Biomedical subjects

S Erat

Publications and source records attributed to S Erat.

10 recordsLinked to original sources

PubMed1998

Receptor- and age-selective effects of dopamine oxidation on receptor-G protein interactions in the striatum.

The striatum contains a high concentration of oxidizable dopamine (DA), and the aged organism shows a decreased ability to respond to oxidative stress (OS), making this area extremely vulnerable to free radical insult. To determine the receptor specificity of this putative increase in OS sensitivity, striatal slices from 6- and 24-month-old animals were incubated (30 min, 37 degrees C) in a modified Krebs medium containing 0 to 500 microM DA with or without a preincubation (15 min) in a nitrone trapping agent, 1 or 5 mM alpha-phenyl-n-tert-butyl nitrone (PBN), and changes in low Km GTPase activity (an index of receptor-G protein coupling/uncoupling) assessed in muscarinic, 5-HT1A D1, and D2 receptors stimulated with carbachol, 8 OH-DPAT-HBr, SKF 38393, or quinelorane, respectively. DA exposure induced selective decreases in the stimulated activity in all of these receptor systems, and an overall increase in conjugated dienes (56%) of the young. In the case of carbachol and 8 OH-DPAT-HBr, the DA-induced deficits in GTPase stimulation were seen primarily in the young (61 and 32%, respectively), while DA-induced deficits in quinelorane (D2) stimulation were seen in both age groups. In the case of SKF 38393-stimulation (D1) the DA-induced deficits were higher in the striatal tissue from the old. The DA-induced decreases in carbachol stimulated GTPase activity in the tissue from the young could be prevented by pretreatment with PBN or the DA uptake inhibitor, nomifensin. No effect of nomifensin was seen in the old, because their DA uptake mechanisms were already compromised. These results suggest that although age-related declines in DA uptake may provide some protection against the OS effects in muscarinic or 5-HT1A receptors, other factors may increase the vulnerability of DA neurons to OS, even with reductions in DA uptake.

Aging↗

PubMed1998

CNS effects of heavy particle irradiation in space: behavioral implications.

Research from several sources indicates that young (3 mo) rats exposed to heavy particle irradiation (56Fe irradiation) produces changes in motor behavior as well as alterations in neuronal transmission similar to those seen in aged (22-24 mo) rats. These changes are specific to neuronal systems that are affected by aging. Since 56Fe particles make up approximately 1-2% of cosmic rays, these findings suggest that the neuronal effects of heavy particle irradiation on long-term space flights may be significant, and may even supercede subsequent mutagenic effects in their mission capabilities. It is suggested that among other methods, it may be possible to utilize nutritional modification procedures to offset the putative deleterious effects of these particles in space.

Aging↗

PubMed1998

Effects of exposure to different types of radiation on behaviors mediated by peripheral or central systems.

The effects of exposure to ionizing radiation on behavior may result from effects on peripheral or on central systems. For behavioral endpoints that are mediated by peripheral systems (e.g., radiation-induced conditioned taste aversion or vomiting), the behavioral effects of exposure to heavy particles (56Fe, 600 MeV/n) are qualitatively similar to the effects of exposure to gamma radiation (60Co) and to fission spectrum neutrons. For these endpoints, the only differences between the different types of radiation are in terms of relative behavioral effectiveness. For behavioral endpoints that are mediated by central systems (e.g., amphetamine-induced taste aversion learning), the effects of exposure to 56Fe particles are not seen following exposure to lower LET gamma rays or fission spectrum neutrons. These results indicate that the effects of exposure to heavy particles on behavioral endpoints cannot necessarily be extrapolated from studies using gamma rays, but require the use of heavy particles.

Amphetamine↗

PubMed1997

Cholesterol: a two-edged sword in brain aging.

Previous research from several laboratories has indicated that cholesterol (CHO) accumulates in neuronal membranes and alters their structural and signal transduction (ST) properties during aging. The possible reasons for these increases in membrane CHO have not been specified. However, present findings suggest that such accumulation may actually serve to protect neuronal tissue from oxidative damage. Striatal slices (6, 24 month rats) were preincubated in 1 mM CHO (30 min) followed by incubation with H2O2 (10 microM, 30 min). The slices were then either superfused with 30 mM KCl in the presence or absence of 500 microM oxotremorine (Ox), and K(+)-evoked dopamine release (K(+)-ERDA) examined or assessed for carbachol-stimulated low K(m) GTPase activity. The results indicated that CHO incubation prior to H2O2 in either age group was effective in preventing H2O2 reductions in both non-Ox-enhanced K(+)-ERDA and Ox conditions, as well as sodium nitroprusside (SNP 150 microM)-induced decreases in K(+)-ERDA. In addition, H2O2-induced deficits in carbachol-stimulated low K(m) GTPase activity were reduced in the striatal tissue from the old animals pretreated with CHO. However, if the slices were incubated in H2O2 prior to CHO exposure, CHO enhanced the H2O2 effects in the tissue from the old animals. Thus, depending upon the order of exposure, CHO functioned to enhance or retard the effects of oxidative stress, in an age-dependent manner.

