Cranial dural permeability of inflammatory nociceptive mediators: Potential implications for animal models of migraine

Background Application of inflammatory mediators to the cranial dura has been used as a method to activate and sensitize neurons in the meningeal sensory pathway in preclinical behavioral studies of headache mechanisms. However, the relatively high concentrations and volumes used in these studies raise the question of whether the applied agents might pass through the dura to act directly on central neurons, thus bypassing the dural afferent pathway. Methods We used a radiolabeling approach to quantify the meningeal permeability of two of the inflammatory mediators, 5-HT and PGE2, when applied to the cranial dura as part of an inflammatory mixture used in preclinical headache models. Results Both agents could be detected in samples taken four hours after dural application in the cerebrospinal fluid (CSF) and, in measurements made only for PGE2, in the central nervous system (CNS) as well. Based on our measurements, we made estimates of the CSF and CNS levels that would be attained with the higher concentrations and volumes of 5HT and PGE2 that were exogenously applied in previous pre-clinical headache studies. These estimated levels were comparable to or larger than normal endogenous levels, potentially large enough to have physiological effects. Conclusions The finding that the cranial meninges are permeable to the two tested inflammatory mediators PGE2 and 5-HT raises some uncertainty about whether the behavioral changes observed in prior pre-clinical headache studies with these as well as other agents can be attributed entirely to the activation of dural nociceptors, particularly when the agents are applied at concentrations several orders of magnitude above physiological levels.

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Behavior assessment and applications for BRD diagnosis: preweaned dairy calves

Animal Health Research Reviews ◽

10.1017/s1466252320000213 ◽

2020 ◽

pp. 1-4

Author(s):

Catie Cramer ◽

Theresa L. Ollivett

Keyword(s):

Clinical Signs ◽

Sickness Behavior ◽

Behavioral Changes ◽

Dairy Calves ◽

Detection Methods ◽

Disease Detection ◽

Test Characteristics ◽

Behavioral Studies ◽

Detection Program ◽

Behavioral Assessments

Abstract Bovine respiratory disease (BRD) is an important disease in dairy calves due to its long-lasting effects. Early identification results in better outcomes for the animal, but producers struggle to identify all calves with BRD. Sickness behavior, or the behavioral changes that accompany illness, has been investigated for its usefulness as a disease detection tool. Behavioral changes associated with BRD include decreased milk intake and drinking speed, depressed attitude, and less likelihood of approaching a novel object or stationary human. Behavioral measurements are useful, as they can be collected automatically or with little financial input. However, one limitation of many BRD behavioral studies includes the use of either lung auscultation or clinical signs as reference methods, which are imperfect. Additionally, external factors may influence the expression of sickness behavior, which can affect if and when behavior can be used to identify calves with BRD. Behavioral measures available to detect BRD lack adequate sensitivity and specificity to be the sole means of disease detection, especially when detection tools, such as calf lung ultrasound, have better test characteristics. However, using behavioral assessments in addition to other detection methods can allow for a robust BRD detection program that can ameliorate the consequences of BRD.

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NMR Structure and Action on Nicotinic Acetylcholine Receptors of Water-soluble Domain of Human LYNX1

Journal of Biological Chemistry ◽

10.1074/jbc.m110.189100 ◽

2011 ◽

Vol 286 (12) ◽

pp. 10618-10627 ◽

Cited By ~ 59

Author(s):

Ekaterina N. Lyukmanova ◽

Zakhar O. Shenkarev ◽

Mikhail A. Shulepko ◽

Konstantin S. Mineev ◽

Dieter D'Hoedt ◽

...

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Nmr Structure ◽

Water Soluble ◽

Gpi Anchor ◽

Nicotinic Acetylcholine ◽

Brain Functions ◽

The Central Nervous System ◽

High Concentrations

Discovery of proteins expressed in the central nervous system sharing the three-finger structure with snake α-neurotoxins provoked much interest to their role in brain functions. Prototoxin LYNX1, having homology both to Ly6 proteins and three-finger neurotoxins, is the first identified member of this family membrane-tethered by a GPI anchor, which considerably complicates in vitro studies. We report for the first time the NMR spatial structure for the water-soluble domain of human LYNX1 lacking a GPI anchor (ws-LYNX1) and its concentration-dependent activity on nicotinic acetylcholine receptors (nAChRs). At 5–30 μm, ws-LYNX1 competed with 125I-α-bungarotoxin for binding to the acetylcholine-binding proteins (AChBPs) and to Torpedo nAChR. Exposure of Xenopus oocytes expressing α7 nAChRs to 1 μm ws-LYNX1 enhanced the response to acetylcholine, but no effect was detected on α4β2 and α3β2 nAChRs. Increasing ws-LYNX1 concentration to 10 μm caused a modest inhibition of these three nAChR subtypes. A common feature for ws-LYNX1 and LYNX1 is a decrease of nAChR sensitivity to high concentrations of acetylcholine. NMR and functional analysis both demonstrate that ws-LYNX1 is an appropriate model to shed light on the mechanism of LYNX1 action. Computer modeling, based on ws-LYNX1 NMR structure and AChBP x-ray structure, revealed a possible mode of ws-LYNX1 binding.

