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Biomedical subjects

S R Robinson

Publications and source records attributed to S R Robinson.

At least 19 recordsLinked to original sources
PubMed2006

TNF alpha affects the expression of GFAP and S100B: implications for Alzheimer's disease.

Neurodegenerative disorders such as Alzheimer's disease are characterized by increased intracellular and extracellular concentrations of the astrocytic proteins glial fibrillary acidic protein (GFAP) and S100B. The present study examined the potential contribution of tumor necrosis factor alpha (TNFalpha) to these changes by measuring astrocyte viability along with the intracellular and extracellular expression of GFAP and S100B following exposure to this cytokine. Although TNFalpha did not affect astrocyte viability, the extracellular levels of both proteins were increased three-fold with associated reductions in immunocytochemical labeling.

Alzheimer Disease↗
PubMed2006

HIV-1 protein gp120 rapidly impairs memory in chicks by interrupting the glutamate-glutamine cycle.

Learning and memory impairments are frequently observed in patients suffering from AIDS Dementia Complex (ADC). These effects have been linked to the presence of gp120, an HIV viral coat glycoprotein. The present study investigated the possibility that gp120 prevents the uptake of extracellular glutamate by astrocytes, leading to an interruption of the glutamate-glutamine cycle and a subsequent impairment of memory. Ten microliters of 10nM gp120 was bilaterally injected into the region of the intermediate medial mesopallium of day-old chicks at various times before, or after, training using a single-trial passive avoidance task. Gp120 was found to significantly impair memory retention when injected 10-40 min after training. Memory impairments were evident within 5 min of gp120 administration and remained evident 24h later. Further, the amnestic effect of gp120 could be overcome with glutamine or with precursors of glutamate synthesis, but only weakly by glutamate. These results support the conclusion that the amnestic effect of gp120 is due to an impaired uptake of glutamate by astrocytes and a subsequent interruption of glutamine supply to neurones. The data indicate that the glutamate-glutamine cycle may be a useful therapeutic target in the treatment of ADC.

Amnesia↗
PubMed2006

Glutathione peroxidase-1 contributes to the protection of glutamine synthetase in astrocytes during oxidative stress.

Glutamine synthetase (GS) is an astrocytic enzyme that is essential for the glutamate-glutamine cycle between neurons and astrocytes. To measure the effects of oxidative stress on the activity of GS in astrocytes, astrocyte-rich primary cultures from the brains of wild-type and glutathione peroxidase-1 deficient mice (GPx1(-/-)) were exposed to a chronic hydrogen peroxide-generating system consisting of xanthine oxidase, hypoxanthine and superoxide dismutase. The specific activity of GS was strongly diminished by chronic exposure to hydrogen peroxide in astrocytes cultured from both mouse lines. After 60 min of oxidative stress in the presence of 5 mU/mL, 10 mU/mL and 20 mU/mL of xanthine oxidase, the specific GS activity of wild-type astrocytes was reduced to 47%, 22% and 13% of the initial activity, respectively. For all activities of xanthine oxidase applied, astrocytes from GPx1(-/-) mice experienced a significantly greater rate of GS inactivation compared to their wild-type counterparts. These results confirm that GS is sensitive to inactivation by chronic peroxide stress in viable astrocytes and show that glutathione peroxidase-1 helps to protect GS from inactivation by oxidative stress.

Animals↗
PubMed2003

Altered cellular distribution of iron in rat cerebral cortex during the oestrous cycle.

Iron levels in blood, liver and the substantia nigra fluctuate during the oestrous cycle but it is not known whether the cellular distribution also changes. This study shows that during dioestrus, when serum levels of oestradiol are low, the amount of histochemically detectable iron in the cerebral cortex is significantly lower than in proestrus when oestradiol levels are highest. During dioestrus iron is concentrated within neurones, and the transition to proestrus is associated with a shift in iron localisation from neurones to vascular endothelial cells and oligodendrocytes. These data raise the possibility that changes in the concentration of serum oestrogen (or other reproductive hormones) during the oestrous cycle can influence the intercellular transport of iron in the brain.

