Biomedical subjects

Peter Styles

Publications and source records attributed to Peter Styles.

At least 19 recordsLinked to original sources

PubMed2006

Chronic oral ascorbic acid therapy worsens skeletal muscle metabolism in patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is associated with abnormalities of skeletal muscle metabolism. This may be due to impaired oxygen delivery as a result of endothelial dysfunction. AIMS: We postulated that ascorbic acid would improve oxygen delivery to exercising muscle and improve skeletal muscle metabolism. METHODS: We studied skeletal muscle metabolism using (31)P magnetic resonance spectroscopy in 39 CHF patients. Endothelial function was assessed by changes in pulse wave velocity. Subjects were randomised to receive 4 g ascorbic acid daily for 4 weeks in a placebo-controlled double-blind study. RESULTS: Ascorbic acid significantly increased phosphocreatine utilization during exercise. In addition, glycolytic ATP synthesis increased in the ascorbic acid group (change in rate of ATP synthesis at 1 min -0.21+/-0.76 with placebo, 2.06+/-0.60 following ascorbic acid; p<0.05). Phosphocreatine and ADP recovery after exercise were not changed. The fall in pulse wave velocity during reactive hyperaemia was increased by ascorbic acid from -6.3+/-2.6% to -12.1+/-2.0% (p<0.05). CONCLUSIONS: These findings suggest that ascorbic acid increased both phosphocreatine utilization and glycolytic ATP synthesis during exercise in patients with CHF implying worsened skeletal muscle metabolism despite improvements in endothelial function.

Adenosine Triphosphate↗

PubMed2005

Antioxidant treatment of patients with Friedreich ataxia: four-year follow-up.

BACKGROUND: Decreased mitochondrial respiratory chain function and increased oxidative stress have been implicated in the pathogenesis of Friedreich ataxia (FRDA), raising the possibility that energy enhancement and antioxidant therapies may be an effective treatment. OBJECTIVE: To evaluate the long-term efficacy of a combined antioxidant and mitochondrial enhancement therapy on the bioenergetics and clinical course of FRDA. DESIGN: Open-labeled pilot trial over 47 months.Patients Seventy-seven patients with clinical and genetically defined FRDA. Intervention A combined coenzyme Q(10) (400 mg/d) and vitamin E (2100 IU/d) therapy of 10 patients with FRDA over 47 months. MAIN OUTCOME MEASURES: Clinical assessment using echocardiography and the International Cooperative Ataxia Rating Scale and cardiac and skeletal muscle bioenergetics as assessed using phosphorus P 31 magnetic resonance spectroscopy. RESULTS: There was a significant improvement in cardiac and skeletal muscle bioenergetics that was maintained throughout the 47 months of therapy. Echocardiographic data revealed significantly increased fractional shortening at the 35- and 47-month time points. Comparison with cross-sectional data from 77 patients with FRDA indicated the changes in total International Cooperative Ataxia Rating Scale and kinetic scores over the trial period were better than predicted for 7 patients, but the posture and gait and hand dexterity scores progressed as predicted. CONCLUSION: This therapy resulted in sustained improvement in mitochondrial energy synthesis that was associated with a slowing of the progression of certain clinical features and a significant improvement in cardiac function.

Adolescent↗

PubMed2005

MRI reveals that early changes in cerebral blood volume precede blood-brain barrier breakdown and overt pathology in MS-like lesions in rat brain.

Magnetic resonance imaging (MRI) is an established clinical tool for diagnosing multiple sclerosis (MS), the archetypal central nervous system neuroinflammatory disease. In this study, we have used a model of delayed-type hypersensitivity in the rat brain, which bears many of the hallmarks of an MS lesion, to investigate the development of MRI-detectable changes before the appearance of conventional indices of lesion development. In addition, we have correlated the MRI-detectable changes with the developing histopathology. Significant increases in regional cerebral blood volume (rCBV) preceded overt changes in blood-brain barrier (BBB) permeability, T2 relaxation and the diffusion properties of tissue water. Thus, changes in rCBV might be a more sensitive indicator of lesion onset than the conventional indices used clinically in MS patients, such as contrast enhancement. In addition, we show that BBB breakdown, and consequent edema formation, are more closely correlated with astrogliosis than any other histopathologic changes, while regions of T1 and T2 hypointensity appear to reflect hypercellularity.

