Cyclic GMP-phosphodiesterase inhibition does not alter cerebral oxygen consumption

The effect of zaprinast, a cyclic guanosine monophosphate inhibitor, on the level of cyclic GMP and cerebral O₂ consumption was determined. Anesthetized male Long-Evans rats were divided into a control group (n=15) and a zaprinast treated group (n=15). Vehicle was applied topically to the left cortex and 3·10⁻³ M zaprinast was applied to the right cortex. A saline treated control group was also studied. Regional cerebral blood flow was determined by [¹⁴C]-iodoantipyrine and regional O₂ extraction was determined by microspectrophotometry. The level of cyclic GMP was measured by radioimmunoassay. There were no hemodynamic or blood gas differences between groups. The level of cyclic GMP was not significantly different between the right and left cerebral cortex of the control group (17.0±4.3 and 17.7±4.6 pmol/g). In the zaprinast treated group, there was a significant (46%) increase in the level of cyclic GMP in the zaprinast treated cortex (20.5±8.1) in comparison to the vehicle treated cortex (14.0±5.7). Zaprinast did not significantly alter cerebral blood flow. There were no significant differences in regional O₂ extraction. The O₂ consumption of the zaprinast treated cortex (8.0±3.3 ml O₂·min⁻¹·100 g⁻¹) was not different from that of the vehicle treated cortex (7.0±2.9) or those of the control group. Thus, our data indicated that the increased level of cyclic GMP had no significant effect on cerebral oxygen consumption.     

Insulin resistance does not impair contractile responses of cerebral arteries

Insulin resistance (IR) impairs endothelium-mediated vasodilation in cerebral arteries as well as K+ channel function in vascular smooth muscle. Peripheral arteries also show an impaired endothelium-dependent vasodilation in IR and concomitantly show an enhanced contractile response to endothelin-1 (ET-1). However, the contractile responses of the cerebral arteries in IR have not been examined systematically. This study examined the contractile responses of pressurized isolated middle cerebral arteries (MCAs) in fructose-fed IR and control rats. IR MCAs showed no difference in pressure-mediated (80 mmHg) vasoconstriction compared to controls, either in time to develop spontaneous tone (control: 61+/-3 min, n=30; IR: 63+/-2 min, n=26) or in the degree of that tone (control: 60 min: 33+/-2%, n=22 vs. IR 60 min: 34+/-3%, n=17). MCAs treated with ET-1 (10(-8.5) M) constrict similarly in control (53+/-3%, n=14) and IR (53+/-3%, n=14) arteries. Constrictor responses to U46619 (10(-6) M) are also similar in control (48+/-9%, n=8) and IR (42+/-5%, n=6) MCAs as are responses to extraluminal uridine 5'-triphosphate (UTP; 10(-4.5) M) (control: 35+/-7%, n=11 vs. IR: 38+/-3%, n=10). These findings demonstrate that constrictor responses remain intact in IR despite a selective impairment of dilator responses and endothelial and vascular smooth muscle K+ channel function in cerebral arteries. Thus, it appears that the increased susceptibility to cerebrovascular abnormalities associated with IR and diabetes (including cerebral ischemia, stroke, vertebrobasilar transient ischemic attacks) is not due to an enhanced vasoreactivity to constrictor agents.     

Endogenous enkephalin does not contribute to the cerebral anti-hyperalgesic action of gabapentin

The aim of this study was to investigate the role of endogenous enkephalin in the cerebral antihyperalgesic action of gabapentin. Neuropathic pain models and antihyperalgesic effect of gabapentin were confirmed by the presentation and changes of mechanical allodynia and thermal hyperalgesia of operated mouse hind paws. The results suggested that endogenous enkephalin may not be involved in the antihyperalgesic effect of gabapentin.     

