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TGFβ Signaling Related Moleculars in the Mechanism of Epilepsy

Author: DuYingShi
Tutor: LvYang
School: Chongqing Medical University
Course: Geriatrics
Keywords: epilepsy SNX25 SARA rats TLE
CLC: R742.1
Type: Master's thesis
Year: 2013
Downloads: 36
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Abstract


Purpose: Researches show that transforming growth factor beta(TGF-β) signal pathway involved in epileptogenesis and could become apotential treatment target. Sorting Nexin25(SNX25) has been recentlyproposed to modulate TGF-β signaling through endosomal sorting ofTGF-β receptors for lysosomal degradation. Studies on SNX25may revealthe particular mechanisms and cellular pathways that bridge TGF-βsignaling and seizures. The other important protein, Smad Anchor forReceptor Activation (SARA), as a regulator of TGF-β signaling, recruitsSmad2/3to type TβR. However, it is still unknown whether SARAactivation via TGF-β signaling leads to epilepsy.Methods: We investigated the expression of SNX25and SARA in thebrain tissues of patients with temporal lobe epilepsy (TLE) and in thepilocarpine-induced rat model of epilepsy using western blotting, real-timequantitative RT-PCR, immunohistochemistry and double-labelimmunofluorescence. Phospho-Smad3(P-smad3) was also analyzed inhuman and rat temporal tissues to identify whether the SARA-Smad3signals regulate downstream molecules of TGF-β signaling in epilepsy. Additionally, SARA expression in the hippocampus of pilocarpine-kindeledrats was blocked by using recombinant lentiviral vector (SARA k.d.) anddetected by using western blotting and real time qRT-PCR and behaviorcharacteristics.Results: The expression of SNX25was significantly increased in TLEpatients in comparison to controls (0.21±0.07versus0.11±0.03, P<0.05). Inthe lithium-pilocarpine induced epileptic rats, significant elevation ofSNX25levels was detected in the chronic phase, while no SNX25alteration occurred in the acute and latent phases. Moreover, SNX25localized to astrocytes and neurons, in both human samples and animalmodels. In the hippocampus of pilocarpine-kindeled rats, SARA wassignificantly increased at all time point after the onset of status epileptics(SE) compared with the normal rats. In the temporal lobe cortex ofepileptic rats, SARA was significantly higher from24hours to2monthsafter SE onset than the normal rats. Simultaneously, p-Smad3in thehippocampus/temporal lobe of epileptic rats was detectable consistentlywith SARA using immunohistochemistry and western blotting. qRT-PCRanalysis showed that SARA mRNA levels were significantly increased andreached peak as early as6hours after SE onset, then fluctuated betweennormal and increased levels and remained stably increased in chronic phasecompared with the normal rats. Double-label immunofluorescence showedthat SARA was located in both astrocytes and neurons in epileptic rats but only in neurons in the normal rats. After SARA k.d. in the hippocampus ofrat models, decreased SARA and P-smad3expression was detected and SEonset was delayed.Conclusion: Our results indicate that upregulation of SNX25might beinvolved in the development of temporal lobe epilepsy. SARA/Smad3signaling pathway is causative to epileptogenesis and SARA in TGF-βsignaling may be a potential therapeutic target for epilepsy.

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CLC: > Medicine, health > Neurology and psychiatry > Neurology > Brain diseases > Epilepsy
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