Animals↗

PubMed2004

Abnormal cardiac energetics in patients carrying the A3243G mtDNA mutation measured in vivo using phosphorus MR spectroscopy.

Cardiomyopathy is a frequent cause of morbidity and mortality in patients carrying the A3243G transition in the mitochondrial DNA (mtDNA) tRNALeu(UUR) gene, the most common heteroplasmic single mtDNA defect. We used phosphorus magnetic resonance spectroscopy (31P-MRS) to look for evidence of an in vivo bioenergetics defect in patients carrying the A3243G mtDNA mutation with and without echocardiographic signs of left ventricle hypertrophy (LVH). Eight patients, three with LVH, carrying the A3243G mtDNA mutation and 10 healthy subjects underwent one-dimensional chemical shift imaging 31P-MRS. In the patients, mean cardiac phosphocreatine to adenosine triphosphate ratio (PCr/ATP) (1.55 +/- 0.58) was significantly reduced compared to the control group (2.34 +/- 0.14; P < 0.001). Cardiac PCr/ATP was within the normal range only in one case that showed normal echocardiography. Our results point to a central role of bioenergetics deficit in the development of cardiac hypertrophy in patients with the A3243G mtDNA mutation. Impaired cardiac energy metabolism in patients with normal echocardiography suggests that the enhancement of mitochondrial function may be beneficial not only to patients with cardiac hypertrophy but also to those patients carrying the mutation in the absence of signs of cardiac hypertrophy and/or dysfunction but with cardiac bioenergetics deficit.

Adult↗

PubMed2004

Study of cytokine induced neuropathology by high resolution proton NMR spectroscopy of rat urine.

Multiple sclerosis is a major cause of non-traumatic neurological disability. The identification of markers that differentiate disease progression is critical to effective therapy. A combination of NMR spectroscopic metabolic profiling of urine and statistical pattern recognition was used to detect focal inflammatory central nervous system (CNS) lesions induced by microinjection of a replication-deficient recombinant adenovirus expressing TNF-alpha or IL1-beta cDNA into the brains of Wistar rats. These animals were compared with a group of naïve rats and a group of animals injected with an equivalent null adenovirus. Urine samples were collected 7 days after adenovirus injection, when the inflammatory lesion is maximally active. Principal components analysis and Partial Least Squares-Discriminate analysis of the urine (1)H NMR spectra revealed significant differences between each of the cytokine adenovirus groups and the control groups; for the TNF-alpha group the main differences lay in citrate and succinate, while for the IL-1beta group the predominant changes occurred in leucine, isoleucine, valine and myo-inositol. Thus, we can identify urinary metabolic vectors that not only separate rats with inflammatory lesions in the brain from control animals, but also distinguish between different types of CNS inflammatory lesions.

Adenoviridae↗

PubMed2004

MRI detection of early endothelial activation in brain inflammation.

MRI is an increasingly important clinical tool, but it is clear that conventional imaging fails to identify the full extent of lesion load in certain conditions, such as multiple sclerosis. The aim of this study was to determine whether a novel contrast agent (Gd-DTPA-B(sLeX)A, which contains an sLeX mimetic moiety that enables it to bind to the adhesion molecule E-selectin) can be used to identify endothelial activation in the brain. Microinjection of the proinflammatory cytokines IL-1beta or TNF-alpha into the striatum of Wistar rats rapidly induces focal adhesion molecule expression on the endothelium in the absence of MRI-visible changes. This phenomenon was used to investigate the potential of Gd-DTPA-B(sLeX)A to reveal MRI-invisible brain pathology. T1-weighted serial images were acquired in anesthetized animals before and after administration of Gd-DTPA-B(sLeX)A, 3-4 hr after cytokine was injected intracerebrally. Both TNF-alpha and IL-1beta up-regulated E-selectin on the brain endothelium, which correlated with increased signal intensity observed after administration of the novel contrast agent. No enhancement was visible with the nonselective contrast agent Gd-DTPA-BMA, indicating that there was no leakage of the agent across the blood-brain barrier (BBB) or nonselective binding to the endothelium. These data demonstrate the potential of such contrast agents for the early detection of brain injury and inflammation.

Animals↗

PubMed2004

Increase in apparent diffusion coefficient in normal appearing white matter following human traumatic brain injury correlates with injury severity.

