Abstract
Neuroprotective Levels of IGF-1 Exacerbate Epileptogenesis after Brain Injury
Song Y, Pimentel C, Walters K, Boller L, Ghiasvand S, Liu J, Staley KJ, Berdichevsky Y. Sci Rep 2016;6:32095.
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.
Commentary
Inflammatory processes are emerging as potential pathological mechanisms contributing to the development and worsening of the epilepsies (for review see (1) and (2)). Recent interest in inflammation in the epilepsies stems from evidence that epilepsy is associated with increased levels of soluble factors and their receptors, such as cytokines with proinflammatory properties, which can influence neuronal excitability and seizure susceptibility (for review see (1)). Thus, there is enthusiasm regarding the potential of targeting components of the immune system for the treatment of epilepsy.
The highlighted manuscript focuses on the neuroprotective effects of insulin-like growth factor-1 (IGF-1) and the impact on network excitability. Although IGF-1 is predominantly known for its role as a growth factor, IGF-1 has also been shown to exert neuroprotective effects and modulate immune function. The rationale for the current study is based on the evidence that IGF-1 is neuroprotective in experimental models of brain injury (for review see (3–4)). This study investigates whether IGF-1 also exerts neuroprotective effects in a model of posttraumatic epilepsy.
IGF-1 levels have been shown to be elevated in tissue resected from patients with epilepsy and in animal models of epilepsy (5). In addition, the IGF-1 receptor is phosphorylated, indicating activation, in both patients with temporal lobe epilepsy and in experimental epilepsy models (5). Here, the authors investigate whether IGF-1 exerts neuroprotective effects in an organotypic slice model of brain injury and epileptogenesis. Acute, exogenous IGF-1 treatment immediately following the tissue trauma (slicing, 0–3 DIV) decreased cell death in the CA1 and CA3 subregions of the hippocampus. However, delayed and prolonged IGF-1 treatment following tissue trauma (slicing, 3–25 DIV) was not neuroprotective. In fact, prolonged IGF-1 treatment exacerbated epileptiform activity in the organotypic slice model. The duration and number of epileptiform events were increased by prolonged IGF-1 treatment, leading to an increase in the duration of seizure-like activity per hour. This study demonstrates a dichotomy in the actions of IGF-1 following brain injury, producing neuroprotective effects but exacerbating epileptogenesis.
In contrast, acute IGF-1 treatment did not exert any effects on epileptiform activity, suggesting that the effect of prolonged IGF-1 treatment on epileptogenesis is not due to an acute proconvulsant effect, but is rather influencing epileptogenesis through a downstream pathway. The authors demonstrate an early increase in the phosphorylation of Akt at Ser473 and S6 at Ser235/236 and Ser240/244, suggesting activation of the PI3K/Akt/mTOR pathway, previously implicated by this group in epileptogenesis in the same posttraumatic epilepsy model (6).
The mammalian target of rapamycin (mTOR) is part of an elaborate signaling cascade involved in increased protein synthesis, cell survival, proliferation, and axonal growth (for review see (7)). Interest in mTOR in epilepsy seemingly blossomed from evidence of mTOR hyperactivation in tuberous sclerosis complex (TSC), which is an autosomal dominant disorder resulting from mutations in TSC1 or TSC2 genes, leading to the formation of brain lesions, such as cortical tubers, cognitive impairments, and epilepsy. Because the TSC1-TSC2 complex is a negative regulator of mTOR signaling, TSC (caused by loss-of-function mutations in TSC1 or TSC2) is associated with hyper-activation of mTOR, and mTOR inhibitors, such as rapamycin, are being explored for treatment of TSC (8).
There is also abundant evidence for a role for mTOR in mossy fiber sprouting associated with epileptogenesis (9). However, the impact on seizure frequency is less clear. Blocking mTOR signaling with rapamycin following pilocarpine-induced status epilepticus was sufficient to decrease mossy fiber sprouting, but did not impact seizure frequency (10,11), suggesting that mTOR-mediated mossy fiber sprouting does not exacerbate or suppress epileptogenesis. However, another study demonstrated that pretreatment with rapamycin prior to kainic acid–induced status epilepticus decreased cell death, neurogenesis, mossy fiber sprouting, and the development of spontaneous seizures (12). Rapamycin treatment 24 hours following status epilepticus decreased mossy fiber sprouting and the development of spontaneous seizures, but did not alter neurogenesis or neuronal cell death (12).
These data suggest commonalities between excessive mTOR signaling and the development of epilepsy in both in vitro (organotypic slices) and in vivo (TSC and posttraumatic) epilepsy models. One consideration is the fact that the incidence of epilepsy in the organotypic brain injury model is more prevalent than in vivo epilepsy models. The authors note that it is possible that prolonged IGF-1 treatment exacerbates ictal activity in tissue that is already epileptic, but may decrease the incidence of epilepsy in physiological models with a lower risk for developing epilepsy. These data suggest that there may be a time and a place for IGF-1 treatment, exerting acute neuroprotective effects; whereas, prolonged treatment may have adverse consequences including increasing seizure risk.
Another consideration is the possibility that rescuing neurons that may be “better off dead,” according to the authors, may cause pathological changes leading to epilepsy. This concept is reminiscent of the idea that ectopic granule cells (13) or mossy cell loss/mossy fiber sprouting (14) may contribute to hyperexcitability of the network and seizure generation. Therefore, neuroprotection may not be enough to spare the network, but requires that the remaining neurons are organized and wired appropriately.