PGE2/EP4 skeleton interoception activity reduces vertebral endplate porosity and spinal pain with low-dose celecoxib

AbstractSkeletal interoception regulates bone homeostasis through the prostaglandin E2 (PGE2) concentration in bone. Vertebral endplates undergo ossification and become highly porous during intervertebral disc degeneration and aging. We found that the PGE2 concentration was elevated in porous endplates to generate spinal pain. Importantly, treatment with a high-dose cyclooxygenase 2 inhibitor (celecoxib, 80 mg·kg−1 per day) decreased the prostaglandin E2 concentration and attenuated spinal pain in mice with lumbar spine instability. However, this treatment impaired bone formation in porous endplates, and spinal pain recurred after discontinuing the treatment. Interestingly, low-dose celecoxib (20 mg·kg−1 per day, which is equivalent to one-quarter of the clinical maximum dosage) induced a latent inhibition of spinal pain at 3 weeks post-treatment, which persisted even after discontinuing treatment. Furthermore, when the prostaglandin E2 concentration was maintained at the physiological level with low-dose celecoxib, endplate porosity was reduced significantly, which was associated with decreased sensory nerve innervation and spinal pain. These findings suggest that low-dose celecoxib may help to maintain skeletal interoception and decrease vertebral endplate porosity, thereby reducing sensory innervation and spinal pain in mice.

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Nerve conduction velocities in radiologic technologists: A pilot study

Indian Journal of Physiology and Pharmacology ◽

10.25259/ijpp_77_2020 ◽

2021 ◽

Vol 64 ◽

pp. 293-297

Author(s):

Shefali Singhal ◽

Gaurav Jain ◽

Prachi Arya ◽

Virandra Verma ◽

Ajit Singh Rajput

Keyword(s):

Action Potential ◽

Radiation Exposure ◽

Nerve Conduction ◽

Low Dose ◽

Compound Muscle Action Potential ◽

Sensory Nerve ◽

Sensory Nerves ◽

High Dose ◽

Healthy Individuals ◽

Radiologic Technologists

Objectives: Radiologic technologists (RTs) are typically exposed to low doses of radiations for longer periods, which have a health risk over many organs and tissues. Resistant tissues like nerves have shown neuropathic changes due to acute high-dose radiation exposure in the form of radiation therapy but the effect of low-dose chronic radiation exposure over peripheral nerves in RTs has been studied scantily. Materials and Methods: Nerve conduction parameters were recorded from 30 RTs and 30 age- and sex-matched healthy individuals who were not exposed to radiation. Motor nerve conduction study (NCS) of bilateral median, ulnar, radial, common peroneal and tibial nerves and sensory NCS of bilateral median, ulnar and radial nerves were recorded and compared. Results: Significant changes were observed in the form of reduction in motor and sensory nerve conduction velocity (P < 0.05) in all the examined nerves. Sensory nerve action potential (SNAP) amplitudes were reduced and latencies were prolonged significantly (P < 0.05) in all the examined sensory nerves. We also found reduced compound muscle action potential amplitude (significant in ulnar, radial, common peroneal and tibial nerves) along with prolonged motor distal latencies (significant in median, ulnar and tibial nerves) among RTs compared to healthy individuals. Conclusion: Chronic low-dose exposure of ionising radiation causes sub-clinical neuropathies affecting both sensory and motor nerves.

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SAT-607 The Vagus Nerve and the Hypothalamus Mediate Different Aspects of the Anorectic Effects of PYY3-36

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1337 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Aldara Martin Alonso ◽

Simon C Cork ◽

Yue Ma ◽

Myrtha Arnold ◽

Herbert Herzog ◽

...

Keyword(s):

Weight Loss ◽

Food Intake ◽

Vagus Nerve ◽

Low Dose ◽

Peptide Yy ◽

Sensory Nerve ◽

Positive Control ◽

Vagal Afferents ◽

High Dose ◽

Gut Hormone

Abstract Background: Drugs that safely promote weight loss are required to treat the obesity crisis. The gut hormone peptide YY 3-36 (PYY3-36) is secreted post-prandially to suppress appetite via the Y2 receptor (Y2R). However, it is unclear whether PYY3-36 acts directly on the Y2R in the hypothalamic arcuate nucleus (ARC) or the afferent vagus nerve to inhibit food intake. Understanding the pathways by which PYY3-36 mediates its anorectic effects may facilitate the therapeutic targeting of this system. Methods: Y2R knockdown in the ARC (ARC-Y2R-KD) was achieved by stereotactic injection of Cre-expressing adeno-associated virus (AAV-Cre) in Y2R-flox C57Bl/6 mice. Y2R KD in the vagus was achieved by bilateral microinjection of AAV-Cre into the nodose ganglia (NG), where the cell bodies of vagal afferents reside. An alternative germline model of sensory nerve Y2R knockdown was generated using Nav1.8-Cre mice crossed with the Y2R-flox strain (Nav1.8-Y2R-KD). Feeding behaviour over 10 days in metabolic cages and the effects of endogenously released (after oral gavage of a nutrient bolus) or exogenously-administered PYY3-36 were investigated. Results: NG-Y2R-KD animals had 60% reduction in NG Y2R mRNA but remained responsive to cholecystokinin, a positive control of vagal functionality. This is the first example of receptor specific adult vagal deafferentation in mice. The Nav1.8-Y2R-KD model achieved 30% receptor KD. Feeding patterns in the ARC-Y2R-KD and NG-Y2R-KD groups were highly different from their controls, with smaller, faster meals in the KD groups. The anorectic effects (at the next meal) of endogenous PYY3-36 were attenuated in NG-Y2R-KD. Low dose exogenous PYY3-36 at 5 µg/kg significantly reduced 2h post injection food intake (FI) in the control groups (n=8; P=0.045) but this was abrogated in the NG-Y2R-KD group. This pattern was mirrored in the Nav1.8-Y2R-KD model: low dose PYY3-36 significantly reduced FI 1h post-IP compared to vehicle in controls (-0.19±0.05 g; P =0.036; n=8) but not in the Nav1.8-Y2R-KD (-0.004±0.111 g; n=3). Peripherally-administered PYY3-36 at a high dose (30 µg/kg) decreased FI in all groups, including ARC-Y2R-KD. Summary: These results suggest that endogenous PYY3-36 modulates meal patterning. The vagus nerve mediates physiological PYY3-36 signalling but alternative pathways, not exclusively via the ARC, may be more important in mediating its pharmacological effects. This is relevant for the design of more effective weight loss agents.

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Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis

Nature Communications ◽

10.1038/s41467-018-08097-7 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 28

Author(s):

Hao Chen ◽

Bo Hu ◽

Xiao Lv ◽

Shouan Zhu ◽

Gehua Zhen ◽

...

Keyword(s):

Prostaglandin E2 ◽

Sensory Nerve ◽

Bone Homeostasis ◽

Nerve Regulation

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Acetaminophen: Neonatal hepatotoxicity due to late pregnancy exposure

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100127906 ◽

1987 ◽

Vol 45 ◽

pp. 718-719

Author(s):

G.A. Miranda ◽

M.A. Arroyo ◽

C.A. Lucio ◽

M. Mongeotti ◽

S.S. Poolsawat

Keyword(s):

Low Dose ◽

Fetal Liver ◽

Late Pregnancy ◽

Toxic Chemicals ◽

Control Group ◽

High Dose ◽

Over The Counter ◽

Liver And Kidney ◽

Neonatal Liver ◽

Childbearing Women

Exposure to drugs and toxic chemicals, during late pregnancy, is a common occurrence in childbearing women. Some studies have reported that more than 90% of pregnant women use at least 1 prescription; of this, 60% used more than one. Another study indicated that 80% of the consumed drugs were not prescribed, and of this figure, 95% were “over-the-counter” drugs. Acetaminophen, the safest of all over-the-counter drugs, has been reported to induce fetal liver necrosis in man and animals and to have abortifacient and embryocidal action in mice. This study examines the degree to which acetaminophen affects the neonatal liver and kidney, when a fatty diet is simultaneously fed to the mother during late pregnancy.Timed Swiss Webster female mice were gavaged during late pregnancy (days 16-19) with fat suspended acetaminophen at a high dose, HD = 84.50 mg/kg, and a low dose, LD = 42.25 mg/kg; a control group received fat alone.

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Evaluation of hippocampus in rhesus monkeys after chronic (1-year) inhalation exposure to marijuana: I. Electron microscopy

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100159539 ◽

1990 ◽

Vol 48 (3) ◽

pp. 398-399

Author(s):

A.M. Andrews ◽

S.W. Wilson ◽

A.C. Scallet ◽

S.F. Ali ◽

J. Bailey ◽

...

Keyword(s):

Synaptic Vesicles ◽

Rhesus Monkeys ◽

Low Dose ◽

Inhalation Exposure ◽

Synaptic Cleft ◽

High Dose ◽

Withdrawal Time ◽

Treatment Groups ◽

Ultrastructural Evidence ◽

Male Rhesus

Exposure of rhesus monkeys (Macaca mulatta) to marijuana via inhalation or to intravenous delta-9-tetrahydrocannabinol (THC), reportedly caused ultrastructural evidence of increased synaptic width. Chronic marijuana smoke in a single rhesus monkey examined after a six month withdrawal time caused ultrastructure changes in the septal, hippocampal and amygdala regions; the synaptic cleft was widened, electron opaque material was found in the cleft and in the pre- and postsynaptic regions, with some clumping of the synaptic vesicles. The objective of our study was to assess neuropathological alterations produced by chronic inhalation of marijuana smoke.Nineteen male rhesus monkeys, 3-5 years of age and weighing 3-8 kg, were divided into four treatment groups: a) sham control, b) placebo smoke (7 days/ week) c) low dose marijuana (2 times/week with 5 days/week sham) and d) high dose marijuana (7 times/week). A smoke exposure consisted of smoke from one cigarette (2.6% THC) burned down to 10 mm butt length. Smoke was administered via smoke generator (ADL II, Arthur D. Little, Inc. Cambridge, MA) and nose-mouth only masks (local production) equipped with one-way valves.