Inhibition of nitric oxide synthase does not alter dynamic cerebral autoregulation in humans

The aim of this study was to determine whether inhibition of nitric oxide synthase (NOS) alters dynamic cerebral autoregulation in humans. Beat-to-beat blood pressure (BP) and cerebral blood flow (CBF) velocity (transcranial Doppler) were measured in eight healthy subjects in the supine position and during 60 degrees head-up tilt (HUT). NOS was inhibited by intravenous NG-monomethyl-L-arginine (L-NMMA) infusion. Dynamic cerebral autoregulation was quantified by transfer function analysis of beat-to-beat changes in BP and CBF velocity. Pressor effects of L-NMMA on cerebral hemodynamics were compared with those of phenylephrine infusion. In the supine position, L-NMMA increased mean BP from 83+/-3 to 94+/-3 mmHg (P < 0.01). However, CBF velocity remained unchanged. Consequently, cerebrovascular resistance index (CVRI) increased by 15% (P < 0.05). BP and CBF velocity variability and transfer function gain at the low frequencies of 0.07-0.20 Hz did not change with L-NMMA infusion. Similar changes in mean BP, CBF velocity, and CVRI were observed after phenylephrine infusion, suggesting that increase in CVRI after L-NMMA was mediated myogenically by increase in arterial pressure rather than a direct effect of cerebrovascular NOS inhibition. During baseline tilt without L-NMMA, steady-state BP increased and CBF velocity decreased. BP and CBF velocity variability at low frequencies increased in parallel by 277% and 217%, respectively (P < 0.05). However, transfer function gain remained unchanged. During tilt with L-NMMA, changes in steady-state hemodynamics and BP and CBF velocity variability as well as transfer gain and phase were similar to those without L-NMMA. These data suggest that inhibition of tonic production of NO does not appear to alter dynamic cerebral autoregulation in humans.     

Concurrent gastro-intestinal nematode infection does not alter the development of experimental cerebral malaria

Concurrent helminth infections have been suggested to be associated with protection against cerebral malaria in humans, a condition characterised by systemic inflammation. Here we show that a concurrent chronic gastro-intestinal nematode infection does not alter the course of murine cerebral malaria. Mice infected with Heligmosomoides polygyrus, and co-infected with Plasmodium berghei ANKA 14 days later, developed malaria parasitemia, weight loss and anemia, at the same rate as mice without nematode infection. Both groups developed cerebral malaria around the same time point. The data suggest that a chronic helminth infection does not affect the development of cerebral malaria in a murine model.     

Standing up to the challenge of standing: a siphon does not support cerebral blood flow in humans

Model studies have been advanced to suggest both that a siphon does and does not support cerebral blood flow in an upright position. If a siphon is established with the head raised, it would mean that internal jugular pressure reflects right atrium pressure minus the hydrostatic difference from the brain. This study measured spinal fluid pressure in the upright position, the pressure and the ultrasound-determined size of the internal jugular vein in the supine and sitting positions, and the internal jugular venous pressure during seated exercise. When the head was elevated approximately 25 cm above the level of the heart, internal jugular venous pressure decreased from 9.5 (SD 2.8) to 0.2 (SD 1.0) mmHg [n = 15; values are means (SD); P < 0.01]. Similarly, central venous pressure decreased from 6.2 (SD 1.8) to 0.6 (SD 2.6) mmHg (P < 0.05). No apparent lumen was detected in any of the 31 left or right internal veins imaged at 40 degrees head-up tilt, and submaximal (n = 7) and maximal exercise (n = 4) did not significantly affect internal jugular venous pressure. While seven subjects were sitting up, spinal fluid pressure at the lumbar level was 26 (SD 4) mmHg corresponding to 0.1 (SD 4.1) mmHg at the base of the brain. These results demonstrate that both for venous outflow from the brain and for spinal fluid, the prevailing pressure approaches zero at the base of the brain when humans are upright, which negates that a siphon supports cerebral blood flow.     

