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.
Highlights
Insulin-Like Growth Factor-1 (IGF-1) signaling is involved in neural differentiation, survival, and response to brain injury[1,2]
We used confocal microscopy to evaluate and compare numbers of neurons in organotypic hippocampal cultures when IGF-1 was included in medium immediately after trauma on days in vitro (DIV) 0–3
We found that cultures maintained in the presence of 20 nM IGF-1 had significantly more surviving CA3c and CA1 neurons (ANOVA p < 0.001, with post-hoc p < 0.001 in both cases, n = 6 cultures) after DIV 3 than cultures maintained in medium without IGF-1 or other growth factors (Fig. 2a,b)
Summary
Insulin-Like Growth Factor-1 (IGF-1) signaling is involved in neural differentiation, survival, and response to brain injury[1,2]. One of the effectors of Akt signaling is the mTOR cascade[20], and traumatic brain injury was found to cause changes in the mTOR pathway, including an increase in phosphorylation of ribosomal S6 protein[19,21,22]. In an animal model of TBI and posttraumatic epileptogenesis, the mTOR inhibitor rapamycin decreased the seizure frequency and rate of development of posttraumatic epilepsy[22]. In the organotypic culture model of post-traumatic epileptogenesis, mTOR activation was mediated by PI3K-Akt pathway suggesting that growth factor signaling may be involved[31]. Since brain injury is associated with changes in IGF-1 signaling, and one of the downstream effectors of IGF-1 signaling, mTOR pathway, is involved in epileptogenesis, it is possible that neuroprotective levels of IGF-1 may play a role in the development of epilepsy. In this in vitro model, the critical features of clinical epileptogenesis are captured on a compressed scale: latent period after injury characterized by axon sprouting, followed by gradual onset of population spiking activity and spontaneous electrographic seizures, seizure clustering and status epilepticus that leads to activity-dependent neuron death[36] (Fig. 1)
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