Male Fischer 344 (F-344) rats of three different ages (4, 13, and 25 months) and male Brown Norway (BN/BIRIJ) rats (4 months) were injected (IP) with a hypnotic dose of ethanol (3.0 g/kg, 10% w/v in saline). Half of the animals were decapitated and brains extracted immediately upon loss of the righting reflex (LRR), while the other half were allowed to reach recovery of the righting reflex (RRR), at which time brains were extracted. Brain alcohol analyses revealed significantly higher concentrations in young F-344 rats at both LRR and RRR, indicating less sensitivity of target tissue to ethanol hypnosis in the young of that strain. All age groups of the F-344 rats as well as the young BN/BIRIJ rats displayed lower brain concentrations of ethanol at RRR than at LRR, a finding opposite to that characteristic of acute tolerance. The relationship of LRR to RRR values did not differ among the age groups of F-344 rats. We conclude that the F-344 and BN/BIRIJ strains do not develop acute tolerance to ethanol hypnosis. The findings are consistent with the hypothesis that animals with low ethanol preferences, such as the F-344 and BN/BIRIJ strains, also have low capabilities to develop acute tolerance to ethanol hypnosis.
Increased expression of intercellular adhesion molecule 1 (ICAM1), a protein known to contribute to inflammatory responses, has been detected in the brain tissue of patients with Alzheimer's disease (AD) and animals modelled to mimic AD or Parkinson's disease (PD). ICAM1 may, thus, be implicated in the pathogenesis of these disorders. Our purpose was to investigate whether genetic variants of the ICAM1 gene have a role in causing susceptibility to AD and/or PD. We genotyped the E469K polymorphism of ICAM1 in 196 AD, 52 PD and 202 control patients of Finnish origin. The distributions of the genotype and allele frequencies of the polymorphism did not differ significantly between the AD, PD or the control patients. We therefore conclude that the E469K polymorphism of ICAM1 is not a risk factor for AD or PD.
In experiments in white Wistar rats of three-age groups (immature, mature and old rats) content of glial fibrous acidic protein (GFAP) was investigated in cerebral cortex, hippocampus, thalamus and brain stem after the carrying out of laparotomy. The correlation between emotional activity and the level of GFAP has been found in the given structures of a brain. In immature animals, the activation of emotional component of behaviour was accompanied by decrease in polypeptide's soluble and insoluble fractions in brain stem by 16% and 18%, respectively (p
We have recently reported that inbred Wistar-Kyoto rats which are highly reactive to stressful stimuli, have a much shorter mean life-span (21.5) compared to the less reactive Brown-Norway rats (31.0 +/- 4.5 months). In the present study we found a reduction in forebrain cholinergic neurotransmission indices in 24-month-old Wistar-Kyotos but not in Brown-Norways as compared to their respective young (3-month-old) counterparts. Also only in Wistar-Kyotos dopamine uptake was reduced in the aged striatum, but in the septum it remained unchanged in both strains. In Brown-Norways, age-related changes were observed only in choline acetyltransferase activity and only in brain regions known to contain mainly cholinergic nerve cell bodies. We conclude that at 24 months of age, reductions in brain cholinergic and dopaminergic neurotransmission are more prominent in the highly stress-reactive and shorter-lived Wistar-Kyoto strain, and may be genetically determined.
Stress induced changes in neurochemical indices of neurotransmission are more pronounced in the septohippocampal cholinergic system of Wistar Kyoto rats, which are behaviorally more reactive to stressors and have a shorter life span, than in Brown Norway rats. Moreover, pronounced degeneration of septohippocampal cholinergic neurons occurs earlier in life in Wistar Kyoto rats. In the present study the high affinity synaptosomal uptakes of choline and glutamate were used as indices for cholinergic and glutamatergic systems respectively. Following 2 hr of mild restrain stress increases in both uptake systems were observed in all regions examined (hippocampus, septum and frontal cortex). The stress-induced increases were generally similar in young (3 months) and aged (20 months) rats of both strains. The noted exception was that choline uptake levels, which were reduced in the hippocampus of unhandled aged WKY rats, remained unchanged after stress. The results confirm the involvement of the septohippocampal cholinergic system in the response to acute stress and extend the findings to include the hippocamposeptal glutamatergic system activation as well. It is suggested that in spite of neuronal degeneration during aging, these responses to stress can be maintained by compensatory efforts of neurons that remain intact.