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Normal Vestibular Function in Chicks After Partial Exposure to Microgravity During Development

Journal of Vestibular Research ◽

10.3233/ves-1995-5405 ◽

1995 ◽

Vol 5 (4) ◽

pp. 289-298

Author(s):

R.V. Kenyon ◽

R. Kerschmann ◽

R. Sgarioto ◽

S. Jun ◽

J. Vellinger

Keyword(s):

Vestibular Function ◽

Head Movements ◽

Behavioral Changes ◽

Ground Control ◽

Consistent Difference ◽

Morphological Examination ◽

Behavioral Studies ◽

Temporal Bones ◽

Critical Developmental Period ◽

Chicken Eggs

Sixty-four fertilized chicken eggs, half at developmental Day 2 and half at Day 9, were exposed to micro-gravity for 5 days aboard the shuttle. Postflight examination showed that none of the Day 2 flight embryos had survived, whereas the Day 9 flight group and both groups of synchronous ground control embryos appeared viable. One-half of the Day 9 flight and ground control embryos were dissected and the temporal bones preserved in acetone for morphological examination. The other half was allowed to hatch to examine vestibularly related behavioral changes. Morphology of the lagenar otoconia was evaluated by scanning electron microscopy. Behavioral changes were accessed by a battery of reflex tests and recordings of spontaneous and vestibularly driven head movements. The results from both the morphological and behavioral studies showed no consistent difference between the flight and the control animals. Several hypotheses may account for this negative result. Because all the Day 2 embryos failed to survive, the remaining Day 9 chicks may have passed the critical developmental period of the chick’s vestibular system. Also, the reexposure of the developing chick embryo to earth’s 1-g environment may have masked any adverse behavioral effects that exposure to Microgravity may have caused.

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The Effect of Bacterial Endotoxin LPS on Serotonergic Modulation of Glutamatergic Synaptic Transmission

Biology ◽

10.3390/biology9080210 ◽

2020 ◽

Vol 9 (8) ◽

pp. 210

Author(s):

Jate Bernard ◽

Abigail Greenhalgh ◽

Oscar Istas ◽

Nicole T. Marguerite ◽

Robin L. Cooper

Keyword(s):

Synaptic Transmission ◽

Motor Neurons ◽

Positive Outcome ◽

The Body ◽

Receptor Subtype ◽

Pharmacological Agents ◽

Enhanced Transmission ◽

Glutamatergic Synaptic Transmission ◽

The Central Nervous System ◽

High Concentrations

The release of the endotoxin lipopolysaccharides (LPS) from gram-negative bacteria is key in the induction of the downstream cytokine release from cells targeting cells throughout the body. However, LPS itself has direct effects on cellular activity and can alter synaptic transmission. Animals experiencing septicemia are generally in a critical state and are often treated with various pharmacological agents. Since antidepressants related to the serotonergic system have been shown to have a positive outcome for septicemic conditions impacting the central nervous system, the actions of serotonin (5-HT) on neurons also exposed to LPS were investigated. At the model glutamatergic synapse of the crayfish neuromuscular junction (NMJ), 5-HT primarily acts through a 5-HT2A receptor subtype to enhance transmission to the motor neurons. LPS from Serratia marcescens also enhances transmission at the crayfish NMJ but by a currently unknown mechanism. LPS at 100 µg/mL had no significant effect on transmission or on altering the response to 5-HT. LPS at 500 µg/mL increased the amplitude of the evoked synaptic excitatory junction potential, and 5-HT in combination with 500 µg/mL LPS continued to promote enhanced transmission. The preparations maintained responsiveness to serotonin in the presence of low or high concentrations of LPS.