Development: Hedgehog does the two-step

Hedgehog signalling establishes spatial correspondence between olfactory receptor neurons and their targets in the brain through a two-step mechanism.     

Hearing: cortical activation does matter

Lesion studies have suggested that the auditory cortex may not be involved in many aspects of hearing. A recent report casts doubt on this long-held view by showing that reversible inactivation of the auditory cortex leads to a transient impairment in tone detection and frequency discrimination.     

On clinical efficacy: Why biofeedback does—and does not—Work

Questions of clinical efficacy are becoming more prominent in this era of diminishing funds for research and clinical care, and new treatment procedures, in particular, are being rigorously scrutinized. This presents a challenge for the relatively recent field of biofeedback and applied psychophysiology. This field has a strong scientific orientation and a rapidly expanding research base, which includes many well-controlled clinical outcome studies. The point is raised, and illustrated with data from current clinical outcome studies, that it is time for a shift in emphasis away from simply piling study upon study and toward more thoughtful interpretation of experimental and clinical findings and the development of a clearer conceptual framework for biofeedback therapy and research.Preparation of this paper was supported in part by NIDRR grant No. H133G90085, Department of Education, DHEW.     

FTY720 reduces post-ischemic brain lymphocyte influx but does not improve outcome in permanent murine cerebral ischemia

Background

The contribution of neuroinflammation and specifically brain lymphocyte invasion is increasingly recognised as a substantial pathophysiological mechanism after stroke. FTY720 is a potent treatment for primary neuroinflammatory diseases by inhibiting lymphocyte circulation and brain immigration. Previous studies using transient focal ischemia models showed a protective effect of FTY720 but did only partially characterize the involved pathways. We tested the neuroprotective properties of FTY720 in permanent and transient cortical ischemia and analyzed the underlying neuroimmunological mechanisms.

Methodology/Principal Findings

FTY720 treatment resulted in substantial reduction of circulating lymphocytes while blood monocyte counts were significantly increased. The number of histologically and flow cytometrically analyzed brain invading T- and B lymphocytes was significantly reduced in FTY720 treated mice. However, despite testing a variety of treatment protocols, infarct volume and behavioural dysfunction were not reduced 7d after permanent occlusion of the distal middle cerebral artery (MCAO). Additionally, we did not measure a significant reduction in infarct volume at 24h after 60 min filament-induced MCAO, and did not see differences in brain edema between PBS and FTY720 treatment. Analysis of brain cytokine expression revealed complex effects of FTY720 on postischemic neuroinflammation comprising a substantial reduction of delayed proinflammatory cytokine expression at 3d but an early increase of IL-1β and IFN-γ at 24 h after MCAO. Also, serum cytokine levels of IL-6 and TNF-α were increased in FTY720 treated animals compared to controls.

Conclusions/Significance

In the present study we were able to detect a reduction of lymphocyte brain invasion by FTY720 but could not achieve a significant reduction of infarct volumes and behavioural dysfunction. This lack of neuroprotection despite effective lymphopenia might be attributed to a divergent impact of FTY720 on cytokine expression and possible activation of innate immune cells after brain ischemia.     

Ribosomal translocation: LepA does it backwards

During translation, mRNA is threaded through the ribosome in precise and directional three-nucleotide steps. A recent paper identifies a new GTPase, LepA, which catalyzes unexpected one-codon backward movement on the ribosome.     

Gamma-tubulin complexes: size does matter.

gamma-Tubulin is a conserved component of all microtubule-organizing centres and is required for these organelles to nucleate microtubule polymerization. However, the mechanism of nucleation is not known. In addition to its localization to organizing centres, a large pool of gamma-tubulin exists in the cytoplasm in a complex with other proteins. The size of the gamma-tubulin complex and number of associated proteins vary among organisms, and the functional significance of these differences is unknown. Recently, the nature of these gamma-tubulin complexes has been explored in different organisms, and this has led us closer to a molecular understanding of microtubule nucleation.