Aging adults are a growing segment of the U.S. population and are likely to exhibit increased susceptibility to many environmental toxicants. However, there is little information on the susceptibility of the aged to toxicants. The toxicity of toluene has been well characterized in young adult rodents but there is little information in the aged. Three approaches were used: (1) pharmacokinetic (PK), (2) cardiac biomarkers, and (3) whole-animal physiology to assess whether aging increases susceptibility to toluene in the Brown Norway (BN) rat. Three life stages, young adult, middle aged, and aged (4, 12, and 24 mo, respectively), were administered toluene orally at doses of 0, 0.3, 0.65, or 1 g/kg and subjected to the following: terminated at 45 min or 4 h post dosing, and blood and brain toluene concentration were measured; terminated at 4 h post dosing, and biomarkers of cardiac function were measured; or monitor heart rate (HR), core temperature (Tc), and motor activity (MA) by radiotelemetry before and after dosing. Brain toluene concentration was significantly elevated in aged rats at 4 h after dosing with either 0.3 or 1 g/kg. Blood toluene concentrations were unaffected by age. There were various interactions between aging and toluene-induced effects on cardiac biomarkers. Most notably, toluene exposure led to reductions in mRNA markers for oxidative stress in aged but not younger animals. Toluene also produced a reduction in cardiac endothelin-1 in aged rats. Higher doses of toluene led to tachycardia, hypothermia, and a transient elevation in MA. Aged rats were less sensitive to the tachycardic effects of toluene but showed a prolonged hypothermic response. Elevated brain levels of toluene in aged rats may be attributed to their suppressed cardiovascular and respiratory responses. The expression of several cardiac biochemical markers of toluene exposure in the aged may also reflect differential susceptibility to this toxicant.
In most subjects with Parkinson's disease and dementia with Lewy bodies, alpha-synuclein (alphaS) immunoreactive pathology is found not only in the brain but also in the autonomic nuclei of the spinal cord. However, neither has the temporal course of alphaS pathology in the spinal cord in relation to the brain progression been established, nor has the extent of alphaS pathology in the spinal cord been analyzed in population-based studies. Using immunohistochemistry, the frequency and distribution of alphaS pathology were assessed semiquantitatively in the brains and spinal cord nuclei of 304 subjects who were aged at least 85 in the population-based Vantaa 85+ study. alphaS pathology was common in the spinal cord; 102 (34%) subjects had classic alphaS pathology in the thoracic and/or sacral autonomic nuclei. Moreover, 134 (44%) subjects showed grain- or dot-like immunoreactivity in neuropil (mini-aggregates) without classic Lewy neurites or Lewy bodies (LBs). The latter type of alphaS accumulation is associated with age, but also the classic alphaS pathology was found more often in the oldest compared to the youngest age group. The severity of alphaS pathology in the spinal cord autonomic nuclei is significantly associated with the extent and severity of alphaS pathology in the brain. Of the subjects, 60% with moderate to severe thoracic alphaS pathology and up to 89% with moderate to severe sacral alphaS pathology had diffuse neocortical type of LB pathology in the brain. alphaS pathology exclusively in the spinal cord was rare. Our study indicates that in general alphaS pathology in the spinal cord autonomic nuclei is associated with similar pathology in the brain.
The Arctic mutation (APP E693G) is unique, since it is located within the amyloid-beta (Abeta) sequence and leads to Alzheimer's disease (AD). Arctic Abeta peptides more easily form Abeta protofibrils in vitro, but little is known about the pathogenic mechanism of the Arctic mutation in vivo. Here, we analyzed APP transgenic mice with both the Swedish and Arctic mutations (tg-APPArcSwe) and transgenic mice with the Swedish mutation alone (tg-APPSwe). Intense intraneuronal Abeta-immunoreactive staining was present in young tg-APPArcSwe mice, but not in tg-APPSwe mice. Intracellular Abeta aggregates in tg-APPArcSwe were strongly stained by antibodies recognizing the N-terminus of Abeta, while those recognizing the C-terminus of Abeta stained weakly. The Abeta aggregates inside neurons increased with age and predated extracellular Abeta deposition in both tg-APPArcSwe and tg-APPSwe mice. Senile plaque deposition was markedly accelerated in tg-APPArcSwe mice, as compared to tg-APPSwe mice. We conclude that the Arctic mutation causes AD by facilitating amyloidosis through early accumulation of intracellular Abeta aggregates in association with a rapid onset of senile plaque deposition.
Cerebral ischemia-reperfusion (I/R) injury initiates a cascade of events, generating nitric oxide (NO) and superoxide(O2•-) to form peroxynitrite (ONOO-), a potent oxidant. Arctic ground squirrels (AGS; Urocitellus parryii) show high tolerance to I/R injury. However, the underlying mechanism remains elusive. We hypothesize that tolerance to I/R modeled in an acute hippocampal slice preparation in AGS is modulated by reduced oxidative and nitrative stress. Hippocampal slices (400µm) from rat and AGS were subjected to oxygen glucose deprivation (OGD) using a novel microperfusion technique. Slices were exposed to NO, O2.- donors with and without OGD; pretreatment with inhibitors of NO, O2.- and ONOO- followed by OGD. Perfusates collected every 15min were analyzed for LDH release, a marker of cell death. 3-nitrotyrosine (3NT) and 4-hydroxynonenal (4HNE) were measured to assess oxidative and nitrative stress. Results show that NO/O2.- alone is not sufficient to cause ischemic-like cell death, but with OGD enhances cell death more in rat than in AGS. A NOS inhibitor, SOD mimetic and ONOO- inhibitor attenuates OGD injury in rat but has no effect in AGS. Rats also show a higher level of 3NT and 4HNE with OGD than AGS suggesting the greater level of injury in rat is via formation of ONOO-.
Cites: Free Radic Res Commun. 1993;18(4):195-9 PMID 8396550