Aging↗

PubMed1996

Increased sensitivity to oxidative stress and the loss of muscarinic receptor responsiveness in senescence.

Although there are numerous findings which suggest that the pathogenesis of age-related neurodegenerative disorders (e.g., AD and PD) may involve oxidative stress (OS), relationships between functional age-related neuronal deficits, especially those with behavioral correlates, and OS have been difficult to establish. We have attempted to establish such relationships by determining the role of OS in the loss of muscarinic receptor (mAChR) sensitivity in aging. These decrements are expressed as age-related reductions in oxotremorine enhancement of K(+)-evoked dopamine release (K(+)-ERDA) from superfused striatal slices. Using this model we have found that: a) The reductions can be restored with in vivo administration of the free-radical trapping agent, N-tert-butyl-alpha-phenylnitrone (PBN); b) Striatal slices from old animals showed increased sensitivity (e.g., reduced DA release or oxo-enhancement of K(+)-ERDA) to the in vitro application of sodium nitroprusside, a potent NO generator or to H2O2 which treatment of striatal slices from young animals with these agents or exposure of young animals to low doses of whole-body 56Fe irradiation decreased mAChR sensitivity and signal transduction (ST). Protection from the NO- or H2O2-induced deficits could be prevented with Trolox, PBN or cholesterol pretreatment. Evidence derived from PC-12 cells suggests that OS may directly affect ST by decreasing Ca2+ flux and increasing the length of the recovery period (i.e., return to baseline Ca2+ levels) after KCI (30 mM) depolarization.

Aging↗

PubMed1996

Age differences in sensitivity to H2O2- or NO-induced reductions in K(+)-evoked dopamine release from superfused striatal slices: reversals by PBN or Trolox.

Previous research has indicated that many age-related functional alterations may be the result of a decreased ability of the organism to respond to oxidative stress (OS). However, this hypothesis is based on indirect indices of function (e.g., increased vulnerability of hepatocytes from senescent animals to H2O2-induced DNA damage, increases in lipofuscin accumulation). More direct tests of this hypothesis, especially as it relates to brain aging, have not been extensively undertaken. Present experiments were carried out to make such tests by examining age differences in the sensitivity to OS on reductions in striatal dopamine (DA) release. Thus, K(+)-evoked DA (K(+)-ERDA) release from superfused striatal slices from young (6-8 month) and old (24-25 month) animals was examined following either: (a) application of the NO-generator sodium nitroprusside or (b) preincubation with H2O2. In order to assess the specific effects of OS on muscarinic (mAChR) sensitivity, oxotremorine-enhancement of K(+) -ERDA was examined following incubation with H2O2. Results showed that the striatal tissue from the old animals showed greater sensitivity to both H2O2 and NO than young animals, and stimulated DA decreased at lower concentrations of these agents (e.g., NO--100 microM young, 30 microM old). In addition, H2O2 was also effective in reducing oxo-enhanced K(+)-ERDA and was more effective as a function of age. If the striatal tissue was incubated in either Trolox (alpha-tocopherol) or alpha-phenyl-n-tert-butyl nitrone (PBN) prior to OS, the negative effects of NO. and H2O2 were reversed in both age groups. Results are discussed in terms of age-related membrane and endogenous antioxidant alterations that could induce increases in sensitivity to OS and the specificity of antioxidants in reducing this sensitivity in key functional systems.

Aging↗

PubMed1995

Age-related impairment in striatal muscarinic cholinergic signal transduction is associated with reduced membrane bilayer width measured by small angle X-ray diffraction.

In order to determine whether age-related changes in neuronal membrane structure contribute to previously reported changes in muscarinic cholinergic signal transduction, striata from 3, 13 and 23 month old F344 male rats were examined for both carbachol-stimulated low Km GTPase activity and membrane one-dimensional electron density profile using small angle X-ray diffraction. Increasing age was associated with both a reduction in stimulated GTPase activity and a decrease in membrane bilayer width. These findings suggest the possibility that fundamental membrane structural changes may contribute to alterations in signal transduction seen with aging.

Aging↗

PubMed1995

Dissociation of striatal GTPase and dopamine release responses to muscarinic cholinergic agonists in F344 rats: influence of age and dietary manipulation.

