Hypothalamic-Pituitary-Adrenal Axis and Epilepsy

Abstract

Epilepsy is a recurrent, transient seizure disorder of the nervous system that affects the intellectual development, life and work, and psychological health of patients. People with epilepsy worldwide experience great suffering. Stressful stimuli such as infection, mental stress, and sleep deprivation are important triggers of epilepsy, and chronic stressful stimuli can lead to frequent seizures and comorbidities. The hypothalamic-pituitary-adrenal (HPA) axis is the most important system involved in the body’s stress response, and dysfunction thereof is thought to be associated with core epilepsy symptoms and related psychopathology. This article explores the intrinsic relationships of corticotropin-releasing hormone, adrenocorticotropic hormone, and glucocorticoids with epilepsy in order to reveal the role of the HPA axis in the pathogenesis of epilepsy. We hope that this information will yield future possible directions and ideas for fully understanding the pathogenesis of epilepsy and developing antiepileptic drugs.

INTRODUCTION

Epilepsy is a serious brain disorder involving long-term recurrent seizures that can affect all age groups and lead to adverse neurobiological, cognitive, and psychological outcomes.¹ Prolonged seizures markedly increase the risk of comorbid neuropsychiatric disorders such as depression and anxiety, and cause premature death in some patients.² Seizures usually result from a combination of multilevel, multiple factors such as neuronal damage, immune stress, metabolic abnormalities, and genetic susceptibility.³ Due to the complexity and diversity of the pathogenesis of epilepsy and the heterogeneity of clinical manifestations, one-third of patients continue to experience uncontrolled seizures after routine drug, surgery, and diet interventions, which makes the treatment of epilepsy a major challenge.⁴

The hypothalamic-pituitary-adrenal (HPA) axis is the most important stress-response pathway in the body, and its rhythmic activity precisely regulates the secretion of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and glucocorticoids (GCs).⁵ This rhythmic activity of the HPA axis is also strongly associated with the body’s metabolic, inflammatory, cognitive, and stress responses.⁶ The release of ACTH and GCs from the HPA axis is more pronounced in adolescents than in adults, which might be associated with enhanced neurocentral drive or delayed development of feedback mechanisms.⁷ In old age, aging similarly increases basal HPA-axis function and responsiveness, contributing to increased secretion of GCs, which is thought to be associated with a deficiency in mineralocorticoids in the hippocampal receptor that disrupts negative-feedback mechanisms.⁸ It is particularly interesting that the incidence of epilepsy shows a bimodal distribution with age (i.e., the epilepsy risk is higher in infants and older adults), which seems to be linked with the age-related activity of the HPA axis.⁹

Progress in brain science research and various proposal animal models is resulting in accumulating evidence that the HPA axis is involved in the pathogenesis of a various neurological disorders, including epilepsy, depression, anxiety, and Alzheimer’s disease.¹⁰,¹¹ Most scholars now believe that HPA-axis dysfunction may be one of the important etiological mechanisms of seizures and related psychopathology.¹² In patients with temporal lobe epilepsy (TLE) and in rodent models thereof, substantial cell loss and neuronal reorganization are observed in critical stress regulatory areas such as the hippocampus, and the normal structure of these regulatory areas plays an important role in the normal activation of the HPA axis, so that alterations in this structure can lead to dysfunction of the HPA axis.¹³,¹⁴ Similarly, repeated activation of the HPA axis can lead to abnormally high levels of GCs in the excitable part of the hippocampus, thereby exacerbating persistent epilepsy.¹⁵ In short, seizures can lead to dysregulation of the HPA axis that, in turn, can promote seizures.

This article presents the intrinsic relationships of CRH, ACTH, and GCs in the HPA axis as an important regulatory pathway with epilepsy through a literature review, with the aim of identifying new targets for epilepsy treatment.