Following diffuse traumatic brain injury, there may be persistent functional or psychological deficits despite the presence of normal conventional MR images. Previous experimental animal and human studies have shown diffusion abnormalities following focal brain injury. Our aim was to quantify changes in apparent diffusion coefficient (ADC) and absolute relaxation times of normal appearing white matter (NAWM) in humans following traumatic brain injury. Twenty-three patients admitted with a diagnosis of head injury (nine mild, eight moderate, and six severe) were scanned an average of 7.6 days after injury using a quantitative echo planar imaging acquisition to obtain co-registered T1, T2, and ADC parametric maps. Mean NAWM values were compared with a control group (n = 13). The patient group showed a small but significant increase in ADC in NAWM, with no significant change in T1 or T2 relaxation times. There was a correlation between injury severity and increasing ADC (p = 0.03) but no correlation with either T1 or T2, suggesting that ADC is a sensitive and independent marker of diffuse white matter tissue damage following traumatic insult. None of the patients had a reduced ADC, making ischaemia unlikely in this cohort. Pathophysiological mechanisms that may explain diffusely raised ADC include vasogenic edema, chronic ischemic phenomena, or changes in tissue cytoarchitecture or neurofilament alignment.

Adolescent↗

PubMed2003

Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes.

BACKGROUND: It is well known that patients with type 2 diabetes have increased risk of cardiovascular disease, but it is not known whether they have underlying abnormalities in cardiac or skeletal muscle high-energy phosphate metabolism. METHODS AND RESULTS: We studied 21 patients with type 2 diabetes with no evidence of coronary artery disease or impaired cardiac function, as determined by echocardiography, and 15 age-, sex-, and body mass index-matched control subjects. Cardiac high-energy phosphate metabolites were measured at rest using 31P nuclear magnetic resonance spectroscopy (MRS). Skeletal muscle high-energy phosphate metabolites, intracellular pH, and oxygenation were measured using 31P MRS and near infrared spectrophotometry, respectively, before, during, and after exercise. Although their cardiac morphology, mass, and function appeared to be normal, the patients with diabetes had significantly lower phosphocreatine (PCr)/ATP ratios, at 1.50+/-0.11, than the healthy volunteers, at 2.30+/-0.12. The cardiac PCr/ATP ratios correlated negatively with the fasting plasma free fatty acid concentrations. Although skeletal muscle energetics and pH were normal at rest, PCr loss and pH decrease were significantly faster during exercise in the patients with diabetes, who had lower exercise tolerance. After exercise, PCr recovery was slower in the patients with diabetes and correlated with tissue reoxygenation times. The exercise times correlated negatively with the deoxygenation rates and the hemoglobin (Hb)A1c levels and the reoxygenation times correlated positively with the HbA1c levels. CONCLUSIONS: Type 2 diabetic patients with apparently normal cardiac function have impaired myocardial and skeletal muscle energy metabolism related to changes in circulating metabolic substrates.

Adenosine Diphosphate↗

PubMed2003

Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy.

OBJECTIVES: We investigated cardiac energetics in subjects with mutations in three different familial hypertrophic cardiomyopathy (HCM) disease genes, some of whom were nonpenetrant carriers without hypertrophy, using phosphorus-31 magnetic resonance spectroscopy. BACKGROUND: Familial hypertrophic cardiomyopathy is caused by mutations in sarcomeric protein genes. The mechanism by which these mutant proteins cause disease is uncertain. A defect of myocyte contractility had been proposed, but in vitro studies of force generation have subsequently shown opposing results in different classes of mutation. An alternative hypothesis of "energy compromise" resulting from inefficient utilization of adenosine triphosphate (ATP) has been suggested, but in vivo data in humans with genotyped HCM are lacking. METHODS: The cardiac phosphocreatine (PCr) to ATP ratio was determined at rest in 31 patients harboring mutations in the genes for either beta-myosin heavy chain, cardiac troponin T, or myosin-binding protein C, and in 24 controls. Transthoracic echocardiography was used to measure left ventricular (LV) dimensions and maximal wall thickness. RESULTS: The PCr/ATP was reduced in the HCM subjects by 30% relative to controls (1.70 +/- 0.43 vs. 2.44 +/- 0.30; p < 0.001), and the reduction was of a similar magnitude in all three disease-gene groups. The PCr/ATP was equally reduced in subjects with (n = 24) and without (n = 7) LV hypertrophy. CONCLUSIONS: Our data provide evidence of a bioenergetic deficit in genotype-confirmed HCM, which is present to a similar degree in three disease-gene groups. The presence of energetic abnormalities, even in those without hypertrophy, supports a proposed link between altered cardiac energetics and development of the disease phenotype.

