Soluble Epoxide Hydrolase and Brain Cholesterol Metabolism.

The bifunctional enzyme soluble epoxide hydrolase (sEH) is found in all regions of the brain. It has two different catalytic activities, each assigned to one of its terminal domains: the C-terminal domain presents hydrolase activity, whereas the N-terminal domain exhibits phosphatase activity. The enzyme's C-terminal domain has been linked to cardiovascular protective and anti-inflammatory effects. Cholesterol-related disorders have been associated with sEH, which plays an important role in the metabolism of cholesterol precursors. The role of sEH's phosphatase activity has been so far poorly investigated in the context of the central nervous system physiology. Given that brain cholesterol disturbances play a role in the onset of Alzheimer's disease (AD) as well as of other neurodegenerative diseases, understanding the functions of this enzyme could provide pivotal information on the pathophysiology of these conditions. Moreover, the sEH phosphatase domain could represent an underexplored target for drug design and therapeutic strategies to improve symptoms related to neurodegenerative diseases. This review discusses the function of sEH in mammals and its protein structure and catalytic activities. Particular attention was given to the distribution and expression of sEH in the human brain, deepening into the enzyme's phosphatase activity and its participation in brain cholesterol synthesis. Finally, this review focused on the metabolism of cholesterol and its association with AD.

Peptide YY (3-36) modulates intracellular calcium through activation of the phosphatidylinositol pathway in hippocampal neurons.

Peptide YY (PYY) belongs to the neuropeptide Y (NPY) family, which also includes the pancreatic polypeptide (PP) and NPY. PYY is secreted by the intestinal L cells, being present in the blood stream in two active forms capable of crossing the blood brain barrier, PYY (1-36) and its cleavage product, PYY (3-36). PYY is a selective agonist for the Y2 receptor (Y2R) and these receptors are abundant in the hippocampus. Here we investigated the mechanisms by which PYY (3-36) regulates intracellular Ca2+ concentrations ([Ca2+]i) in hippocampal neurons by employing a calcium imaging technique in hippocampal cultures. Alterations in [Ca2+]i were detected by changes in the Fluo-4 AM reagent emission. PYY (3-36) significantly increased [Ca2+] from the concentration of 10-11M as compared to the controls (infusion of HEPES-buffered solution (HBS) solution alone). The PYY (3-36)-increase in [Ca2+]i remained unchanged even in Ca2+-free extracellular solutions. Sarcoplasmic/endoplasmic reticulum Ca2+-ATPase pump (SERCA pump) inhibition partially prevent the PYY (3-36)-increase of [Ca2+]i and inositol 1,4,5-triphosphate receptor (IP3R) inhibition also decreased the PYY (3-36)-increase of [Ca2+]i. Taken together, our data strongly suggest that PYY (3-36) mobilizes calcium from the neuronal endoplasmic reticulum (ER) stores towards the cytoplasm. Next, we showed that PYY (3-36) inhibited high K+-induced increases of [Ca2+]i, suggesting that PYY (3-36) could also act by activating G-protein coupled inwardly rectifying potassium K+ channels. Finally, the co-infusion of the Y2 receptor (Y2R) antagonist BIIE0246 with PYY (3-36) abolished the [Ca2+]i increase induced by the peptide, suggesting that PYY (3-36)-induced [Ca2+]i increase in hippocampal neurons occurs via Y2Rs.

Validation of noninvasive blood pressure equipment: which peripheral artery is best for comparison studies in dogs?

OBJECTIVES: 1) To determine which peripheral artery commonly used for invasive arterial blood pressure (IBP) monitoring yields the least bias when compared with noninvasive blood pressure (NIBP) values obtained at the antebrachium of the dog, and 2) to identify and describe differences in systolic (SAP), mean (MAP) and diastolic arterial pressures (DAP) among different anatomical locations. STUDY DESIGN: Prospective experimental study. ANIMALS: Twenty adult hound dogs weighing 24.5 ± 1.1 kg (mean ± standard deviation). METHODS: Four peripheral arteries-dorsal pedal, median caudal, intermediate auricular and superficial palmar arteries-were catheterized with 20 gauge, 3.8 cm catheters. One NIBP cuff was placed in the middle third of the antebrachium. Four sets of IBP and NIBP measurements were simultaneously collected every 2 minutes. A linear mixed model was performed to analyze the collected data. RESULTS: IBP values varied depending on the arterial catheterization site. The difference was greater for SAP. NIBP measured at the antebrachium had the best agreement with IBP measured at the median caudal artery. CONCLUSION AND CLINICAL RELEVANCE: IBP varies among anatomical locations. The smallest bias and narrowest limits of agreement were obtained at the median caudal artery, providing the best overall agreement with the equipment studied. The median caudal artery may be the preferable anatomical location for clinical comparison studies between IBP and NIBP in dogs when the cuff is on the antebrachium.