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Effect of Nicotine on the Synapse of the Central Nervous System

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1958.192.3.447 ◽

1958 ◽

Vol 192 (3) ◽

pp. 447-452 ◽

Cited By ~ 4

Author(s):

Sadayuki F. Takagi ◽

Yutaka Oomura

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Synaptic Transmission ◽

Reflex Activity ◽

Synaptic Delay ◽

Synaptic Potential ◽

Before And After ◽

The Central Nervous System ◽

High Concentrations

The effect of nicotine on synaptic transmission in the frog and cat spinal cord was studied. Both a regular wick electrode and a microelectrode of the Ling-Gerard type were used. The reflex activity of the bullfrog spinal cord is facilitated by 0.01% nicotine solution, but is depressed and abolished by 0.1% solution. In the cat, intravenous administration of 150 mg/kg fails to block reflex activity, but topical application does block. The intracellular potential, of both frog and cat motoneurones, shows no change in the synaptic potential after application of the drug, but the spike appears after a shorter synaptic delay and one or more additional spikes appear. When the synaptic delay becomes sufficiently short, however, all spikes suddenly disappear, leaving the still unchanged synaptic potential. Occasionally the synaptic delay is again increased just before the spike potentials disappear. The excitability of a frog motoneurone was measured, by a recording microelectrode, before and after nicotine application. The drug first increased and then decreases excitability. Epinephrine can restore a reflex discharge depressed or abolished by nicotine. It is concluded that high concentrations of nicotine block synaptic transmission in the central nervous system, acting on the cell body but not on the synaptic potential.

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Memory deficit associated with increased brain proinflammatory cytokine levels and neurodegeneration in acute ischemic stroke

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20150083 ◽

2015 ◽

Vol 73 (8) ◽

pp. 655-659 ◽

Cited By ~ 22

Author(s):

Bruno Silva ◽

Larissa Sousa ◽

Aline Miranda ◽

Anilton Vasconcelos ◽

Helton Reis ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Inflammatory Mediators ◽

Recognition Task ◽

Artery Occlusion ◽

Carotid Artery Occlusion ◽

Behavioral Changes ◽

Acute Ischemia ◽

Long Term Memory ◽

Histopathological Analysis

The present study aimed to investigate behavioral changes and neuroinflammatory process following left unilateral common carotid artery occlusion (UCCAO), a model of cerebral ischemia. Post-ischemic behavioral changes following 15 min UCCAO were recorded 24 hours after reperfusion. The novel object recognition task was used to assess learning and memory. After behavioral test, brains from sham and ischemic mice were removed and processed to evaluate central nervous system pathology by TTC and H&E techniques as well as inflammatory mediators by ELISA. UCCAO promoted long-term memory impairment after reperfusion. Infarct areas were observed in the cerebrum by TTC stain. Moreover, the histopathological analysis revealed cerebral necrotic cavities surrounded by ischemic neurons and hippocampal neurodegeneration. In parallel with memory dysfunction, brain levels of TNF-a, IL-1b and CXCL1 were increased post ischemia compared with sham-operated group. These ﬁndings suggest an involvement of central nervous system inﬂammatory mediators and brain damage in cognitive impairment following unilateral acute ischemia.

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Modulation of amino acid neurotransmitter actions by other neurotransmitters: some examples

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y91-163 ◽

1991 ◽

Vol 69 (7) ◽

pp. 1115-1122 ◽

Cited By ~ 13

Author(s):

Kenneth C. Marshall ◽

Huangui Xiong

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Angiotensin Ii ◽

Experimental Studies ◽

Membrane Properties ◽

Receptor Subtypes ◽

Long Term Effects ◽

Central Neurons ◽

Specific Effects ◽

The Central Nervous System

Developments in the field of central neurotransmission indicate that amino acids serve as important and widespread transmitters throughout the central nervous system. There are increasing indications from recent experimental studies that several of the other central neurotransmitters may exert potent effects on central neurons by modulating the actions of amino acids. Noradrenaline and serotonin have received particular attention as potential modulators, and a wide variety of actions has been reported for them. Modulatory actions have been reported at both pre- and post-synaptic levels, including both short- and long-term effects and facilitation or inhibition of amino acid actions. Selectivity has been found both for specific receptor subtypes of the neuromodulator and for specific effects of amino acids. Examples of such selectivity are modification of actions of an amino acid with little effect on spontaneous activity or membrane properties of the target cell, or in comparison to the actions of other neurotransmitters, or even other selective amino acid analogs. Modulatory actions on amino acids have also been reported for several other neurotransmitters including acetylcholine and various peptides. Recent studies of angiotensin II demonstrate that when iontophoretically applied, it can potently and selectively block the depolarizing action of glutamate on locus coeruleus neurons. It is possible that physiological influences of these various transmitter substances are expressed through modification of amino acid actions, rather than through direct effects on central neurons.Key words: neuromodulation, neurotransmitters, glutamic acid, noradrenaline, angiotensin II.

