# Targeting CRHR1 Signaling in Experimental Infantile Epileptic Spasms Syndrome: Evidence for Route-Dependent Efficacy

## TL;DR

Blocking CRHR1 can reduce infantile epileptic spasms, but the effect depends on the drug and delivery route, with SN003 showing better results than CP376395 when given systemically.

## Contribution

The study reveals route- and drug-specific efficacy of CRHR1 antagonists in suppressing infantile spasms, suggesting SN003 is a better candidate for future therapies.

## Key findings

- CRHR1 antagonists suppress spasms in a route-, drug-, and brain-site-specific manner.
- Systemic SN003 reduces spasms, while systemic CP376395 paradoxically worsens them.
- The hypothalamic arcuate nucleus is a key site for spasm generation and therapeutic targeting.

## Abstract

What are the main findings?
CRHR1 antagonists suppress experimental infantile spasms in a route-, drug-, and brain-site-specific manner.Systemic SN003 reduces spasms, whereas systemic CP376395 paradoxically exacerbates them, despite both being effective when delivered intracranially.

CRHR1 antagonists suppress experimental infantile spasms in a route-, drug-, and brain-site-specific manner.

Systemic SN003 reduces spasms, whereas systemic CP376395 paradoxically exacerbates them, despite both being effective when delivered intracranially.

What are the implications of the main findings?
Discrete hypothalamic circuits, particularly the arcuate nucleus, play a pivotal role in spasm generation and are viable therapeutic targets.SN003 may be a better option for further translational development than CP376395 for CRHR1-targeted therapy in infantile epileptic spasms syndrome.

Discrete hypothalamic circuits, particularly the arcuate nucleus, play a pivotal role in spasm generation and are viable therapeutic targets.

SN003 may be a better option for further translational development than CP376395 for CRHR1-targeted therapy in infantile epileptic spasms syndrome.

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.