby seizures activate the HPA axis remain unknown. Here we demonstrate that seizure-induced activation of the HPA axis involves compromised GABAergic control of CRH neurons, which govern HPA axis function. Following seizure activity, there is a collapse of the chloride gradient due to changes in NKCC1 and KCC2 expression, resulting in reduced amplitude of sIPSPs and even depolarizing effects of GABA on CRH neurons. Seizure-induced activation of the HPA axis results in future seizure susceptibility which can be blocked by treatment with an NKCC1 inhibitor, bumetanide, or blocking the CRH signaling with Antalarmin. These data suggest that compromised GABAergic control of CRH neurons following an initial seizure event may cause hyperexcitability of the HPA axis and increase future seizure susceptibility.

In vivo effects of bumetanide at brain concentrations incompatible with NKCC1 inhibition on newborn DGC structure and spontaneous EEG seizures following hypoxia-induced neonatal seizures

“…The stress hormone CRH was an excitatory neuropeptide with proconvulsant actions in both adult and neonatal brain, which were more sensitive to CRH (Baram and Hatalski, 1998). The production of stress hormones was mediated by the hypothalamicpituitary-adrenal (HPA) axis, involving the release of CRH from the hypothalamus (Maguire and Salpekar, 2013;O'Toole et al, 2014). There were evidences showing that CRH was released from neurosecretory nerve terminals of the paraventricular nucleus (PVN), located in the median eminence which received robust GABAergic input (Maguire and Salpekar, 2013).…”

Primed for Problems: Stress Confers Vulnerability to Epilepsy and Associated Comorbidities

“…Interestingly, recent studies demonstrated that seizures themselves activate the HPA axis (4,8), and seizure-induced elevations in corticosterone levels correlated with increased depression-like behaviors (9). It is possible that the "first hit" alters HPA axis reactivity, whereby in response to the "second hit, " there is hyperexcitability of the HPA axis that contributes to increased seizure susceptibility and associated comorbidities.…”

The role of the melatoninergic system in epilepsy and comorbid psychiatric disorders

“…Furthermore, close relationships between the sleep-wake cycle and the diurnal rhythmicity of seizure activity (Quigg, 2000), as well as between seizure susceptibility and HPA axis activity (O'Toole et al, 2014), have been found. Mostly prescribed for resynchronization of disturbed biological rhythms in a variety of pathological conditions, melatonin has low toxicity, neuroprotective effects, and a powerful antioxidant action.…”

“…i) Melatonin-mediated restoration of a disrupted hypothalamic-pituitary-adrenal axisClinical data and experimental models have shown that the HPA axis is hyperexcited in 22 epilepsy (Culebras et al, 1987;Mazarati et al, 2009;O'Toole et al, 2014) and in depression (Cai et al, 2013;Chen et al, 2015) and that melatonin can correct glucocorticoid-induced HPA axis disruption (Konakchieva et al, 1998). Because stress responses are regulated by the hypothalamic paraventicular nucleus (Laryea et al, 2013), and MT2 receptors are present in this area (Lacoste et al, 2015), we may speculate that melatonin could correct HPA axis disruption by acting on these receptors.…”

“…These comorbid disorders are characterized by disturbed circadian rhythms of a number of parameters as well as dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis (Maes et al, 1993;Mazarati et al, 2008;Pariante and Lightman, 2008;O'Toole et al, 2014).…”