Adenosine Triphosphate↗

PubMed2003

Maternal neuronal antibodies associated with autism and a language disorder.

Neurodevelopmental disorders could be caused by maternal antibodies or other serum factors. We detected serum antibodies binding to rodent Purkinje cells and other neurons in a mother of three children: the first normal, the second with autism, and the third with a severe specific language disorder. We injected the serum (0.5-1.0 ml/day) into pregnant mice during gestation and found altered exploration and motor coordination and changes in cerebellar magnetic resonance spectroscopy in the mouse offspring, comparing with offspring of mice injected with sera from mothers of healthy children. This evidence supports a role for maternal antibodies in some forms of neurodevelopmental disorder.

Adult↗

PubMed2003

In vivo monitoring of rat brain metabolites during vigabatrin treatment using localized 2D-COSY.

A two-dimensional COSY-based localization sequence was designed to allow the in vivo monitoring of proton metabolites in rat brain [particularly gamma-aminobutyric acid (GABA), glutamine, taurine and myo-inositol]. The sequence incorporated OSIRIS signal localization, B1-insensitive water suppression and phase-sensitive COSY acquisition. The method was used to study the effects of the GABA-transaminase inhibitor vigabatrin on rat brain metabolite concentrations. Wistar rats were treated daily for 3 days with an oral dose of vigabatrin (200 mg/kg, n = 4). Localized COSY spectra were obtained during a 120 min acquisition from a 270 microl central brain voxel and compared with nine untreated control animals. Significant elevations were observed in GABA (267% of control, p < 0.005, Mann-Witney test), glutamine (130% of control, p < 0.005) and taurine (113% of control, p < 0.05). Changes in GABA and taurine were consistent with previous data on the action of Vigabatrin, and support a previously hypothesized link between these compounds. The increase in glutamine was more surprising and may reflect the balance between the level and/or site of GABA-transaminase inhibition and downregulation of GABA synthesis.

Animals↗

PubMed2003

Multi-modal MRI in normal pressure hydrocephalus identifies pre-operative haemodynamic and diffusion coefficient changes in normal appearing white matter correlating with surgical outcome.

Magnetic resonance techniques were used to investigate haemodynamic abnormalities and their consequences in normal pressure hydrocephalus (NPH) and to assess changes in these parameters following surgery. Eleven patients with NPH were studied pre- and post-operatively using perfusion and diffusion weighted imaging and compared with ten age-matched controls. Pre-operative periventricular relative cerebral blood volume (rCBV) was reduced in patients (0.76+/-0.11) compared with control (1.16+/-0.16, P<0.01). There was no difference between outcome groups and no change in haemodynamic parameters following surgery. The periventricular apparent diffusion coefficient (ADC) was elevated in the poor outcome group (1.67+/-0.3 x 10(-3) mm(2) s(-1)) compared with both controls (1.04+/-0.4 x 10(-3) mm(2) s(-1), P<0.05) and the good outcome group (0.99+/-0.3 x 10(-3) mm(2) s(-1), P<0.05) despite appearing normal on conventional imaging. In white matter hyperintensities (WMH), rCBV was reduced (0.70+/-0.12 vs. 1.00+/-0.10, P<0.01), and the ADC was increased (1.98+/-0.6 vs. 1.04+/-0.4 x 10(-3) mm(2) s(-1), P<0.05) compared with the same anatomical location in controls. As low rCBV and high ADC is characteristic of chronic infarction, the findings in WMH regions suggest they are irreversibly damaged. Normal appearing periventricular tissue rCBV was reduced, implying that significant haemodynamic consequences contribute to symptoms in NPH. The elevated pre-operative ADC of the same region, was correlated with poor outcome, and may, therefore, be useful in selecting patients for surgery.

Aged↗

PubMed2002

Elimination of Nyquist ghosting caused by read-out to phase-encode gradient cross-terms in EPI.

