Pediatric spasm (CP) is a severe epileptic syndrome of infancy and accounts for 50% of all cases of epilepsy occurring in infants during the first year of life. Current treatments for this condition are limited, and most affected infants grow with developmental delays, intellectual disabilities, and other types of severe epilepsy. A groundbreaking study by Dr. John Swan, director of laboratories at the Gordon and Mary Kane Foundation for Pediatric Neurology, a researcher at the Ian and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, and Professor Baynell of the University of Texas at the University of Texas. -1 (IGF-1) and its downstream signaling are reduced in the brains of both IP patients and animal models. In addition, they found that the introduction of an IGF-1 analog to the animal model of IS successfully eliminated spasms and abnormal brain activity. This is an exciting study published in Annals of Neurologyhas the potential to change the treatment landscape of infants with infantile spasms.
Dr. Swan is a leading expert in epilepsy research, and a few years ago his team’s groundbreaking discoveries led to FDA-approved treatment for severe epilepsy among patients with tuberous sclerosis. He and his team had a long-standing interest and experience in studying infantile spasms, an epileptic disorder that is diagnosed in approximately 2,500 infants in the United States each year.
Brain damage in early life lowers IGF-1 levels and disrupts the IGF-1 signaling pathway
“It has previously been reported that patients with IP with pre-existing brain abnormalities have low levels of IGF-1 in cerebrospinal fluid, and based on this study we were interested in a study where IGF-1 levels were altered in the brains of animals and patients with IS” said Swan.
For their research, the team used a well-established method to induce spontaneous epileptic seizures in rodents. This methodology, developed in 2008 at Swann Laboratory, involves chronic infusion of tetradotoxin (TTX) into the cerebral cortex of infant rats, causing damage to the infusoria site and leading to spasms that are virtually identical to those seen in patients with IP. .
“As expected after the traumatic brain injury, we saw an increase in IGF-1 levels in non-neuronal support cells (aka glia) at the TTX infusion site. However, we were most intrigued by the significant and widespread decrease in IGF Expression -1 in cortical neurons in the head the brain adjacent to or farther from the TTX injection site is a phenomenon that has never been reported before, ”Swan said.
The team then examined resected cortical tissues in patients with IP who had previously suffered a perinatal stroke and underwent surgery to control their intractable seizures. The results were remarkably similar to what they saw in animal IP.
“More importantly, we found that this decrease in IGF-1 levels had significant effects on animal IS models because it weakened the overall activity of the IGF-1 molecular signaling pathways that regulate many important biological processes involved in early development. brain and neuronal function. “, – said Dr. Carlos Balester-Rasada, a postdoctoral fellow in the Swann laboratory and the first author of the study.
The IGF-1 analogue eliminates infantile spasms in animals
To determine whether an increase in IGF-1 levels in the cortex of animals with IS could alleviate spasms, the team used a smaller version of IGF-1 that can cross the blood-brain barrier more easily than full-length hormone. The IGF-1 tripeptide they tested is a natural byproduct of IGF-1 breakdown that is commonly found in the brain. Moreover, it has previously been shown that this analogue successfully eliminates behavioral defects in animal models of other nervous system disorders such as Rhett syndrome and Phelan-McDermid syndrome.
“Using several pieces of evidence, we first confirmed that this IGF-1 tripeptide is capable of activating the IGF-1 signaling cascade in mice,” Swan said. “Then we found – to our surprise – that the introduction of IGF-1 successfully eliminated spasms and IS-specific chaotic brain activity called hypsorrhythmia in most animals with IS. We are excited because these findings increase the exciting possibility that it is an analogue of IGF -1 could be used to treat patients with IP in the future. ”
The study involved John Le, Trang Lam, Carrie Mohila, Sandy Lam, Anne Anderson and James Frost. The authors are affiliated with one or more of the following institutions: the Cain Foundation Laboratories, the Jan and Dan Duncan Institute for Neurological Research at Texas Children’s Hospital, and Baylor College of Medicine. The study was funded by the CURE Epilepsy Infantile Spasm Initiative, grants from the National Institutes of Health (RO1 NS018309, RO1 NS105913 and R61 / R33 NS112553) and Centers for Intellectual and Developmental Disabilities (1U5094 Kenedy National Institute of Health, 1U5092 HD083). and human development.
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