Dataset Information

Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment.

ABSTRACT: We hypothesized that chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, to young adult male rats would prevent/ameliorate fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Eighty 12-14-week-old young adult male Fischer 344 rats received either: (1) sham irradiation, (2) 40 Gy of fractionated whole-brain irradiation delivered as two 5 Gy fractions/week for 4 weeks, (3) sham irradiation plus continuous administration of 15 mg/L of ramipril in the drinking water starting 3 days before irradiation, or (4) fractionated whole-brain irradiation plus ramipril. Cognitive function was assessed using a perirhinal cortex-dependent version of the novel object recognition task 26 weeks after irradiation. Microglial activation was determined in the perirhinal cortex and the dentate gyrus of the hippocampus 28 weeks after irradiation using the ED1 antibody. Neurogenesis was assessed in the granular cell layer and subgranular zones of the dentate gyrus using a doublecortin antibody. Fractionated whole-brain irradiation led to: (1) a significant impairment in perirhinal cortex-dependent cognitive function, (2) a significant increase in activated microglia in the dentate gyrus but not in the perirhinal cortex, and (3) a significant decrease in neurogenesis. Continuous administration of ramipril before, during, and after irradiation prevented the fractionated whole-brain irradiation-induced changes in perirhinal cortex-dependent cognitive function, as well as in microglial activation in the dentate gyrus. Thus, as hypothesized, continuous administration of the angiotensin-converting enzyme inhibitor, ramipril, can prevent the fractionated whole-brain irradiation-induced impairment in perirhinal cortex-dependent cognitive function.

SUBMITTER: Lee TC

PROVIDER: S-EPMC3422865 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment.

Lee Tammy C TC Greene-Schloesser Dana D Payne Valerie V Diz Debra I DI Hsu Fang-Chi FC Kooshki Mitra M Mustafa Rashida R Riddle David R DR Zhao Weiling W Chan Michael D MD Robbins Mike E ME

Radiation research 20120612 1

We hypothesized that chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, to young adult male rats would prevent/ameliorate fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Eighty 12-14-week-old young adult male Fischer 344 rats received either: (1) sham irradiation, (2) 40 Gy of fractionated whole-brain irradiation delivered as two 5 Gy fractions/week for 4 weeks, (3) sham irradiation plus continuous administration of 15 ...[more]

PMID: 22687052

Similar Datasets

Project description:Radiation-induced impairment of neurogenesis in the hippocampal dentate gyrus is a concern due to its reported association with cognitive detriments after radiotherapy for brain cancers and the possible risks to astronauts chronically exposed to space radiation. Here, we have extended our recent work in a mouse model of impaired neurogenesis after exposure to low-linear energy transfer (LET) radiation to heavy ion irradiation. To our knowledge, this is the first report of a predictive mathematical model of radiation-induced changes to neurogenesis for a variety of radiation types after acute or fractionated irradiation. We used a system of nonlinear ordinary differential equations (ODEs) to represent age, time after exposure and dose-dependent changes to several cell populations participating in neurogenesis, as reported in mouse experiments. We considered four compartments to model hippocampal neurogenesis and, consequently, the effects of radiation in altering neurogenesis: 1. neural stem cells (NSCs); 2. neuronal progenitor cells or neuroblasts (NB); 3. immature neurons (ImN); and 4. glioblasts (GB), with additional consideration of microglial activation. The model describes the negative feedback regulation on early and late neuronal proliferation after irradiation, and the dynamics of the age dependence of neurogenesis. We compared our model to experimental data for X rays, and protons, carbon and iron particles, including data for fractionated iron-particle irradiation. Heavy-ion irradiation is predicted to lead to poor recovery or no recovery from impaired neurogenesis at doses as low as 0.5 Gy in mice. This is only partially ameliorated by dose fractionation, which suggests important implications for Hardon therapy near the Bragg peak, and possibly for space radiation exposures as well. Predictions of the threshold doses where neurogenesis recovery fails for given radiation types are described, and the role of subthreshold transient impairments are briefly discussed.