Animals↗
PubMed2003

Deposits of fibrillar A beta do not cause neuronal loss or ferritin expression in adult rat brain.

In Alzheimer's disease (AD), senile plaques containing amyloid-beta (Abeta) are associated with neurodegeneration, yet little quantitative data are available concerning the spatiotemporal patterns of neuronal death that result from exposure to Abeta deposits. Furthermore, plaques are accompanied by ferritin-rich cells but no data exist regarding the spatiotemporal expression of ferritin in response to Abeta. The present study has obtained such data after injecting aged Abeta peptide into the parietal cortex of adult rats. Injected deposits of fibrillar Abeta (1 microliter of 1 mM in saline) were cleared within 7 days but did not cause a significant increase in ferritin expression. Counts of dying neurones showed that human Abeta1-40 killed as many neurones as control injections of saline, while human Abeta1-42 and rat Abeta1-40 killed significantly less. We conclude that the fibrillar Abeta in plaques is not likely to be directly responsible for the neurodegeneration and ferritin expression that occurs in AD.

Amyloid beta-Peptides↗
PubMed2003

Anti-AGEing defences against Alzheimer's disease.

Accumulation of insoluble protein deposits and their cross-linking by AGEs (advanced glycation end products) in the brain is a feature of aging and neurodegeneration, especially in AD (Alzheimer's disease). In AD, two types of fibrillar protein aggregates are present: extracellular deposits (plaques) consisting mainly of Abeta (beta-amyloid peptide), and intracellular deposits (tangles) composed predominantly of microtubule-associated protein tau. Both plaques and tangles are modified by AGEs, which occurs particularly at lysine and arginine residues. Interaction of a synthetic amyloid plaque (fibrillar Abeta) with microglia leads to a strong pro-inflammatory response, indicating that priming of immune cells with beta-amyloid potentiates their response to secondary stimuli such as AGE and cytokines such as interferon-gamma. Formation of hyperphosphorylated and cross-linked microtubule-associated protein tau aggregates, especially tau dimers as the first step in tangle formation, can be induced in vitro by the combination of okadaic acid, a PP2A phosphatase inhibitor, and methylglyoxal. These results suggest that excess production of reactive carbonyl compound ("carbonyl stress") and subsequent AGE formation can contribute to cross-linking of protein fibrils and to pathological pro-inflammatory signalling, which all contribute to pathological changes and dementia progression in AD. However, the human brain has developed the glyoxalase system, a most effective defence system to scavenge small dicarbonyl compounds such as glyoxal and methylglyoxal. Very importantly, this system needs GSH as a rate-limiting cofactor. Since GSH is limited under conditions of oxidative stress and inflammation, supplementation with antioxidants such as lipoic acid, vitamin E or flavonoids could indirectly strengthen the anti-glycation defence system in AD. In addition, synthetic carbonyl scavengers and anti-inflammatory drugs could also be valuable drugs for the "anti-glycation" treatment of AD.

Alzheimer Disease↗
PubMed2002

Alzheimer's vaccine: a cure as dangerous as the disease?

Studies in transgenic mouse models of Alzheimer's disease suggested the potential for a vaccine development. However, some patients in the human clinical trials developed symptoms of brain inflammation, demonstrating the high risk of a deliberately induced auto-immune response.

Adjuvants, Immunologic↗
PubMed2002

Potential neurotoxic inflammatory responses to Abeta vaccination in humans.

