RGD Reference Report - Expression profiles of hippocampal regenerative sprouting-related genes and their regulation by E-64d in a developmental rat model of penicillin-induced recurrent epilepticus.

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Expression profiles of hippocampal regenerative sprouting-related genes and their regulation by E-64d in a developmental rat model of penicillin-induced recurrent epilepticus.
Authors:	Ni, H Ren, SY Zhang, LL Sun, Q Tian, T Feng, X
Citation:	Ni H, etal., Toxicol Lett. 2013 Feb 27;217(2):162-9. doi: 10.1016/j.toxlet.2012.12.010. Epub 2012 Dec 21.
RGD ID:	9685809
Pubmed:	PMID:23266720 (View Abstract at PubMed)
DOI:	DOI:10.1016/j.toxlet.2012.12.010 (Journal Full-text)
E-64d (a calpain and autophagy inhibitor) has previously been shown safe for the treatment of Alzheimer's disease in humans. In the present study, the potential protective mechanism of E-64d on hippocampal aberrant mossy fiber sprouting was examined in a developmental rat model of penicillin-induced recurrent epilepticus. A seizure was induced by penicillin every other day in Sprague-Dawley rats from postnatal day 21 (P21). The rats were randomly assigned into the control group (CONT1), the control plus E-64d (CONT2), the seizure group (EXP1) and the seizure plus E-64d (EXP2). On P51, mossy fiber sprouting and related gene expression in hippocampus were assessed by Timm staining and real-time RT-PCR methods, respectively. To validate the RT-PCR results, western blot analysis was performed on selected genes. E-64d obviously suppressed the aberrant mossy fiber sprouting in the supragranular region of dentate gyrus and CA3 subfield of hippocampus. Among the total twelve genes, six genes were strongly up- (MT-3, ACAT1, clusterin and ApoE) or down- (ZnT-1 and PRG-3) regulated by developmental seizures (EXP1) compared with that in the CONT1. Up-regulation of ApoE and Clusterin was blocked by pretreatment with E-64d both in mRNA and protein levels. Further, E-64d-pretreated seizure rats (EXP2) showed a significant downregulation of mRNA expression of PRG-1, PRG-3 and PRG-5, cathepsin B and ApoE, as well as up-regulated nSMase and ANX7 in hippocampus when compared with EXP1 rats. The results of the present study suggest that E-64d, an elective inhibitor of calpain and autophagy, is potentially useful in the treatment of developmental seizure-induced brain damage both by regulating abnormal zinc signal transduction and through the modulation of altered lipid metabolism via ApoE/clusterin pathway in hippocampus.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
MT3	Human	visual epilepsy	treatment	ISO	Mt3 (Rattus norvegicus)		RGD
Mt3	Rat	visual epilepsy	treatment	IEP			RGD
Mt3	Mouse	visual epilepsy	treatment	ISO	Mt3 (Rattus norvegicus)		RGD

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Genes (Rattus norvegicus)

Mt3 (metallothionein 3)

Genes (Mus musculus)

Mt3 (metallothionein 3)

Genes (Homo sapiens)

MT3 (metallothionein 3)

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Expression profiles of hippocampal regenerative sprouting-related genes and their regulation by E-64d in a developmental rat model of penicillin-induced recurrent epilepticus.