Abstract
Many neurological disorders of gluten-related diseases (GRD), not directly referable to the gastrointestinal tract, have been reported in association with celiac disease (CD), including ataxia, neuropathy and epilepsy. In particular, people with epilepsy diagnosed with CD seems to be characterized by intractable seizure. In these patients, gluten restriction diet has resulted in a reduction of both seizure frequency and antiepileptic medication. Many hypotheses have been suggested, however, molecular mechanisms that associates GRD and epileptogenesis are yet unknown. In this study, we examined the effects of the toxic gliadin peptide 31-43 in in vivo and in vitro models of kainate-induced-epilepsy. We observed that p31-43 exacerbates kainate neurotoxicity in epilepsy models, through the involvement of the enzymatic activity of transglutaminases. Moreover, electrophysiological recordings in CA3 pyramidal neurons of organotypic hippocampal slices show that p31-43 increases the inward current induced by kainate, the average sEPSC amplitude and the total number of evoked action potentials when applicated alone, thus suggesting that p31-43 is able to influence CA3-CA1 neurotransmission and can potentiate postsynaptic kainate receptors. Our results suggest a possible mechanism underlying the relationship between GRD and epilepsy through a potentiation of kainate-induced neurotoxicity and links the toxic effects of gluten to epilepsy.
Highlights
The symptoms of Celiac Disease (CD) or gluten-related diseases (GRD) are mostly characterized by digestive symptoms, which are often the first perceived signs of gluten intolerance
We studied the effects of gliadin peptide 31-43 in in vivo and in vitro models of kainate-induced-epilepsy and we observed that p31-43 exacerbates kainate neurotoxicity in epilepsy models, suggesting an increased excitotoxic synaptic activity of CA3-CA1 neurotransmission
The gliadin peptide p31-43 increases kainate-induced inward current in CA3 pyramidal cells of organotypic hippocampal slices
Summary
The symptoms of Celiac Disease (CD) or gluten-related diseases (GRD) are mostly characterized by digestive symptoms, which are often the first perceived signs of gluten intolerance. Converging evidences suggest that the gluten-mediated immune response is frequently associated with neurological and psychiatric manifestations, including ataxia, neuropathy and epilepsy[1]. The anti-TG2 antibodies are used as serological tests for identifying CD patients, but have been recently implicated in the pathogenesis of several neurodegenerative diseases[10]. Another enzyme of the transglutaminase family primarily expressed in the central nervous system is transglutaminase 6 (TG6)[11]. TG6 antibodies were identified in immune-mediated ataxia in patients with gluten sensitivity suggesting a critical role for TG6 in cortical and cerebellar neurons[12].
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