Echo-planar imaging (EPI) commonly suffers from ghosting artifacts caused by zero- or first-order phase differences between the odd and even echoes that constitute an EPI dataset. Small-bore imaging systems with shielded gradients may suffer significantly from cross-term eddy currents due to the high degree of manufacturing precision required in such systems compared to larger whole-body coils. A Nyquist ghost caused by cross-term eddy current contributions from the read-out to the phase-encode axis was identified in a small-bore system and characterized using a modified EPI experiment and a computer simulation. The artifact was corrected for using both a postprocessing approach and compensation blips along the phase-encode axis. Correction using compensation blips proved to be a more effective strategy to reduce this artifact than the postprocessing method used.

Artifacts↗

PubMed2002

Cerebellar morphology in developmental dyslexia.

Recent evidence has suggested cerebellar anomalies in developmental dyslexia. Therefore, we investigated cerebellar morphology in subjects with documented reading disabilities. We obtained T1-weighted magnetic resonance images in the coronal and sagittal planes from 11 males with prior histories of developmental dyslexia, and nine similarly-aged male controls. Proton magnetic resonance spectra (TE=136ms, TR=2.4s) were obtained bilaterally in the cerebellum. Phonological decoding skill was measured using non-word reading. Handedness was assessed using both the Annett questionnaire of hand preference and Annett's peg moving task. Cerebellar symmetry was observed in the dyslexics but there was significant asymmetry (right grey matter>left grey matter) in controls. The interpretation of these results depended whether a motor- or questionnaire-based method was used to determine handedness. The degree of cerebellar symmetry was correlated with the severity of dyslexics' phonological decoding deficit. Those with more symmetric cerebella made more errors on a nonsense word reading measure of phonological decoding ability. Left cerebellar metabolite ratios were shown to correlate significantly with the degree of cerebellar asymmetry (P<0.05) in controls. This relationship was absent in developmental dyslexics. Cerebellar morphology reflects the higher degree of symmetry found previously in the temporal and parietal cortex of dyslexics. The relationship of cerebellar asymmetry to phonological decoding ability and handedness, together with our previous finding of altered metabolite ratios in the cerebellum of dyslexics, lead us to suggest that there are alterations in the neurological organisation of the cerebellum which relate to phonological decoding skills, in addition to motor skills and handedness.

Adult↗

PubMed2002

Maternal antibody-mediated dyslexia? Evidence for a pathogenic serum factor in a mother of two dyslexic children shown by transfer to mice using behavioural studies and magnetic resonance spectroscopy.

The causes of dyslexia are unknown, but previous studies have suggested an immunological basis in some cases. We hypothesised that maternal antibodies, which cross the placenta and bind to fetal antigens, could be responsible, particularly when the dyslexia recurs in consecutive pregnancies. We injected serum samples from five mothers of two or more children with dyslexia into pregnant mice, and tested the offspring for behavioural abnormalities and cerebellar metabolites by magnetic resonance spectroscopy (MRS). Mice exposed in utero to serum factors from one woman with two dyslexic children, who had also had three spontaneous fetal losses, showed deficits in motor tests which correlated with cerebellar choline (Cho) and creatine (Cr) levels. These preliminary results are consistent with a role for maternal serum factors, probably antibodies, in causing some of the features of dyslexia, and possibly in other neurodevelopmental disorders.

Animals↗

PubMed2002

Reduced oxidative phosphorylation and proton efflux suggest reduced capillary blood supply in skeletal muscle of patients with dermatomyositis and polymyositis: a quantitative 31P-magnetic resonance spectroscopy and MRI study.

Quantitative MRI and phosphorus magnetic resonance spectroscopy ((31)P-MRS) were used to investigate skeletal muscle metabolism in vivo in patients with dermatomyositis (DM) and polymyositis (PM) in order to evaluate the role of mitochondrial abnormalities in the pathogenesis and clinical expression of these conditions. Nine patients with DM (mean age +/- SD, 57 +/- 14 years) and five with PM (42 +/- 12 years) and with age at disease onset 53 +/- 16 and 38 +/- 12 years, respectively, were included in the study together with 18 age-matched controls. Post-exercise (31)P-MRS indices of muscle oxidative metabolism were all impaired in DM and PM. In both groups of patients, the phosphocreatine and adenosine diphosphate recovery half-times were almost twice as long as in controls (P < 0.05 for each variable) and the maximum rate of mitochondrial ATP production was half that found in normal subjects (P < 0.001). The rate of proton efflux from muscle fibres was significantly reduced in DM (P < 0.001) and PM (P = 0.02). The impairment of (31)P-MRS recovery indices in DM and PM patients was similar to that found in a group of 10 patients with a primary mitochondrial disorder that showed a normal proton efflux rate. There was no correlation between the MRS-detectable abnormalities and the degree of inflammation or fatty infiltration of the muscle, as measured by MRI. The in vivo findings in DM and PM patients indicate impaired muscle aerobic function, which, considering the reduced proton efflux, is likely to be secondary to an impaired blood supply. Our results suggest that the abnormal mitochondria seen in some muscle biopsies are unlikely to be the primary cause of the oxidative insufficiency in these patients.