Methylprednisolone as a memory enhancer in rats: Effects on aversive memory, long-term potentiation and calcium influx.

It is well recognized that stress or glucocorticoids hormones treatment can modulate memory performance in both directions, either impairing or enhancing it. Despite the high number of studies aiming at explaining the effects of glucocorticoids on memory, this has not yet been completely elucidated. Here, we demonstrate that a low daily dose of methylprednisolone (MP, 5mg/kg, i.p.) administered for 10-days favors aversive memory persistence in adult rats, without any effect on the exploring behavior, locomotor activity, anxiety levels and pain perception. Enhanced performance on the inhibitory avoidance task was correlated with long-term potentiation (LTP), a phenomenon that was strengthen in hippocampal slices of rats injected with MP (5mg/kg) during 10days. Additionally, in vitro incubation with MP (30-300µM) concentration-dependently increased intracellular [Ca2+]i in cultured hippocampal neurons depolarized by KCl (35mM). In conclusion, a low daily dose of MP for 10days may promote aversive memory persistence in rats.

Bothriurus bonariensis scorpion venom activates voltage-dependent sodium channels in insect and mammalian nervous systems.

Animal venoms have been widely recognized as a major source of biologically active molecules. Bothriurus bonariensis, popularly known as black scorpion, is the arthropod responsible for the highest number of accidents involving scorpion sting in Southern Brazil. Here we reported the first attempt to investigate the neurobiology of B. bonariensis venom (BBV) in the insect and mammalian nervous system. BBV (32 µg/g) induced a slow neuromuscular blockade in the in vivo cockroach nerve-muscle preparations (70 ± 4%, n = 6, p < 0.001), provoking repetitive twitches and significantly decreasing the frequency of spontaneous leg action potentials (SNCAPs) from 82 ± 3 min(-1) to 36 ± 1.3 min(-1) (n = 6, p < 0.05), without affecting the amplitude. When tested in primary cultures of rat hippocampal cells, BBV induced a massive increase of Ca(2+) influx (250 ± 1% peak increase, n = 3, p < 0.0001). The disturbance of calcium homeostasis induced by BBV on the mammalian central nervous system was not accompanied by cellular death and was prevented by the co-treatment of the hippocampal cells with tetrodotoxin, a selective sodium channel blocker. The results suggest that the biological activity of BBV is mostly related to a modulation of sodium channels function. Our biological activity survey suggests that BBV may have a promising insecticidal and therapeutic potential.

Agreement between two oscillometric blood pressure technologies and invasively measured arterial pressure in the dog.

