Insulin-like growth factor-1 (IGF-1) is known to promote neurogenesis and survival. However, recent studies have suggested that IGF-1 regulates neuronal firing and excitatory neurotransmission. In the present study, focusing on temporal lobe epilepsy, we found that IGF-1 levels and IGF-1 receptor activation are increased in human epileptogenic tissues, and pilocarpine- and pentylenetetrazole-treated rat models. Using an acute model of seizures, we showed that lateral cerebroventricular infusion of IGF-1 elevates IGF-1 receptor (IGF-1R) signalling before pilocarpine application had proconvulsant effects. In vivo electroencephalogram recordings and power spectrogram analysis of local field potential revealed that IGF-1 promotes epileptiform activities. This effect is diminished by co-application of an IGF-1R inhibitor. In an in vitro electrophysiological study, we demonstrated that IGF-1 enhancement of excitatory neurotransmission and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor- and N-methyl-D-aspartate receptor-mediated currents is inhibited by IGF-1R inhibitor. Finally, activation of extracellular signal-related kinase (ERK)-1/2 and protein kinase B (Akt) in seizures in rats is increased by exogenous IGF-1 and diminished by picropodophyllin. A behavioural study reveals that the ERK1/2 or Akt inhibitor attenuates seizure activity. These results indicate that increased IGF-1 levels after recurrent hippocampal neuronal firings might, in turn, promote seizure activity via IGF-1R-dependent mechanisms. The present study presents a previously unappreciated role of IGF-1R in the development of seizure activity.
Repulsive guidance molecule a (RGMa) is a membrane-bound protein that inhibits axon outgrowth in the central nervous system. Temporal lobe epilepsy (TLE) is a common neurological disorder characterized by recurrent spontaneous seizures. To explore the role of RGMa in epilepsy, we investigated the expression of RGMa in patients with TLE, pilocarpine-induced rat model, and pentylenetetrazol kindling model of epilepsy, and then we performed behavioral, histological, and electrophysiological analysis by lentivirus-mediated overexpression of RGMa in the hippocampus of animal model. We found that RGMa was significantly decreased in TLE patients and in experimental rats from 6 h to 60 days after pilocarpine-induced seizures. In two types of epileptic animal models, pilocarpine-induced model and pentylenetetrazol kindling model, overexpression of RGMa in the hippocampus of rats exerted seizure-suppressant effects. The reduced spontaneous seizures were accompanied by attenuation of hippocampal mossy fiber sprouting. In addition, overexpression of RGMa inhibited hyperexcitability of hippocampal neurons via suppressing NMDAR-mediated currents in Mg-free-induced organotypic slice model. Collectively, these results demonstrate that overexpression of RGMa could be an alternative strategy for epilepsy therapy.
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