Adenosine Diphosphate↗

PubMed2002

Longitudinal quantitative proton magnetic resonance spectroscopy of the hippocampus in Alzheimer's disease.

Changes in metabolites detected by proton magnetic resonance spectroscopy ((1)H MRS) of the brain have been demonstrated in Alzheimer's disease. Our objectives were, first, longitudinally to measure absolute concentrations of metabolites in both hippocampi, the sites of early Alzheimer's disease, in patients with clinical Alzheimer's disease and controls; secondly, to separate the relative contribution of atrophy and metabolite concentration change to overall signal change; and, thirdly, to determine whether metabolite concentrations in the hippocampus relate to cognitive scores. (1)H MR spectra were acquired from a single voxel (12 x 15 x 25 mm(3) = 4.5 ml) aligned to the long axis of each hippocampus in nine probable or possible Alzheimer's disease subjects diagnosed according to the National Institute of Neurologic and Cognitive Disorders and Stroke (NINCDS) compared with 14 age-matched NINCDS-negative Alzheimer's disease controls. Metabolite concentrations were corrected for the amount of CSF present in the voxel. Hippocampal volumes were measured at the same time. The same protocol was repeated approximately 1 year later. We found that atrophy-corrected hippocampal N-acetylaspartate (NAA) concentration was lower in cognitively impaired subjects compared with controls. This was significant for the left hippocampus (baseline 87% of control, P = 0.013; and at 1 year 76% of control, P = 0.020). Hippocampal volumes also differed significantly between the groups, and decreased significantly over 1 year in the Alzheimer's disease group (12%, P = 0.017). The decrease in [NAA] over 1 year was not significant in either group. Discriminant analysis revealed that the best classification of subjects was by including both left NAA concentration and left hippocampal volume. myo-Inositol signals from these small voxels had poor signal-to-noise and demonstrated no significant changes. We conclude that (1)HMRS-detectable metabolites can be quantified from the hippocampi of cognitively impaired individuals, and that hippocampal [NAA] is significantly reduced in Alzheimer's disease, in excess of atrophy. In our cohort, the differences were more significant for the left hippocampus.

Aged↗

PubMed2002

TNF-alpha reduces cerebral blood volume and disrupts tissue homeostasis via an endothelin- and TNFR2-dependent pathway.

TNF-alpha expression is elevated in a variety of neuropathologies, including multiple sclerosis, cerebral malaria and HIV encephalitis. However, the consequences of such high cerebral TNF-alpha expression remain unresolved. Here, using MRI, we demonstrate that a focal intrastriatal injection of TNF-alpha causes a significant, acute reduction (15-30%) in cerebral blood volume (CBV), which is dependent on TNF-alpha-type 2 receptor (TNFR2) activation, and can be ameliorated by pre-treatment with a non-specific endothelin (ET) receptor antagonist. An acute breakdown of the blood-cerebrospinal fluid barrier (B-CSF-B) and a delayed breakdown of the blood-brain barrier (BBB) were also observed using contrast-enhanced MRI. Furthermore, a significant reduction in tissue water diffusion was apparent 24 h after intrastriatal injection of TNF-alpha injection, which may indicate compromise of tissue energy metabolism. Prolonged expression of endogenous TNF-alpha, achieved through the use of an adenoviral vector expressing TNF-alpha cDNA (Ad5TNF-alpha(m)), caused a sustained depression in CBV in accordance with the single TNF-alpha bolus data. These findings identify vasoconstriction, disrupted tissue homeostasis and damage to the BBBs as adverse effects of TNF-alpha within the brain, and suggest that antagonists of the endothelin and TNF-alpha type 2 receptors may be therapeutic in TNF-alpha-associated neuropathologies.

Animals↗