Blockade of Corticotropin-Releasing Hormone Receptor 1 Receptors in the Arcuate Nucleus May Effectively Treat Infantile Epileptic Spasms Syndrome

Abstract

Targeting Corticotropin-Releasing Hormone Receptor 1 Signaling in Experimental Infantile Epileptic Spasms Syndrome: Evidence for Route-Dependent Efficacy.

Chachua T, Yum MS, Chern CR, Vieira K, Velíšková J, Velíšek L. Targeting CRHR1 Signaling in Experimental Infantile Epileptic Spasms Syndrome: Evidence for Route-Dependent Efficacy. Children (Basel). 2026 Jan 14;13(1):125. doi: 10.3390/children13010125. PMID: 41597133; PMCID: PMC12840083.

Background/Objectives: Infantile epileptic spasms syndrome (IESS) is a severe epilepsy of infancy. Corticotropin (ACTH) and vigabatrin are the only FDA-approved therapies. The efficacy of ACTH together with the strong convulsant effects of corticotropin-releasing hormone (CRH) suggests that excess CRH, secondary to impaired ACTH feedback, may contribute to spasms. We therefore hypothesized that CRH receptor 1 (CRHR1) antagonists would suppress spasms in a route- and drug-dependent manner. Methods: Using our validated rat model of IESS, in which prenatal priming with betamethasone was followed by postnatal triggering of spasms with N-methyl-D-aspartic acid (NMDA), we tested two CRHR1 antagonists, CP376395 and SN003, delivered intracranially (via intracerebroventricular or intraparenchymal infusion) or systemically. Results: Intracerebroventricular infusion of both antagonists suppressed spasms, with CP376395 providing more consistent effects. Intraparenchymal administration into the hypothalamic arcuate nucleus also reduced spasms, whereas misses into the mammillary bodies were ineffective, highlighting site specificity. Systemic administration yielded divergent results: SN003 robustly suppressed spasms, whereas CP376395 unexpectedly exacerbated them. No sex differences were observed. Conclusions: These findings demonstrate that CRHR1 blockade modifies experimental spasms in a route- and drug-specific manner and implicates discrete hypothalamic circuits, particularly those including the arcuate nucleus, in spasm generation. The divergent systemic responses between CP376395 and SN003 likely reflect differences in CRHR1 engagement (competitive and non-competitive antagonism, respectively) as well as differences in binding properties that may include differential network interactions beyond local CRH signaling or duration of receptor occupancy. In conclusion, SN003 may be a better option than CP376395 for further development as a CRHR1-targeted therapy pending additional pharmacokinetic/pharmacodynamic studies. Further work should explore dosing paradigms of CP376395 to determine if a therapeutic range for CP376395 exists.

Commentary

Our inability to identify the underlying pathophysiology and to effectively control seizures in patients with IESS), a developmental and epileptic encephalopathy, remains a significant pediatric clinical challenge. Infantile spasms (IS) consisting of seizures during infancy accompanied by behavioral spasms and developmental regression were first described by West in the 1800s and termed West Syndrome. Once the EEG became available, the additional feature of a chaotic interictal EEG termed hypsarrhythmia was added to the diagnostic criteria. ¹ However, the recognition that not all patients who develop seizures during the first 2 years of life exhibit a developmental regression or hypsarrhythmia in the EEG led the ILAE to create the broader classification of IESS to include patients who exhibit epileptic spasms during the first two years of life accompanied by an epileptiform EEG. ² The observation that the spasms could be treated with adrenal corticotropin hormone (ACTH)^3,4 independent of an increase in cortisol ⁵ and experimental evidence that central administration of CRH could trigger the spasms ⁶ led to the CRH excess theory as the potential mechanism for the generation of the spasms.^7,8 The theory hypothesized that stress triggers an increase in the release of CRH during infancy when the expression of CRH receptors is elevated. The increase in CRH is accompanied by a decrease in ACTH feedback leading to the development of spasms.^7,8 Currently, ACTH and vigabatrin are used to treat patients with IESS but their efficacy is limited and often accompanied by significant side effects. ²

