Modulation of PTZ-induced convulsions in rats using topiramate alone or combined with low dose gamma irradiation: involving AKT/m-TOR pathway.

The current study evaluates the anticonvulsant effect low dose whole body gamma irradiation (LDR) alone or combined with topiramate against pentylenetetrazole (PTZ)-induced convulsions. Male Wister rats received either saline or PTZ (75 mg/kg i.p.). The other three groups were pretreated with single low dose radiation (0.5 Gy), topiramate (50 mg/kg, p.o., seven days) and TPM with LDR respectively before PTZ injection. Racine' score, latency, and duration of the convulsions were assessed. Glutamate and GABA were measured. AKT/m-TOR signaling pathway including AKT (protein kinase B), mammalian target of rapamycin (m-TOR), protein S6, and caspase 3 were also assessed. Measurements of markers of oxidative stress including malondialdehyde (MDA), glutathione (GSH), and nitric oxide (NO) were carried out. Histological examinations of hippocampi were done. PTZ produced behavioral changes (high Racine score, short latency, and long duration). It elevated MDA and NO contents, while reduced GSH content. TPM treatment alone or combined with LDR ameliorated the PTZ-induced convulsions and caused significant improvement in behavioral changes, brain mediators, m-TOR pathway, oxidative stress, and histological pictures in hippocampal regions. Histopathological examinations of the normal group showed normal structure with intact cells, while PTZ-treated rats exhibited necrosis, pyknosis, and atrophy of pyramidal cells. The histological findings corroborated with the amendment of biochemical parameters. The positive effects of LDR could offer a possible contributor in management of convulsions due to modulation of AkT/m-TOR signaling pathway, reduction of oxidative stress and modulation of brain amino acids. LDR improved the oxidative stress side effects of topiramate.

Resveratrol Modulates the Inflammatory Profile of Immune Responses and Circulating Endothelial Cells' (CECs') Population During Acute Whole Body Gamma Irradiation.

Wistar rats were whole body irradiated with a single dose of 2 Gy post administration with 10 or 100 mg/kg of resveratrol (RSV) intraperitoneally for 30 days. Rats' livers were dissected and processed to analyze immune response profiles of Th1, Th2, Th9, Th17, and Th22 by flow cytometry. In addition, peripheral blood samples were collected and circulating endothelial cells (CECs) were counted as an indicator for endothelial damage. Results demonstrated that resveratrol at 100 mg/kg enhanced liver immunological response influenced by irradiation by inducing Th2 immune response that was revealed by an increase in IL-10 secretion to more than 5,000 pmol/ml post irradiation. Results also indicated that RSV, at a dose of 100 mg/kg, decreased levels of the main pro-inflammatory cytokines such as INF-γ, IL-22, IL-17A, and GM-CSF post irradiation. In addition, the same RSV was bound to upregulate the expression of IL-10 mRNA in isolated Kupffer cells (KCs) and their secretion of IL-10 post irradiation. The result demonstrated that KCs were the central source of this anti-inflammatory response mediated mainly by IL10. These results, proposed for the first time, clearly states that RSV promotes IL-10 mediated immune resolution by Kupffer cells and not by hepatocytes. This implies that KCs have a crucial role in radiotherapy. Additionally, this study showed that RSV had an anti-apoptotic effect through re-increasing the number of CECs, which is implicated in irradiation damage. Result of the current work discloses novel findings about the potential of RSV as a radio-protector agent of a natural origin and suggests novel roles of KCs as a pharmacological target during radiation exposure.

Fractionated whole body gamma irradiation modulates the hepatic response in type II diabetes of high fat diet model rats.

HFD animals were exposed to a low rate of different fractionated whole body gamma irradiation doses (0.5, 1 and 2 Gy, three fractions per week for two consecutive months) and the expression of certain genes involved in type 2 diabetes mellitus (T2DM) in livers and brains of HFD Wistar rats was investigated. Additionally, levels of diabetes-related proteins encoded by the studied genes were analyzed. Results indicated that mRNA level of incretin glucagon like peptite-1 receptor (GLP-1R) was augmented in livers and brains exposed to 1 and 2 Gy doses. Moreover, the mitochondrial uncoupling proteins 2 and 3 (UCP2/3) expressions in animals fed on HFD compared to those fed on normal chow diet were significantly increased at all applied doses. GLP-1R and UCP3 protein levels were up regulated in livers. Total protein content increased at 0.5 and 1 Gy gamma irradiation exposure and returned to its normal level at 2 Gy dose. Results could be an indicator of type 2 diabetes delayed development during irradiation exposure and support the importance of GLP-1R as a target gene in radiotherapy against T2DM and its chronic complications. A new hypothesis of brain-liver and intestine interface is speculated by which an increase in the hepatic GLP-1R is influenced by the effect of fractionated whole body gamma irradiation.

Balance of pro- and anti-inflammatory cytokines in livers of high fat diet rats exposed to fractionated gamma irradiation.

OBJECTIVE: In this work, the effects of irradiation and high fat diet (HFD) intake have been examined in Wistar rat livers. HFD Wistar rats were exposed three times per week for 2 months to three different doses (0.5, 1, and 2 Gy) of a fractionated whole body gamma irradiation (FWBGI). Hepatic mRNA of these rats was evaluated for five cytokines, TNFα, IL1ß, IL6, CRP and IL10. In addition, some critical protein levels were evaluated. RESULTS: Results demonstrated that FWBGI was able to omit the inflammatory state already induced by the HFD through the depression of all pro-inflammatory genes. In addition, TNFα/IL10 IL1ß/IL10, IL6/IL10 and CRP/IL10 ratios were less than 1 at all studied irradiation doses. IL6/IL10 ratio (mRNA and protein) was the best that represented an anti-inflammatory state with all used doses. Results could be of great importance in liver radiotherapy in HFD animal models and may give indicators about the inflammatory state improvement during FWBGI.

The role of gut in type 2 diabetes mellitus during whole body gamma irradiation in high-fat diet Wistar rats.

PURPOSE: The effects of a low rate (100 mGy/min) fractionated whole body gamma irradiation (FWBGI) at different doses were assessed using a real-time PCR technique on the expression of some target genes implicated in the development of type 2 diabetes mellitus in high-fat diet (HFD) Wistar rats. METHOD: HFD Wistar rats were exposed to different doses (12, 24 and 48 Gy) divided into 24 fractions (three times a week for two months), thus, the daily doses were 0.5, 1, 2 Gy, respectively. Total RNA was extracted and the expression of target genes was measured in the four intestinal segments (duodenum, jejunum, ileum and colon). RESULTS: The pre-diabetic state already induced by HFD was found to be improved by irradiation exposure. This irradiation effect occurs mainly via altered anti-diabetic gene expressions (mRNA and protein levels) of the incretin glucagon-like peptide-1 (GLP-1) overall bowel segments except the colon which has its own specific response to irradiation exposure by the induction of the insulin receptor substrate 4 (IRS-4) and the uncoupling protein 3 (UCP3). CONCLUSIONS: Results could be of great importance suggesting for the first time, a protective role for FWBGI on HFD animal models by increasing GLP-1 and UCP3 levels.