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I. Environmental Contamination and Biochemical Relationships

Journal of Milk and Food Technology ◽

10.4315/0022-2747-38.5.285 ◽

1975 ◽

Vol 38 (5) ◽

pp. 285-300 ◽

Cited By ~ 7

Author(s):

A. G. HUGUNIN ◽

R. L. BRADLEY

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Methyl Mercury ◽

Sea Water ◽

Inorganic Mercury ◽

Whole Body ◽

Irreversible Damage ◽

Mercury Compounds ◽

The Central Nervous System ◽

Pass Through

Mercury is naturally concentrated in geographical belts, but geological cycling has distributed the element in all strata of the earth. Natural concentrations of mercury are approximately 100 ppb in soil, 0.06 ppb in fresh water, 0.01–0.30 ppb in sea water, and 0.003–0.009 μg/m3 in air. Concentrations vary, being highest near mineral deposits. The concentration of mercury in some areas has been significantly increased by human carelessness. An epidemic among Japanese fishing families, death of Swedish wildlife, and discovery of elevated mercury levels in American fish focused attention on this problem. The discovery that certain species are capable of methylating inorganic mercury indicates pollution with any chemical form of mercury is dangerous. Alkylmercurials are the most dangerous form of mercury in the environment. Alkylmercurials are absorbed from the gastrointestinal tract, diffuse across the blood-brain carrier, and pass through the placental membrane in significantly higher proportions than other mercury compounds. The whole body half-life of methyl mercury in humans is 76 ± 3 days compared to half-lives of 37 ± 3 days for men and 48 ± 5 days for women observed for mercuric salts. Not readily broken down, sufficient concentrations of methyl mercury can cause irreversible damage to the central nervous system. Renal damage usually results from high levels of aryl- or alkoxyalkylmercurials and inorganic mercury; however, vapors of elemented mercury can damage the central nervous system. Organic mercury compounds cause chromosome changes, but the medical implications resulting from levels of mercury in food are unknown. The concentration of mercury in red blood cells and hair is indicative of the exposure to alkylmercurials. On a group basis, blood and urine concentrations of mercury may corrrelate with recent exposure to mercury.

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Erythropoietin in COVID-19-Induced Neuroinflammation; EPO Plus Losartan Might be Promising

Journal of Biostatistics and Epidemiology ◽

10.18502/jbe.v6i2.4879 ◽

2020 ◽

Author(s):

Reza Nejat ◽

Ahmad Shahir Sadr ◽

David Najafi

Keyword(s):

Inflammatory Mediators ◽

Renin Angiotensin System ◽

Oxygen Species ◽

Ang Ii ◽

Angiotensin System ◽

Intracellular Messengers ◽

The Central Nervous System ◽

Harmful Effects

Introduction: Neuroinflammation is the inflammatory reaction in the central nervous system (CNS) provoked by diverse insults. This phenomenon results in a cascade of release of inflammatory mediators and intracellular messengers such as reactive oxygen species. The elicited responses are the cause of many neurological and neurodegenerative disorders. Erythropoietin (EPO) has been considered effective in attenuating this inflammatory process in the CNS, yet its administration in COVID-19 needs meticulously designed studies. Discussion: Neuroinflammation in COVID-19 due to probable contribution of renin-angiotensin system dysregulation resulting in surplus of Ang II and owing to the synergistic interaction between this octapeptide and EPO needs special consideration. Both of these compounds increase intracellular Ca2+ which may induce release of cytokine and inflammatory mediators leading to aggravation of neuroinflammation. In addition, Ang II elevates HIF even in normoxia which by itself increases EPO. It is implicated that EPO and HIF may likely increase in patients with COVID-19 which makes administration of EPO to these patients hazardous. Furthermore, papain-like protease of SARS-CoV2 as a deubiquitinase may also increase HIF. Conclusion: It is hypothesized that administration of EPO to patients with COVID-19-induced neuroinflammation may not be safe and in case EPO is needed for any reason in this disease adding of losartan may block AT1R-mediated post-receptor harmful effects of Ang II in synergism with EPO. Inhibition of papain-like protease might additionally decrease HIF in this disease. More in vitro, in vivo and clinical studies are needed to validate these hypotheses.

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