Studies in transgenic mouse models of Alzheimer's disease suggested the development of a vaccine that would induce the production of antibodies against amyloid-beta (Abeta) peptide, which in turn would stimulate microglia to phagocytose and remove senile plaques. However, some patients in the human clinical trials developed symptoms of brain inflammation, demonstrated by lymphocyte infiltration and elevated protein levels. These parameters are indicative of a breakdown of the blood-brain-barrier and entry of T-cells into the brain. Abeta-specific activated T-helper cells have the potential to amplify the existing pro-inflammatory conditions that are present in the brains of Alzheimer's disease patients. Cytotoxic T-cells might even attack the amyloid precursor protein which is present on the surface of many cells, including neurons. Before undertaking further vaccination trials there is a need to re-assess the risks associated with Abeta vaccination and with the therapeutic containment of a neuroinflammatory response. These risks may not be justified in the light of recent studies which have shown the efficacy of conventional, low-risk treatments in slowing the progress of AD.

Alzheimer Disease↗
PubMed2001

Changes in the cellular distribution of glutamine synthetase in Alzheimer's disease.

The intracellular localization of glutamine synthetase (GS) in the inferior temporal cortices of non-demented elderly individuals was compared with that in brains affected by Alzheimer's disease (AD). The present study confirmed previous reports of a general decrease in GS expression in astrocytes and the expression of GS in some neurons. Several new observations were made: the morphology of astrocytes is generally unaffected by the presence of plaques, GS labeling is present in some diffuse plaques and occasional neuritic plaques, whereas the overall density of astrocytes increases 1.4-fold in AD. In addition, the present study found that the reduction in GS expression is almost entirely due to a loss of GS from perisynaptic regions of the neuropil and from the astrocytic endfeet that normally abut cortical blood vessels. These changes implicate astrocytes in glutamate excitotoxicity and ammonia neurotoxicity. It is suggested that it may be more fruitful to regard AD not as a neuronal disease, but as a disorder of astrocyte-neuron interactions.

Aged↗
PubMed2001

Differential regulation of the dopamine D2 and D3 receptors by G protein-coupled receptor kinases and beta-arrestins.

The D(2) and D(3) receptors (D(2)R and D(3)R), which are potential targets for antipsychotic drugs, have a similar structural architecture and signaling pathway. Furthermore, in some brain regions they are expressed in the same cells, suggesting that differences between the two receptors might lie in other properties such as their regulation. In this study we investigated, using COS-7 and HEK-293 cells, the mechanism underlying the intracellular trafficking of the D(2)R and D(3)R. Activation of D(2)R caused G protein-coupled receptor kinase-dependent receptor phosphorylation, a robust translocation of beta-arrestin to the cell membrane, and profound receptor internalization. The internalization of the D(2)R was dynamin-dependent, suggesting that a clathrin-coated endocytic pathway is involved. In addition, the D(2)R, upon agonist-mediated internalization, localized to intracellular compartments distinct from those utilized by the beta(2)-adrenergic receptor. However, in the case of the D(3)R, only subtle agonist-mediated receptor phosphorylation, beta-arrestin translocation to the plasma membrane, and receptor internalization were observed. Interchange of the second and third intracellular loops of the D(2)R and D(3)R reversed their phenotypes, implicating these regions in the regulatory properties of the two receptors. Our studies thus indicate that functional distinctions between the D(2)R and D(3)R may be found in their desensitization and cellular trafficking properties. The differences in their regulatory properties suggest that they have distinct physiological roles in the brain.

Animals↗
PubMed2001

Quantitative analysis of cell death and ferritin expression in response to cortical iron: implications for hypoxia-ischemia and stroke.