THE HPA AXIS IS INVOLVED IN COPING WITH VARIOUS STRESSES AND MAINTAINING NORMAL BRAIN FUNCTION

The HPA axis can respond rapidly to various stresses in the organism, and different patterns of stressors and their duration affect the activation of the HPA axis. Direct stimulation of the HPA-axis stress response comes mainly from neurons. The expected stress response is mediated by the ventral hippocampus, infralimbic and prelimbic cortex, and the amygdala, and is initiated by transmission via interneurons to CRH neurons in the paraventricular nucleus (PVN) region of the hypothalamus.¹⁶,¹⁷,¹⁸ Rapid activation of the HPA axis is essential for the body to cope with stress, but it is also important that the stress response is terminated in a timely manner to avoid potentially harmful effects of excessive or sustained hormone release. Rapid negative-feedback inhibition of CRH neurons by the organism and persistent feedback inhibition of CRH neurons by the prefrontal cortex, hippocampus, and amygdala are key processes in terminating HPA-axis activation. Various stressful stimuli in early life damage the prefrontal cortex via different mechanisms and impair inhibition of HPA-axis activity by the prefrontal cortex, leading to persistent effects of GCs on neurons in functional areas of the brain.¹⁹ This suggests that the balance of HPA-axis activation and termination after stressful stimuli is particularly important to the health of the organism.

The hippocampus, amygdala, and frontal lobe are closely associated with the occurrence of epilepsy, and the HPA axis is crucial to maintaining the structure and neuronal function of these important functional areas of the brain. The hippocampus is primarily responsible for learning and memory functions. Dysregulation of the HPA axis and excess cortisol produced in response to stress can alter the structure and function of the hippocampus. The volume of the left hippocampus was positively linearly correlated with the circadian cortisol levels in children with early-life adversity, and the hippocampal volume and stress-sensitive hippocampal subregions (CA1, CA3, and the dentate gyrus granular cell layer) were found to be significantly smaller than in controls.²⁰,²¹ Chronic stress inducing long-term excess GC exposure can inhibit the HPA-axis feedback regulatory pathway, leading to a reduction in brain-derived neurotrophic factor, while the glucocorticoid receptor (GR) can interact with neurotrophic factors to mediate changes in hippocampal structure and function.²² The HPA axis also plays a crucial role in regulating hippocampal neurogenesis. Disruption of the GR and neurotrophic factors impairs neurogenesis, reduces dendritic branching, and inhibits synaptogenesis, and also causes neuronal atrophy, most notably in the hippocampus.²³,²⁴,²⁵ Experimental studies have similarly found that chronic circulating corticosterone was increased when mouse skin was exposed to UV light, and its binding to hippocampal GRs led to a significant reduction in hippocampal neurogenesis and synaptic protein expression.²⁶ These changes in the structure and function of the hippocampus caused by alterations in the HPA axis are closely associated with epileptogenesis.

The amygdala is an important brain tissue involved in generating, recognizing, and regulating emotions, and controls learning and memory, and it is critical for physiological arousal and behavioral alertness in response to stimuli.²⁷ Administering pharmacological agonists of the HPA axis can enhance amygdala responsiveness in mice and humans, and increased GC secretion causes dendritic expansion and enhances amygdala excitability.²⁸,²⁹ Alteration of the circulating concentration of cortisol in individuals with chronic early-life stress can lead to relatively immature functional amygdala–prefrontal-cortex connections that make individuals more susceptible to emotions such as anxiety.³⁰ In addition, it has been shown that enhanced cortisol stress responses in early childhood (at age 3–5 years) can lead to a reduction in the size of the bilateral amygdala in later childhood (at age 7–12 years), and that a smaller amygdala may lead to cognitive dysfunction and emotional impairment.³¹,³² Similarly, alterations in the amygdala have been strongly associated with epilepsy. A significant positive correlation was found between left thalamic volume atrophy and seizure frequency in patients with drug-resistant epilepsy, while a significant reduction in left amygdala volume was found in rats with myoclonic epilepsy.³³,³⁴