OBJECTIVES: To compare two commonly used oscillometric technologies for obtaining noninvasive blood pressure (NIBP) measurements and to determine if there is a difference in agreement between these systems and invasive blood pressure (IBP) measurements. STUDY DESIGN: Prospective, experimental study. ANIMALS: Twenty adult laboratory dogs. METHODS: Each dog was anesthetized and its median caudal artery catheterized for IBP monitoring. An NIBP cuff was placed in the middle third of the antebrachium and attached to either monitor-1 or monitor-2. Four pairs of concurrent NIBP and IBP measurements were recorded with each monitor. Agreement between IBP and NIBP measurements was explored using Bland-Altman analysis, as well as the American College of Veterinary Internal Medicine (ACVIM) and Association for the Advancement of Medical Instrumentation (AAMI) guidelines for the validation of NIBP devices. RESULTS: Both NIBP technologies produced results that met the ACVIM and AAMI guidelines for the validation of NIBP devices. For monitor-1, analyses of agreement showed biases of 0.2 mmHg [95% limits of agreement (LoA) -11.8 to 12.3 mmHg] in systolic arterial pressure (SAP) values, -2.6 mmHg (95% LoA -14.4 to 9.1 mmHg) in diastolic arterial pressure (DAP) values, and -2.5 mmHg (95% LoA -12.7 to 7.3 mmHg) in mean arterial pressure (MAP) values. For monitor-2, analyses of agreement showed biases of 3.4 mmHg (95% LoA -8.7 to 15.5 mmHg) in SAP values, 2.2 mmHg (95% LoA -6.6 to 10.9 mmHg) in DAP values, and 1.6 mmHg (95% LoA -5.9 to 8.9 mmHg) in MAP values. CONCLUSIONS AND CLINICAL RELEVANCE: Multi-function monitors can contain components from various manufacturers. Clinicians should consider whether these have been validated in the species to be monitored. Both of the technologies studied here seem appropriate for use in dogs.

Comparison of blood pressure measurements of anesthetized dogs obtained noninvasively with a cylindrical blood pressure cuff and an anatomically modified conical blood pressure cuff.

OBJECTIVE: To compare blood pressure measured noninvasively with an oscillometric device that involved use of a novel conical cuff and a traditional cylindrical blood pressure cuff. ANIMALS: 17 adult hound-type dogs. PROCEDURES: Dogs were anesthetized, and a 20-gauge, 1.5-inch catheter was inserted in the median sacral artery. The catheter was attached to a pressure transducer via fluid-filled noncompliant tubing, and direct blood pressure was recorded with a multifunction monitor. A specially fabricated conical cuff was placed on the antebrachium. Four sets of direct and indirect blood pressure measurements were simultaneously collected every 2 minutes. Four sets of measurements were then obtained by use of a cylindrical cuff. RESULTS: The cylindrical cuff met American College of Veterinary Internal Medicine consensus guidelines for validation of indirect blood pressure measurements for mean arterial blood pressure (MAP), systolic arterial blood pressure (SAP), and diastolic arterial blood pressure (DAP). The conical cuff met the consensus guidelines for difference of paired measurements, SD, and percentages of measurements within 10 and 20 mm Hg of the value for the reference method, but it failed a correlation analysis. In addition, although bias for the conical cuff was less than that for the cylindrical cuff for SAP, MAP, and DAP measurements, the limits of agreement for the conical cuff were wider than those for the cylindrical cuff for SAP and MAP measurements. CONCLUSIONS AND CLINICAL RELEVANCE: On the basis of results of this study, use of a conical cuff for oscillometric blood pressure measurement cannot be recommended.

Comparison of directly measured arterial blood pressure at various anatomic locations in anesthetized dogs.

OBJECTIVE: To determine whether directly measured arterial blood pressure differs among anatomic locations and whether arterial blood pressure is influenced by body position. ANIMALS: 33 client-owned dogs undergoing anesthesia. PROCEDURES: Dogs undergoing anesthetic procedures had 20-gauge catheters placed in both the superficial palmar arch and the contralateral dorsal pedal artery (group 1 [n = 20]) or the superficial palmar arch and median sacral artery (group 2 [13]). Dogs were positioned in dorsal recumbency, and mean arterial blood pressure (MAP), systolic arterial blood pressure (SAP), and diastolic arterial blood pressure (DAP) were recorded for both arteries 4 times (2-minute interval between successive measurements). Dogs were positioned in right lateral recumbency, and blood pressure measurements were repeated. RESULTS: Differences were detected between pressures measured at the 2 arterial sites in both groups. This was especially true for SAP measurements in group 1, in which hind limb measurements were a mean of 16.12 mm Hg higher than carpus measurements when dogs were in dorsal recumbency and 14.70 mm Hg higher than carpus measurements when dogs were in lateral recumbency. Also, there was significant dispersion about the mean for all SAP, DAP, and MAP measurements. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that arterial blood pressures may be dependent on anatomic location and body position. Because this may affect outcomes of studies conducted to validate indirect blood pressure measurement systems, care must be used when developing future studies or interpreting previous results.