Iron that is not bound to storage proteins can catalyse the generation of toxic hydroxyl radicals. Iron can be released from brain storage proteins by hypoxic conditions, such as those that accompany stroke, and the situation can be compounded by iron released from hemoglobin in extravasated blood cells. Despite the neurotoxicity of iron, there is little quantitative data concerning the spatio-temporal extent of its toxicity in vivo. The present study measures the effects of a pathologically relevant concentration of iron (1.0 mM) on neuronal death and on ferritin expression in vivo. Injection of iron (1 microl ferric ammonium citrate) into rat parietal cortex resulted in 7.9-fold more ferritin-labeled cells than did control injections of ammonium citrate at 1 day post-injection. This elevated expression continued for at least 1 week. One day after injection, the mean number of Fluoro-Jade-labeled degenerating neurons in 100 microm sections passing through the center of ferric ammonium citrate injection sites was 664+/-64. This value was 4.5-fold higher than at ammonium citrate injection sites, and this difference increased to 56-fold by day three. By 5 days post-injection, few dying neurons were observed at the control sites, but neurodegeneration continued beyond a week at the iron-injected sites. Thus, iron released during a brief episode of hypoxia-ischemia or during a stroke may be neurotoxic for a protracted period. Therefore, our findings indicate that it may be beneficial to target iron-induced peroxidation throughout the first few weeks following an intracerebral hemorrhage or an hypoxic-ischemic episode.

Animals↗
PubMed2001

Pre-exposure to (+/-)3,4-methylenedioxy-methamphetamine (MDMA) facilitates acquisition of intravenous cocaine self-administration in rats.

Pre-exposure to (+/-)3,4-methylenedioxymeth-amphetamine (MDMA) elevates locomotor activity and extracellular dopamine levels in the nucleus accumbens following a cocaine challenge. The present study determined whether MDMA-induced sensitization to the effects of cocaine could be demonstrated in rats self-administering cocaine. Three groups of rats were treated with saline (Sal), 5 mg/kg MDMA (once per day for 10 days; MDMA-5) or 20 mg/kg MDMA (twice per day for 4 days; MDMA-20). Subsequently, spontaneous acquisition of cocaine self-administration was measured in 12 daily 2-h sessions. During these test sessions, two response levers were present. Responses on one lever delivered infusions of 0.1 mg of cocaine; responses on the other lever had no programmed consequences. Group Sal showed a weak preference for the active lever; whereas, group MDMA-20 exhibited a stronger active lever preference. By day 12, the MDMA-20 group earned approximately twice the number of cocaine infusions as those in group SAL. At this time point, more than twice as many rats in group MDMA-20 were taking a minimum of 10 infusions per session, as compared to group Sal. Rats in group MDMA-5 did not seem to differ from group Sal in terms of lever discrimination, number of cocaine infusions, and percentage of rats obtaining a criterion of 10 infusions. These results indicate that pre-exposure to a high dose of MDMA may facilitate acquisition of cocaine self-administration. This dosing regimen of MDMA is likely to release DA and to be neurotoxic to 5-HT neurons. Either or both of these mechanisms could contribute to the ability of MDMA to facilitate cocaine self-administration.

Adrenergic Uptake Inhibitors↗
PubMed2000

Inhibition of Müller cell glutamine synthetase rapidly impairs the retinal response to light.

It is widely assumed that neurones have sufficient metabolic reserves to allow them to function independently of glial cells for extended periods. The present study investigates the length of time taken before retinal neurones no longer respond normally to light after the inhibition of glial enzymes that are involved in the synthesis of precursors of neuronal glutamate. The glutamine synthetase inhibitor methionine sulfoximine, when injected intraocularly in Wistar rats, caused a time- and dose-dependent suppression of the scotopic electroretinogram b-wave. At the highest dosage (40 mM) the b-wave was significantly reduced within 2 min of injection. Because the b-wave is an indicator of neurotransmission in the retina, it is deduced that inhibition of glutamine synthetase rapidly blocks glutamatergic neurotransmission. Immunohistochemistry revealed a depletion of neuronal glutamate and an accumulation of glutamate in Müller glial cells, in a time course that matched the b-wave suppression. The b-wave was quickly restored by injection of glutamine (4 mM). The rapid reduction of glutamatergic transmission after methionine sulfoximine administration challenges the view that neurones have sufficient reserves to allow them to function independently for extended periods; instead, it indicates that glia are essential for the moment-to-moment sustenance of neuronal function.

Analysis of Variance↗
PubMed2000

Neuronal expression of glutamine synthetase in Alzheimer's disease indicates a profound impairment of metabolic interactions with astrocytes.