There is evidence that dietary lipids and age both influence neuronal membrane composition and receptor G protein-linked signal transduction, but very little information is available on the interaction between these two factors. To investigate this, we obtained striata from 2, 12, and 22-month-old male F344 rats who were fed either a high-cholesterol, high-saturated fat or low-fat diet for 1 month. The striata were assayed for muscarinic agonist-stimulated low-Km GTPase activity using 10(-3) M carbachol and 10(-5) M oxotremorine and for KCl-evoked dopamine release enhancement by 10(-5) M oxotremorine. Membrane cholesterol and phospholipid content and phospholipid class composition were also determined. Mature animals showed significant but divergent changes in GTPase activity and dopamine release for high-cholesterol and low-fat diets: GTPase activity decreased, whereas dopamine release increased in these groups. Alterations in GTPase activity but not in dopamine release were inversely correlated with the cholesterol/phospholipid molar ratio. Old control animals showed reductions in both GTPase activity and oxotremorine-enhanced dopamine release compared with young animals. Whereas none of the experimental diets affected GTPase activity in old animals, the low-fat diet produced a marked decrease in dopamine release. In contrast to mature and old groups, young rats showed no significant change in either GTPase or dopamine release, suggesting a relative "resistance" to such dietary lipid modulation. The observed dissociation in GTPase and dopamine release responses to diet may reflect differing effects of these diets on discrete membrane lipid domains that preferentially influence different signal transduction components. The substantial age-related differences in striatal membrane response to dietary lipid modulation may represent the effects of underlying age differences in membrane lipid metabolism, structure, and/or dynamics. Our findings support the work of other groups that have shown that brain membranes are susceptible to modification by exogenous lipids. They also suggest the need for a more systematic examination of the influence of age on the response to other types of dietary lipid changes.

Aging↗

PubMedDate not supplied

Oxidative stress and age-related neuronal deficits.

Research from our laboratory has indicated that the loss of sensitivity that occurs in several receptor systems as a function of age may be an index of an increasing inability to respond to oxidative stress (OS). This loss occurs partially as a result of altered signal transduction (ST). Assessments have involved determining the nature of age-related reductions in oxotremorine enhancement of K(+)-evoked dopamine release (K(+)-ERDA) from superfused striatal slices. Using this model, we have found that 1. Reductions can be restored with in vivo administration of the free-radical trapping agent, N-tert-butyl-alpha-phenylnitrone (PBN); 2. Decrements in DA release induced by NO or H2O2 from striatal slices from both young and old animals could be restored with alpha-tocopherol or PBN; 3. ST decrements, such as those seen in aging, could be induced with radiation exposure; and 4. Pre-incubation of the striatal slices with cholesterol decreased subsequent deleterious effects of NO or OH. on DA release. Thus, cholesterol, which increases in neuronal membranes as a function of age, may function as a potent antioxidant and protectant against neuronal damage. These results suggest that therapeutic efforts to restore cognitive deficits in aging and age-related disease might begin with antioxidant reversal of ST decrements.

Aging↗

PubMedDate not supplied

A reduced calorie-high fiber diet retards age-associated decreases in muscarinic receptor sensitivity.

The effects of a reduced calorie-high fiber diet (RCHF) were examined on three cholinergic signal transduction (ST) parameters: (a) oxotremorine enhancement of K(+)-evoked dopamine release and (b) carbachol-stimulated low KM GTPase activity [an indicator of muscarinic receptor (mAChR)-G protein coupling/uncoupling], and (c) [3H]Quinuclidinyl benzilate (QNB) autoradiography. Comparisons were made among: young control (6 months), old normal control, old reduced calorie high fiber [both 24 months)]. The results indicated that old reduced calorie high fiber rats (1900 kcal/kg/day, 2.4%, lipids 2.4%, fiber 28%, carbohydrates 40.7%) as compared to the old normal control rats (3000 kcal/kg/day, 4.8% lipids, 4.2% fiber, carbohydrates 61.5%) showed a retardation of age-related deficits in dopamine release (a above) and GTPase activity (b above). These parameters were 25% higher in the old reduced calorie high fiber rats as compared to old normal controls and did not differ from young controls, even though there was no increase in mAChR concentration in the restricted group. Thus, these results indicate that a reduced calorie high fiber diet as utilized in these experiments was effective in retarding the age-related decrements in two of three signal transduction parameters. They are discussed in terms of the induction of membrane changes (e.g., fluidity) or related decreases in oxidative stress by the restricted diet that may be involved in these signal transduction effects.

Aging↗