title: Neuroprotective levels of IGF-1 exacerbate epileptogenesis after brain injury.
abstract: Exogenous Insulin-Like Growth Factor-1 (IGF-1) is neuroprotective in animal models of brain injury, and has been considered as a potential therapeutic. Akt-mTOR and MAPK are downstream targets of IGF-1 signaling that are activated after brain injury. However, both brain injury and mTOR are linked to epilepsy, raising the possibility that IGF-1 may be epileptogenic. Here, we considered the role of IGF-1 in development of epilepsy after brain injury, using the organotypic hippocampal culture model of post-traumatic epileptogenesis. We found that IGF-1 was neuroprotective within a few days of injury but that long-term IGF-1 treatment was pro-epileptic. Pro-epileptic effects of IGF-1 were mediated by Akt-mTOR signaling. We also found that IGF-1 - mediated increase in epileptic activity led to neurotoxicity. The dualistic nature of effects of IGF-1 treatment demonstrates that anabolic enhancement through IGF-1 activation of mTOR cascade can be beneficial or harmful depending on the stage of the disease. Our findings suggest that epilepsy risk may need to be considered in the design of neuroprotective treatments for brain injury.
authors: Bioengineering Program, Lehigh University, Bethlehem, PA 18015, USA.
authors: Yu
authors: Y
authors: Song
authors: Bioengineering Program, Lehigh University, Bethlehem, PA 18015, USA.
authors: Corrin
authors: C
authors: Pimentel
authors: Integrated Degree in Engineering, Arts, and Sciences (IDEAS) Program, Lehigh University, PA 18015, USA.
authors: Katherine
authors: K
authors: Walters
authors: Bioengineering Program, Lehigh University, Bethlehem, PA 18015, USA.
authors: Lauren
authors: L
authors: Boller
authors: Bioengineering Program, Lehigh University, Bethlehem, PA 18015, USA.
authors: Shabnam
authors: S
authors: Ghiasvand
authors: Department of Electrical and Computer Engineering, Lehigh University, Bethlehem, PA 18015, USA.
authors: Jing
authors: J
authors: Liu
authors: Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA.|Harvard Medical School, Boston, MA 02129, USA.
authors: Kevin J
authors: KJ
authors: Staley
authors: Bioengineering Program, Lehigh University, Bethlehem, PA 18015, USA.|Department of Electrical and Computer Engineering, Lehigh University, Bethlehem, PA 18015, USA.
authors: Yevgeny
authors: Y
authors: Berdichevsky
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004827:Epilepsy / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases