Infantile spasms is a severe childhood seizure disorder. The incidence is 1 in every 2000 -3000 live births. The spasms are only a few seconds in duration but occur in clusters of up to 100 in a few minutes. The EEG correlates of the disorder are unique. Coincident with each behavioral spasm is a brief ictal event and the interictal EEG is dominated by a chaotic pattern called hypsarrhythmia. The majority of children are intellectually disabled later in life and most of them develop other forms of drug resistant epilepsy. ACTH and vigabatrin can abolish spasms and hypsarrhythmia in 30-80% of patients - depending on the study. However, both drugs can have significant side effects and usually do not prevent the development of the intellectual disabilities and severe epilepsy seen later. Thus better treatments are needed and the hope is that with the advent of relevant animal models, the discovery of underlying mechanisms will lead to new therapies. Our laboratory has developed a model of infantile spasms that recreates the critical features of the disorder. Like infants, the majority of these animals respond to both ACTH and vigabatrin. However, our work has also pointed to a potential new therapy for this disorder. We have found that the expression of Insulin-like Growth Factor -1 (IGF-1) is suppressed in the neocortex of animals with spasms as is signaling through the PI3K-AKT- mTOR growth pathway. At the same time, the expression of parvalbumin and synaptotagmin 2, biomarkers for an important class of inhibitory interneurons and their presynaptic nerve terminals, are also reduced. This has led us to hypothesize that reduced signaling through the PI3K-AKT-mTOR pathway impairs inhibitory interneuron growth which results in an imbalance in synaptic excitation and inhibition and epileptic spasms. Remarkably, treatment with (1-3)IGF-1, a tripeptide derivative of IGF-1, rescues the inhibitory interneurons and abolishes spasms and hypsarrhythmia in over 60% of animals. Moreover, (1-3)IGF-1 dramatically augments the anticonvulsant effects of vigabatrin, reducing the dosage needed to abolish spasms and potentially eliminates its retinotoxicity. This synergy is likely produced by (1-3)IGF-1?s increase in the number of GABAergic nerve terminals and vigabatrin-induced increase in GABA levels in the same synapses. However, very little is known about (1-3)IGF-1 and experiments proposed here focus on understanding its mechanism of action. We plan to test 2 hypotheses. The first is that (1-3)IGF-1 acts through the IGF-1 receptor to activate the PI3K-AKT-mTOR growth pathway. The second is that (1-3)IGF-1 stimulates the growth of parvalbumin interneurons and thereby adds new GABAergic nerve terminals to the neocortex. Lastly, we will attempt to show that (1-3)IGF-1 acts via the IGF-1 receptor when it augments the anticonvulsant effects of vigabatrin. Our results will advance an understanding of the actions of a novel, naturally occurring neuropeptide that likely plays an important roles in neurodevelopment and neurodevelopmental disorders. Moreover, the combination therapy of (1-3)IGF-1 and vigabatrin has significant potential as a better way to treat infantile spasms.

Public Health Relevance

. Infantile spasms is a severe childhood seizure disorder. Our results show that a novel neuropeptide called (1- 3)IGF-1 when given in combination with the anticonvulsant vigabatrin is very effective in abolishing spasms and it likely will reduce vigabatrin's serious side effects. Experiments proposed here attempt to understand (1- 3)IGF-1 mechanism of action in order to develop a new combination therapy for this epilepsy of early childhood.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS105913-03
Application #
9859474
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
2018-03-15
Project End
2023-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030