The functions of the frontal lobes are mainly related to casual movements and higher mental activities. There is a coordinating role between frontal limbic resting-state connectivity and HPA-axis function, and a positive correlation was found between frontal limbic connectivity and cortisol levels in a healthy population.³⁵ Also, altered DNA methylation patterns of genes related to the HPA axis (e.g., SLC6A4 and FKBP5) were found to be associated with altered frontal limb functional connectivity and structure.³⁶ An important way in which the HPA-axis stress response affects cognitive and emotional function in patients is by regulating frontal lobe activity, which can lead to reduced frontal lobe sensitivity in high-stress situations.³⁷ In addition, the HPA axis is overactivated in chronic stress states, which can lead to neuronal atrophy in the dorsolateral and dorsomedial prefrontal cortices.³⁸ Studies have also shown that an increased cortisol level in the hair is significantly associated with reduced volumes of the frontal, temporal, and cingulate regions of the brain.³⁹ Loss of prefrontal dendritic spines and altered structure were found to be associated with elevated corticosterone.⁴⁰ Inhibiting the overactivation of the HPA axis reduces oxidative stress and regulates neurotransmitter levels in the hippocampus and frontal cortex, which exerts a strong antidepressant effect in animal models.⁴¹

HPA DYSFUNCTION IN PATIENTS WITH EPILEPSY

Investigations of epilepsy and the HPA axis are becoming increasingly refined, and are producing more evidence that HPA-axis dysfunction is closely associated with epilepsy and its comorbidities. Dysregulation of the HPA axis is involved in the pathways associated with epilepsy and its comorbidities, while seizure-induced HPA-axis activation can increase the susceptibility to future seizures.⁴²,⁴³ Investigations of the intrinsic link between the HPA axis and epilepsy cannot ignore the roles of CRH, ACTH, and GCs secreted by the HPA axis in epilepsy (Fig. 1).

Fig. 1. Diagram of the HPA axis and epilepsy mechanism. The HPA axis secretes CRH, ACTH, and Glucocorticoids. Experiencing various stresses such as seizures and early-life stress increases the secretion of these hormones by the HPA axis. CRH can act on both CRHR1 and CRHR2 receptors. Reducing CRHR1 receptor expression will reduce the seizure severity and duration. Cortisol can negatively inhibit the secretion of CRH and ACTH, and acts mainly on GRs. The activation of the GR has an antiepileptic effect. ACTH may be involved in the pathogenesis of epilepsy by ameliorating HPA-axis dysfunction. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; CRHR1, CRH receptors 1; CRHR2, CRH receptors 2; GR, glucocorticoid receptor; HPA, hypothalamic-pituitary-adrenal; MR, mineralocorticoids in the hippocampal receptor.

Corticotropin-releasing hormone

CRH is secreted by the hypothalamic PVN, which can exert biological effects by acting on downstream signaling pathways as well as on itself. CRH can act both by enhancing its own biosynthesis in the hypothalamic PVN and by interacting with specific postsynaptic G-protein-coupled receptors to alter intracellular cyclic adenosine monophosphate (cAMP) levels. It was found that chemical activation of CRH neurons in the PVN of the hypothalamus increased seizure susceptibility, while inhibition of CRH neurons in the PVN of the hypothalamus conversely decreased seizure susceptibility in chronically epileptic mice.⁴⁴ CRH-positive neurons in the PVN are hyperactivated after a seizure, leading to high expression levels of CRH mRNA in these cells and increasing the synthesis and release of CRH. When CRH is released, Ca²⁺ is rapidly endocytosed in various cell types, including astrocytes, which induces the Ca²⁺-dependent release of glutamate and other glial transmitters from glial cells, which can enhance the excitability of astrocytes.⁴⁵ Glial cells activated by CRH can also release inflammatory mediators to induce neurodegeneration in the brain, thus further contributing to the development of epilepsy.⁴⁶,⁴⁷ The role of CRH was further investigated by applying it to the lateral ventricles of rats and injecting exogenous corticosterone into the PVN of the hypothalamus, which increased the seizure sensitivity of CRH neurons and the spontaneous discharge of excitatory postsynaptic currents in rats.¹⁰

CRH-expressing neurons have an important localization in the hippocampus. Exposing rats to stress induces CRH gene activation and expression in several limbic regions. CRH is produced and expressed in cell populations such as hippocampal interneurons and Cajal-Retzius cells, is released by GABAergic interneurons, functions in combination with corticotropin-releasing hormone receptor 1 (CRHR1) and 2 (CRHR2), enhances the excitability of pyramidal cells, and is involved in the maturation of hippocampal circuits.⁴⁸ Furthermore, applying CRH to the rodent hippocampus induced a long-duration enhancement of subthreshold stimulation patterns in the pyramidal cell layer of the CA1 region and damaged CA3 hippocampal neurons, which affects the quality of learning and life of epileptic patients later in life.¹⁰ Early environmental enrichment led to a significant reduction in the number of seizures in the GAERS (Genetic Absence Epilepsy Rat from Strasbourg) and a significant reduction in hippocampal CRH mRNA expression levels in adulthood, and reduced CRH expression was associated with an improved epileptic phenotype.⁴⁹

The expression levels of CRH and CRHR1 were significantly higher in the epileptogenic tissues of patients with infantile spasms than in normal control tissues, and they were positively correlated with the incidence of epilepsy.⁵⁰ It was shown that CRHR1-mediated activity after traumatic brain injury can cause abnormal electrical responses in the amygdala that can induce the onset of epilepsy.⁵¹ The duration and severity of convulsions were experimentally found to increase in stress-induced and adrenalectomized rats, while the severity and duration of seizures in rats when receiving CRHR1 inhibitors were significantly reduced.⁵² Also, antagonists of CRHR1 have been shown to reverse the deleterious effects of GCs on hippocampal dendrite development, spine formation, and synapse formation.⁵³ In addition, mice with CRHR1 deficiency or localized deletion develop resistance to the deleterious effects of stress and are protected from the adverse effects of early chronic stress on learning and memory.⁵⁴

Adrenocorticotropic hormone

ACTH is a 39-amino-acid peptide belonging to the melanocortin family that is released by adenopituitary cells in the anterior pituitary gland, and it plays important roles in maintaining the normal structure of the adrenal cortex and in the synthesis and secretion of GCs. ACTH acts mainly on fasciculata and reticularis cells in the adrenal cortex, promoting the conversion of cholesterol to pregnenolone via the AC-cAMP-PKA and PLC-IP3/DG-PKC pathways, thereby increasing cortisol synthesis.⁵⁵,⁵⁶

ACTH may provide functional neuroprotection by restoring hippocampal long-term potentiation and memory consolidation in epileptic Kcna1-null mice (with targeted deletion of the Kv1.1 potassium channel α subunit protein), and also in the Barnes maze test to restore spatial learning and memory.⁵⁷ Combination treatment of ACTH with melatonin reduces the number of N-methyl-D-aspartate (NMDA)-induced convulsions and prolongs the convulsion latency in rats by reversing dysregulation of the HPA axis.⁵⁸ Epilepsy sensitivity is enhanced in mice with salt-inducible kinase 1 (SIK1) mutations, and these mutations lead to inhibition of the pharmacological effects of ACTH on NMDA-induced seizures, which suggests that SIK1 is involved in the pharmacological mechanism of ACTH treatment.⁵⁹

An intrinsic link between ACTH and its binding central melanocortin receptors may be involved in the development of epilepsy. Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by GC deficiency. Mutations in the ACTH receptor (melanocortin 2 receptor) cause type-1 FGD, which can manifest as low serum cortisol levels, high ACTH levels, and seizures.⁶⁰,⁶¹ Animal experiments have shown that central melanocortin receptors that bind to ACTH are significantly reduced compared with controls when epilepsy is experienced early in life, and this dysregulation of central melanocortin receptors may underlie how ACTH affects cognitive function in patients with epilepsy.⁶² In addition, Iacobaş et al.⁶³ showed experimentally that gene expression in the arcuate nucleus (ARC) becomes active after seizures, and altered gene expression in the ARC, which is upstream of the hypothalamic PVN, may influence the release of endogenous CRH and thus the development of epilepsy. Treatment with ACTH resulted in significant reductions of 72% and 77% of the regulated ARC genes in males and females, respectively, suggesting that ACTH also plays a role in epileptogenesis at the level of gene expression.⁶³

Glucocorticoids

ACTH causes GCs to be released from the adrenal glands, which crosses the blood–brain barrier and acts through GRs in areas such as the hippocampus. Activation of GRs affects neuronal excitability and regulates the expression of genes involved in maintaining cell membrane properties, cellular metabolism, neuronal plasticity, and synaptic transmission, and can affect excitability in limbic areas.⁶⁴

Cortisol (corticosterone) is the main GC secreted by the adrenal glands in response to ACTH stimulation. van Campen et al.⁶⁵ analyzed 21 patients with epilepsy and found that cortisol was significantly and positively correlated with epileptiform discharges. A single convulsive seizure event in epilepsy patients can lead to activation of the HPA axis, which increases cortisol secretion, and the resulting cortisol elevation can persist for longer periods.⁶⁶ Chronic-stress-induced cortisol exposure is associated with memory deficits in patients with TLE, with high cortisol in patients with low memory and a slower decline in cortisol in the afternoon, while high concentrations of cortisol exert an inhibitory effect on cortical synaptic enhancement, which is an important cause of co-occurring memory deficits in patients with TLE.⁶⁷,⁶⁸ Also, daily cortisol injections were found to increase plasma basal cortisol levels and resulted in a significant reduction in the latency of generalized convulsions, prolonged convulsive recovery time, and an increase in the number of seizures of longer duration.⁶⁹ Inducing epilepsy via the systemic injection of pilocarpine or kainate in a rodent model of epilepsy increased serum corticosterone levels, with a significant increase in the median cortisol level at 20 minutes after a seizure (by 531.6% in dogs and 40.5% in their controls), with higher levels maintained at 40 minutes after a seizure (265.1% in dogs and 138.2% in controls), and the degree of corticosterone overproduction was positively correlated with the severity of seizure-like activity.⁷⁰ In addition, the degree and duration of GC elevation after trauma or stress also influence the extent of damage to hippocampal cells. The secretion of chronic excess GCs, involved in the pathological process of neuroinflammation, affects the function of hippocampal neurons and promotes the development of epilepsy, depression, and other diseases.⁷¹,⁷²,⁷³ Progressive damage to the filamentous actin cytoskeleton in the hippocampus is associated with epileptogenesis, and GCs can regulate remodeling of hippocampal dendritic spines by acting on GRs and the dynamics of the filamentous actin cytoskeleton.⁷⁴ Meanwhile, GCs have been found to alter hippocampal plasticity by increasing extracellular glutamate levels and calcium conductance, altering the expression of NMDA receptor subunits and reducing glutamate uptake by glial cells, thereby promoting epileptiform discharges and seizures in animals.⁷⁵

GRs are primarily responsible for the physiological effects of stress-induced secretion of GCs, and their activation has an antiepileptic effect and influences the onset of epileptic comorbidity.⁷⁶,⁷⁷ It was found that GR expression was reduced in patients with focal cortical dysplasia type-II epilepsy and in model rats, and administering the GR agonist dexamethasone reduced the number and duration of seizures in model rats by approximately 85% and 60%, respectively, within 1–2 hours.⁷⁸ For patients with TLE combined with depression, GR expression in dentate-gyrus granule cells and CA1-area pyramidal cells was negatively correlated with the severity of depression.⁷⁹ Korgan et al.⁵³ found that prenatal excess GC exposure resulted in reduced GR expression and increased CRH expression, and could affect the development of fetal PVN neurons. In addition, endogenous anti-inflammatory pathway GR-annexin A1 is impaired during epileptogenesis and spontaneous recurrent seizures, and GR downregulation due to excess cortisol during the chronic stress phase increases HPA-axis hyperfunction and exacerbates seizures.⁴⁸,⁸⁰,⁸¹ A particularly interesting finding was that the GRβ (a subtype of the GR) is upregulated in blood–brain barrier endothelial cells in patients with refractory epilepsy with focal cortical dysplasia and can affect functional proteins in the blood–brain barrier, while the GRα/GRβ ratio differs significantly by sex and age (>45 years).⁸² Neural and microvascular overexpression of the GR in human epileptic brain regions is widely localized to heat-shock proteins, which synergistically enhance drug-metabolizing enzymes and drug-efflux transporters in human epileptic brain endothelial cells, thereby reducing drug accessibility to target epileptic brain regions and leading to the development of drug resistance.⁸³