Project description:BACKGROUND:Transforming growth factor beta (TGF-?)-Smad2/3 is the major signaling pathway of fibrosis, which is characterized by the excessive production and accumulation of extracellular matrix (ECM) components, including collagen. Although the ECM is an essential component of skeletal muscle, fibrosis may be harmful to muscle function. On the other hand, our previous studies have shown that levels of angiotensin II, which acts upstream of TGF-?-Smad2/3 signaling, is increased in mice with myocardial infarction (MI). In this study, we found higher skeletal muscle fibrosis in MI mice compared with control mice, and we investigated the mechanisms involved therein. Moreover, we administered an inhibitor based on the above mechanism and investigated its preventive effects on skeletal muscle fibrosis. METHODS:Male C57BL/6?J mice with MI were created, and sham-operated mice were used as controls. The time course of skeletal muscle fibrosis post-MI was analyzed by picrosirius-red staining (days 1, 3, 7, and 14). Mice were then divided into 3 groups: sham + vehicle (Sham + Veh), MI + Veh, and MI + lisinopril (an angiotensin-converting enzyme [ACE] inhibitor, 20?mg/kg body weight/day in drinking water; MI + Lis). Lis or Veh was administered from immediately after the surgery to 14?days postsurgery. RESULTS:Skeletal muscle fibrosis was significantly increased in MI mice compared with sham mice from 3 to 14?days postsurgery. Although mortality was lower in the MI + Lis mice than the MI + Veh mice, there was no difference in cardiac function between the 2 groups at 14?days. Skeletal muscle fibrosis and hydroxyproline (a key marker of collagen content) were significantly increased in MI + Veh mice compared with the Sham + Veh mice. Consistent with these results, protein expression of TGF-? and phosphorylated Smad2/3 in the skeletal muscle during the early time points after surgery (days 1-7 postsurgery) and blood angiotensin II at 14?days postsurgery was increased in MI mice compared with sham mice. These impairments were improved in MI + Lis mice, without any effects on spontaneous physical activity, muscle strength, muscle weight, and blood pressure. CONCLUSIONS:ACE inhibitor administration prevents increased skeletal muscle fibrosis during the early phase after MI. Our findings indicate a new therapeutic target for ameliorating skeletal muscle abnormalities in heart diseases.

Project description:Our brain disambiguates the objects in our cluttered visual world seemingly effortlessly, enabling us to understand their significance and to act appropriately. The role of anteromedial temporal structures in this process, particularly the perirhinal cortex, is highly controversial. In some accounts, the perirhinal cortex is necessary for differentiating between perceptually and semantically confusable objects. Other models claim that the perirhinal cortex neither disambiguates perceptually confusable objects nor plays a unique role in semantic processing. One major hurdle to resolving this central debate is the fact that brain damage in human patients typically encompasses large portions of the anteromedial temporal lobe, such that the identification of individual substructures and precise neuroanatomical locus of the functional impairments has been difficult. We tested these competing accounts in patients with Alzheimer's disease with varying degrees of atrophy in anteromedial structures, including the perirhinal cortex. To assess the functional contribution of each anteromedial temporal region separately, we used a detailed region of interest approach. From each participant, we obtained magnetic resonance imaging scans and behavioural data from a picture naming task that contrasted naming performance with living and non-living things as a way of manipulating perceptual and semantic confusability; living things are more similar to one another than non-living things, which have more distinctive features. We manually traced neuroanatomical regions of interest on native-space cortical surface reconstructions to obtain mean thickness estimates for the lateral and medial perirhinal cortex and entorhinal cortex. Mean cortical thickness in each region of interest, and hippocampal volume, were submitted to regression analyses predicting naming performance. Importantly, atrophy of the medial perirhinal cortex, but not lateral perirhinal cortex, entorhinal cortex or hippocampus, significantly predicted naming performance on living relative to non-living things. These findings indicate that one specific anteromedial temporal lobe region-the medial perirhinal cortex-is necessary for the disambiguation of perceptually and semantically confusable objects. Taken together, these results support a hierarchical account of object processing, whereby the perirhinal cortex at the apex of the ventral object processing system is required to bind properties of not just perceptually, but also semantically confusable objects together, enabling their disambiguation from other similar objects and thus comprehension. Significantly, this model combining a hierarchical object processing architecture with a semantic feature statistic account explains why category-specific semantic impairments for living things are associated with anteromedial temporal lobe damage, and pinpoints the root of this syndrome to perirhinal cortex damage.

Dataset Information

Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment.

Publications

Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets