Biomedical subjects

G S Roth

Publications and source records attributed to G S Roth.

225 records · Page 13Linked to original sources

PubMedDate not supplied

Similar effects of saponin treatment and aging on coupling of alpha 1-adrenergic receptor-G-protein.

The effects of the nonionic detergent saponin on alpha 1-adrenergic signal transduction were investigated using rat parotid cells and membrane preparations. Fifty microM epinephrine-stimulated 45Ca2+ efflux and inositol 1,4,5-triphosphate (Ins[1,4,5]P3) production in adult parotid cells were significantly decreased after saponin treatment. Saponin did not alter the concentration of alpha 1-adrenergic receptors labeled by [3H]prazosin, but significantly reduced the guanosine imido diphosphate (GppNHp)-induced shift from high to low affinity sites. Fifty microM epinephrine-stimulated high affinity GTPase activity was also reduced by saponin treatment. These data suggest that reduced alpha 1-adrenergic receptor-stimulated functional responsiveness following saponin treatment may be due to impaired uncoupling of receptor-G-protein complexes.

Aging↗

PubMedDate not supplied

Changes in tissue responsiveness to hormones and neurotransmitters during aging.

Responsiveness to many hormones and neurotransmitters by target tissues is altered during aging. Three model systems that are representative of these changes are reviewed. These are (1) striatal dopaminergic regulation of motor function, (2) IP3 and calcium-mediated electrolyte and neurosecretion by the alpha1-adrenergic and muscarinic cholinergic systems in parotid and corpus striatum, and (3) beta adrenergic and epidermal growth factor (EGF) stimulated DNA synthesis in hepatocytes.

Aging↗

PubMedDate not supplied

Evaluating measures of hematology and blood chemistry in male rhesus monkeys as biomarkers of aging.

Reliable and valid biomarkers of aging can provide valuable tools for examining the effectiveness of interventions that may influence the rate of aging processes. However, a standardized method for identifying biomarkers of aging has yet to be developed. The current analysis focused on hematology and blood chemistry variables obtained from a 5-year longitudinal study of male rhesus monkeys (N = 29) on a diet restriction regime known to retard aging processes and extend lifespan in laboratory rodents (70% of the diet intake of controls). For the current analysis, the major screening criteria for identifying candidate biomarkers of aging were cross-sectional and longitudinal correlation with chronological age (CA) and stability of individual differences. Six potential variables from the battery of blood chemistry tests were identified: 1) serum glutamic oxalacetic transaminase; 2) alkaline phosphatase; 3) total protein; 4) globulin; 5) blood urea nitrogen to creatinine ratio; and 6) phosphates. When submitted to principle component analysis, these variables loaded onto a single component that accounted for over 50% of the total variance to indicate marked covariance among them. By applying the factor score coefficients from the first principle component, an equation was derived for estimating a biological age score (BAS) for each individual monkey. A comparison of BAS between control and diet-restricted monkeys revealed no statistically significant difference at present; however, the slope of the regression of BAS onto CA appeared steeper for the control group compared to the experimental group. Thus, while demonstration of the validity of the candidate biomarkers awaits further evidence, a strategy by which additional biomarkers of aging can be identified is proposed as an improvement over past approaches.

Aging↗

PubMedDate not supplied

Age-related decline in striatal volume in monkeys as measured by magnetic resonance imaging.

Age-related declines in striatal markers for the dopamine system have been demonstrated in several species. The current study investigated structural changes during aging in the rhesus monkey striatum. Male monkeys were studied using a volumetric spoiled gradient recall (SPGR) magnetic resonance imaging protocol. The caudate nucleus and putamen were segmented by manual tracing using landmarks made in the orthogonal planes. The whole brain volume (defined as volume of gray and white matter plus cerebrospinal fluid in ventricles and sulci) was measured using a semi-automated algorithm. There was no correlation between age and whole brain volume. There were age-related declines in normalized (i.e. brain region/whole brain volume) caudate nucleus and putamen volumes. Monkeys in the young group (n = 7, 39-45 months old) had larger volumes of both the caudate nucleus and putamen than animals in the middle-age (n = 5, 120-180 months) or old (n = 7, 291-360 months) groups. The current results provide normative data to assess potential interventions (e.g. caloric restriction) in the aging process.

Aging↗

PubMedDate not supplied

Age changes in adrenergic and dopaminergic signal transduction mechanisms: parallels and contrasts.

Age changes in signal transduction exhibit some interesting similarities in the adrenergic and dopaminergic systems of the brain. Although several differences exist with respect to current technical capabilities and characterization of complete signal-response pathways at the organismic level, these systems offer promising models for complimentary elucidation of the mechanisms of altered neurotransmitter action during aging.

Aging↗

PubMedDate not supplied

The effect of aging on rat striatal D1 receptor mRNA-containing neurons.

In situ hybridization of a digoxigenin-labeled oligonucleotide probe combined with computer assisted image assessment was used to directly visualize D1 dopamine receptor mRNA-containing neurons in rat striata, and quantify age-related changes in the sizes and relative mRNA content of these neurons. It was found that 1) numbers of D1 mRNA-containing neurons appear to decrease in striata of aged rats; 2) relative amounts of D1 receptor mRNA in individual striatal neurons do not change during aging; and 3) neurons of all sizes appear to be lost, with the greatest absolute decrease in those larger than 150 microns2. These data confirm the age associated loss of D1 dopamine receptors reported for some other rat strains in that species, and further suggest that neuronal loss is responsible for the decrement. The latter finding contrasts with the aging associated loss of D2 dopamine receptors, which additionally involves decreased amounts of mRNA per cell.

Aging↗

PubMedDate not supplied

Application of gene therapy to treat age-related loss of dopamine D2 receptor.

We have investigated the feasibility of using gene therapy to attenuate the age-related decline in striatal dopamine D2 receptors (D2R) associated with reduced motor control. To this end, we have constructed an adenoviral vector containing the cDNA for the rat D2R. When injected into HeLa and HS24 cells in vitro, the vector induced an abundant message for D2R, as demonstrated by Northern analysis, and produced a membrane-bound protein capable of binding a D2R ligand, [3H]spiperone. When injected into rat striatum in vivo, the vector produced a marked increase in D2R near the site of injection, as evidenced by increased [3H]spiperone binding as well as by another more specific ligand, [125I]iodosulpride. The D2R produced in the striatum were functional, as evidenced by rotational behavior induced by a subcutaneous injection of the dopamine agonist, apomorphine. However, we did not observe any significant improvement in motor performance during preliminary experiments in which aged rats received bilateral striatal injections of the vector. In young rats, vector-induced expression of D2R in striatum was increased markedly three to five days after infection, but then declined to baseline levels by day 21. Loss of expression in aged rats proceeded at a somewhat lower rate. Because of the loss of expression and lack of significant performance enhancement in aged rats following vector injection into the striatum, we are now pursuing other strategies. These include functional assessment of the current vector in D2R null mutant mice as well as construction of new vectors that may yield more long-term expression.

Aging↗

PubMedDate not supplied

Effect of cholesterol content in diet on capillary flow of rat erythrocytes. Part I: geometric and flow characteristics.

Four different groups of male Fisher rats were placed on one of the following diets for a period of one month: normal (control) diet, high cholesterol (HC) diet, high saturated fat (HF) diet and low fat (LF) diet. Subsequently, blood samples were drawn and washed in phosphate buffered saline (PBS), and the red cells were resuspended in the same buffer. These samples were introduced into a polycarbonate capillary flow system and their flow characteristics observed. In addition, the mean cell volumes (MCV) in isotonic PBS and the maximum swollen cell volume (MCVmax) in hypotonic PBS were determined using a Coulter counter. From these, the mean surface area (MSA) and the excess surface area (ESA) were calculated. It was found that rats on a high cholesterol diet develop erythrocyte geometric characteristics which should contribute to improved capillary flow, namely, a decreased mean cell volume and an increased excess surface area. Nevertheless, in these rats a decreased capillary flow was observed as indicated by an increase in mean cell transit time, MCTT, and an appreciable drop in the number of cells per second passing through the capillary flow system. The flow and geometric properties of the high saturated fat and low fat fed rats did not differ significantly from those of the control group.

Animals↗

PubMedDate not supplied

Effect of cholesterol content in diet on capillary flow of rat erythrocytes. Part II: mechanical properties.

Erythrocytes from male Fisher 344 rats on a high cholesterol diet (HC) exhibited a decreased ability to flow through capillaries when compared with those on a normal diet (control), a phenomenon which could not be explained by changes in geometric characteristics. To explain these results, changes in capillary-dependent rheological characteristics and intrinsic mechanical properties of red blood cells (RBC) due to diet were calculated. The hematocrit deficit in the capillary with respect to the reservoir was greater in the high cholesterol diet fed rats than in the control ones. This was attributed to an overall decrease in red cell deformability which, in turn, was related to an increase in the membrane shear viscosity, the cytoplasmic viscosity, the membrane shear modulus of elasticity, and the membrane bending rigidity. By an independent calculation, we determined that the shear modulus of elasticity increased with a high cholesterol diet. The changes in both the capillary hematocrit deficit and the shear modulus of elasticity with a high cholesterol diet were found to be statistically significant (p < or = 0.05).

Animals↗