Based on the CRH excess theory, the highlighted study ⁹ tested the hypothesis that inhibiting the CRH-1 receptor (CRHR1) would prevent or suppress the spasms associated with IESS. The study tested the efficacy of two CRHR1 antagonists: (1) CP376395, a competitive antagonist and (2) SN003, a non-competitive antagonist. Both antagonists were tested intracerebrally and via systemic administration in an established rat model of IESS ¹⁰ in which the animals exhibit spasms accompanied by interictal and ictal EEG patterns similar to what is observed clinically. To execute the model, timed pregnant female Sprague-Dawley rats received two injections of betamethasone phosphate dissolved in saline (0.4 mg/kg, i.p.) on G23. To induce spasms, NMDA (15 mg/kg, i.p.) was injected on P15. For intracerebral drug administration, a guide cannula was implanted on P13 at one of three targets: (1) The lateral ventricle; (2) the third ventricle and (3) the arcuate nucleus. The arcuate nucleus was targeted for intraparenchymal administration due to the presence of a high concentration of CRHR1 receptors ¹¹ and the previous identification of it being involved in the generation of spasms. ¹⁰

In both experiments, the antagonists were administered 1hr prior to the induction of spasms with NMDA. For intracerebral delivery CP376395 (1 µM), SN003 (1 and 10 µM) or saline was microinfused (0.5 µl) into one of the 3 targeted sites. However, SN003 was not delivered to the third ventricle. Histology was performed to confirm placement of the cannulas. For systemic administration, CP376395 (3 mg/kg, i.p.) dissolved in saline or SN003 (0.7 mg/kg, i.p.) dissolved in 1% ethanol in saline, were administered to male and female pups. Controls were treated with the appropriate vehicle. The efficacy of each CRHR1 antagonist was assessed by measuring the latency to the onset of spasms and the number of spasms over 90 min post NMDA administration. Microinfusion of CP376395 into the lateral ventricle significantly increased the latency to the onset of spasms and significantly decreased the number of spasms. However, the infusion of CP376395 into the third ventricle had no effect on latency but did significantly decrease the number of spasms. The intraparenchymal administration of CP376395 into the arcuate nucleus significantly delayed the onset of spasms and decreased their frequency. SN003 (1 µM) microinfused into the lateral ventricle had no effect on spasm latency or number of spasms. The higher concentration of SN003 (10 µM) also had no effect on the latency to onset of spasms however it significantly decreased the number of spasms. Microinfusion of SN003 (10 µM) into the arcuate nucleus also significantly increased latency and decrease the number of spasms. A differential response was observed between the two CRHR1 antagonists when they were administered systemically. Neither drug increased the latency to the onset of spasms and CP376395 unexpectedly significantly increased the number of spasms while SN003 significantly decreased the number of spasms.

The results from the intracerebral administration of both CRHR1 antagonists confirm that activation of CRHR1 receptors in the hypothalamic arcuate nucleus plays a central role in the generation of spasms in this experimental model of IESS. The contribution of the arcuate is further supported by the observation that when intraparenchymal injections of CP376395 missed their target, and were delivered to the mammillary bodies, a structure with lower expression of CRHR1 receptors, there was no effect on latency or the number of spasms. There did not appear to be a concern that the CRHR1 antagonists could diffuse into the hypophyseal portal system to alter pituitary function due to the clinical observation of a diminished ACTH response in patients with IESS. Moving forward it will be important to determine the effect of CRHR1 antagonists on ACTH levels. It was surprising that the intraventricular injection of CP376395 into the lateral ventricle was more effective than injections into the third ventricle given the location of the third ventricle relative to the arcuate. It would have been informative if EEG was also collected during these experiments to determine how inhibition of the CRHR1 receptor affected the electrographic epileptiform activity associated with the spasms. It was also interesting that both drugs showed efficacy against the number of spasms, but often not the latency to onset. An interpretation of the differential response to the route of administration and mechanism of action of the two CRHR1 antagonists is less straightforward. The observation that CP376395 administered systemically exacerbated the number of spasms, opposite of its central effect, suggests the drug was potentially binding to extrahypothalamic sites. Another possibility raised by the authors was a CRH rebound due to CP376395 occupying the receptor for a short duration, but that would also be true after central administration. Independent of the mechanism by which CP376395 exacerbated the incidence of spasms, SN003 appears to be the better candidate for translation to therapy.

In conclusion, the results from the study by Chachua et al. ⁹ support the hypothesis that an excess of CRH binding to the CRHR1 receptor being responsible for the generation of spasms in a model of IESS and confirm the participation of the hypothalamic arcuate nucleus and its potential to be a target for therapeutic intervention. The optimal route for administration of a CRHR1 antagonist and the best mechanism for blocking CRHR1 activation requires further investigation.