HPA AXIS: A NEW THERAPEUTIC TARGET FOR EPILEPSY

The HPA axis is becoming more widely targeted in epilepsy treatments. The CRH acts as a switch in the HPA axis and influences seizure susceptibility. The HPA axis mediated by the organism’s stress response is largely under GABAergic control, and impaired GABAergic control may lead to hyperexcitability of the HPA axis and increased susceptibility to future seizures. Tetrahydrodeoxycorticosterone can modulate ACTH-releasing neurons by acting on GABA(A) subunit receptors, enhancing the inhibitory effect of GABA on CRH neurons, decreasing HPA-axis activity, and reducing seizures.⁸⁴ Activation of the HPA axis can lead to increased susceptibility to future seizure events, and this susceptibility can be reduced by antalarmin-induced blockade of the CRH signaling pathway.⁸⁵ In addition, it was found that decreased miRNA-212 in mice was associated with medial TLE, and miRNA-212 regulates the expression of CRH in hypothalamic and hippocampal cells, which plays a counterregulatory role in CRH expression and HPA-axis activity. A microRNA-based intervention method may be promising in future treatments of epilepsy induced by HPA-axis hyperfunction.⁸⁶

GCs play a bidirectional role in the treatment of epilepsy. Treatment with GR-blocking mifepristone (also known as RU-486) significantly attenuated seizures induced by neurosteroid withdrawal in a rat model of epilepsy. RU-486 treatment also attenuated post-convulsion-induced pathological changes in the hippocampus, reduced the proliferation of pathological cells in the hippocampal dentate lobe, and reduced cell loss in the hippocampus.⁸⁷,⁸⁸ The GR-specific antagonist CORT108297 reduces brain pathological changes after persistent epilepsy and normalizes baseline levels of corticosterone, and may be useful as a new therapy for preventing brain pathological changes after persistent epilepsy.⁸⁹

ACTH is the preferred option for the short-term treatment of infantile spasms. However, studies have found no significant difference between the effects of ACTH and prednisolone treatments for infantile spasms, and prednisolone may be a suitable alternative to ACTH in resource-poor settings.⁷³,⁹⁰ Baicalein restores disturbances in GC signaling pathways and actin-related proteins, inhibits oxidative stress in TLE rats, protects hippocampal neurons, and may be used as an adjuvant in epilepsy treatment.⁹¹ Intravenous GCs are effective in the treatment of acute refractory and superrefractory persistent epilepsy, with a better overall prognosis especially in inflammatory causes of persistent epilepsy.⁹² Acute symptoms such as seizures in PCDH19 female epilepsy—resulting from a heterozygous defect in the gene encoding protocadherin 19 that causes early-onset intractable epilepsy in females—can be significantly and rapidly improved by GC treatment.⁹³

It should also be noted that GCs are effective in the treatment of primary hereditary generalized epilepsy. In particular, in infantile epileptic spasms syndrome, Lennox-Gastaut syndrome, and Landau-Kleffner syndrome, which occur in infants and young children, GCs can significantly inhibit epileptiform discharges and improve nerve function. However, they have no definite effect on focal epilepsy and metabolic epilepsy.

Recent studies have evaluated the efficacy of ACTH in intractable epilepsy. It was found that 72% of patients achieved moderate (50%–80%) or significant (>80%) reductions in seizure frequency and significant improvement in electroencephalogram (EEG) abnormalities at 3 months after treatment.⁹⁴ Treating infantile spasms using high-dose ACTH stopped the spasms, stopped interictal epileptiform discharges on EEG, and reduced self-injurious behavior and sleep disturbance.⁹⁵,⁹⁶,⁹⁷ The AQB-565 molecule includes the first 24 amino acids of ACTH, a 10-amino-acid linker, and a modified melanocyte-stimulating hormone molecule, which has similar efficacy to ACTH but with fewer side effects. AQB-565 was found to inhibit spasticity in rats and is a promising novel approach for the treatment of infantile spasms.⁹⁸

CONCLUSION

The HPA axis plays an important role in the development of epilepsy. The secretion of CRH, ACTH, and GCs affects the abnormal activity of neurons, and seizures also cause the abnormal secretion of these hormones. Further clarification of the mechanisms linking epilepsy and the HPA axis will provide important guidance for future antiepileptic treatments and the development of antiepileptic drugs in the future.

Availability of Data and Material

The data that support the findings of this study are available from the corresponding author, upon reasonable request.