A considerable body of evidence indicates that the activity of glutamine synthetase is decreased in the cerebral cortices of brains affected by Alzheimer's disease. It is difficult to discern the reason for this decrease because it is not known whether the cellular distribution of glutamine synthetase is altered in Alzheimer's disease. Therefore the present study has used immunocytochemistry to compare the cellular distributions of glutamine synthetase in the inferior temporal cortices of six Alzheimer's diseased brains and six age-matched, non-demented brains. Double-label immunocytochemistry has been used to examine whether the distribution of cellular glutamine synthetase is influenced by the distribution of senile plaques. It was found that glutamine synthetase expression in astrocytes is diminished in Alzheimer's disease, particularly in the vicinity of senile plaques. The most striking finding of the present study was that glutamine synthetase was expressed in a subpopulation of pyramidal neurons in all six Alzheimer's diseased brains, whereas glutamine synthetase was not observed in any neurons from control brains. The changed expression of glutamine synthetase may be triggered by toxic agents in senile plaques, a reduced noradrenergic supply to the cerebral cortex, and increased brain ammonia levels. That such dramatic changes occur in the distribution of this critical, and normally stable enzyme, suggests that the glutamate-glutamine cycle is profoundly impaired in Alzheimer's disease. This is significant because impairments of the glutamate-glutamine cycle are known to cause alterations of mood and behaviour, disturbance of sleeping patterns, amnesia, confusion and reduced awareness. Since these behavioural changes are also seen in Alzheimer's disease, it is speculated that they might be attributable to the reduced expression of glutamine synthetase or to impairments of the glutamate-glutamine cycle.

Aged↗
PubMed2000

Spontaneous motor activity in fetal and infant rats is organized into discrete multilimb bouts.

Spontaneous motor activity (SMA) is a ubiquitous feature of fetal and infant behavior. Although SMA appears random, successive limb movements often occur in bouts. Bout organization was evident at all ages in fetal (embryonic day [E] 17-21) and infant (postnatal day [P] 1-9) rats, with nearly all bouts comprising 1-4 movements of different limbs. A computational model of SMA, including spontaneous activity of spinal motor neurons, intrasegmental and intersegmental interactions, recurrent inhibition, and descending influences, produced bouts with the same structure as that observed in perinatal rats. Consistent with the model, bouts were not eliminated on E20 after cervical spinal transection, suggesting that the brain is not necessary to produce bout organization. These investigations provide a foundation for understanding the contributions of SMA to neuromuscular and motor development.

Animals↗
PubMed2000

Reducing post-tonsillectomy pain with cryoanalgesia: a randomized controlled trial.

OBJECTIVE/HYPOTHESIS: To evaluate the use of cryoanalgesia in reducing post-tonsillectomy pain. STUDY DESIGN: A prospective, randomized double-blind study of 59 consecutive patients (age range, 8-40 y) undergoing tonsillectomy for recurrent tonsillitis. METHODS: All patients underwent bipolar tonsillectomy. At the completion of the tonsillectomy patients were randomly assigned to a control or a cryotherapy group. The cryotherapy patients had both their tonsillar fossa "supercooled" to between -20 degrees C and -32 degrees C for 1 minute. Patients recorded their pain using a visual analogue scale over the next 10 days. Patients were also monitored for postoperative complications, time until resumption of a normal diet, time back to work or school, and analgesic consumption. RESULTS: The two groups were similar for age and sex. There was a 28.3% reduction in mean pain scores over the 10 days in the cryotherapy compared to the control group. This difference did not significantly depend on the day after operation or time of the day. Cryotherapy patients also returned to work or school, on average, 4 days earlier than controls. There was no significant difference in postoperative complications between the two groups. CONCLUSION: Cryotherapy is a new technique that significantly reduces post-tonsillectomy pain without evidence of causing additional complications.

Cryotherapy↗