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Benefit/Risk Profile of Combined Antiplatelet Therapy with Ticlopidine and Aspirin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648180 ◽

1991 ◽

Vol 65 (05) ◽

pp. 504-510 ◽

Cited By ~ 20

Author(s):

Raffaele De Caterina ◽

Rosa Sicari ◽

Walter Bernini ◽

Guido Lazzerini ◽

Giuliana Buti Strata ◽

...

Keyword(s):

Platelet Function ◽

Low Dose ◽

Bleeding Time ◽

Ex Vivo ◽

Stable Coronary Artery Disease ◽

High Dose ◽

Single Drug ◽

Before And After ◽

Serum Thromboxane ◽

Artery Disease

SummaryTiclopidine (T) and aspirin (ASA) are two antiplatelet drugs both capable of prolonging bleeding time (BT), with a different mechanism of action. A synergism in BT prolongation has been reported and is currently considered an argument for not recommending their combination. However, a profound suppression of platelet function might be a desirable counterpart of a marked prolongation of BT, with a possible use in selected clinical situations. We therefore studied ex vivo platelet function (aggregation by ADP 0.5-1-2.5 μM; adrenaline 0.75-2.5 μM; collagen 1.5-150 μg/ml; arachidonic acid 1 mM; PAF 1 μM; adrenaline 0.17 μM + ADP 0.62 μM; serum thromboxane ([TX]B2 generation) and BT (Mielke) in 6 patients with stable coronary artery disease receiving such combination. Patients underwent sequential laboratory evaluations at baseline, after 7 days of T 250 mg b.i.d., before and after the intravenous administration of ASA 500 mg, respectively, and, finally, after a minimum of 7 days of sole ASA oral administration (50 mg/day). The experimental design, therefore, allowed a comparison of T and ASA effects (2nd and 4th evaluation), and an assessment of the combination effect (3rd evaluation). Platelet aggregation in response to all doses of ADP was depressed more by T than by ASA. Conversely, responses to adrenaline, and arachidonate were affected more by ASA than by T. For all other agents, differences were not significant. T + ASA combination was more effective (p <0.05) than either treatment alone in depressing responses to high-dose collagen (% over control, mean ± SEM: T: 95 ± 3; ASA: 96 ± 5; T + ASA: 89 ± 4). Serum TXB2 (basal, ng/ml: 380 ± 54) did not change with T (372 ± 36), dropped to <1 ng/ml on ASA injection and slightly re-increased to 9.1 ± 3.1 ng/ml on oral low-dose ASA. BT (basal 7.4 ± 0.6 min) was affected similarly by T (9.2 ± 0.8) or ASA (9.7 ± 0.9) alone, but increased to 15.0 ± 0.7 min on combination treatment (106% increase over control). Thus, the strong synergism in BT prolongation by ASA-T combination has a counterpart in the inhibition of platelet function in response to strong stimuli such as high-dose collagen, not otherwise affected significantly by single-drug treatment. This effect is a possible rationale for the clinical evaluation of T + ASA combination.

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Intensive Initial Oral Anticoagulation and Shorter Heparin Treatment in Deep Vein Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661195 ◽

1984 ◽

Vol 52 (03) ◽

pp. 276-280 ◽

Cited By ~ 17

Author(s):

Sam Schulman ◽

Dieter Lockner ◽

Kurt Bergström ◽

Margareta Blombäck

Keyword(s):

Deep Vein Thrombosis ◽

Oral Anticoagulation ◽

Dose Group ◽

Low Dose ◽

Clinical Signs ◽

Coagulation Factor ◽

High Dose ◽

Vein Thrombosis ◽

Heparin Treatment ◽

Deep Vein

SummaryIn order to investigate whether a more intensive initial oral anticoagulation still would be safe and effective, we performed a prospective randomized study in patients with deep vein thrombosis. They received either the conventional regimen of oral anticoagulation (“low-dose”) and heparin or a more intense oral anticoagulation (“high-dose”) with a shorter period of heparin treatment.In the first part of the study 129 patients were randomized. The “low-dose” group reached a stable therapeutic prothrombin complex (PT)-level after 4.3 and the “high-dose” group after 3.3 days. Heparin was discontinued after 6.0 and 5.0 days respectively. There was no difference in significant hemorrhage between the groups, and no clinical signs of progression of the thrombosis.In the second part of the study another 40 patients were randomized, followed with coagulation factor II, VII, IX and X and with repeated venograms. A stable therapeutic PT-level was achieved after 4.4 (“low-dose”) and 3.7 (“high-dose”) days, and heparin was discontinued after 5.4 and 4.4 days respectively. There were no clinical hemorrhages, the activity of the coagulation factors had dropped to the same level in both groups at the time when heparin was discontinued and no thromboembolic complications occurred.Our oral anticoagulation regimen with heparin treatment for an average of 4.4-5 days seems safe and reduces in-patient costs.

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Effects of Aspirin and Sulfinpyrazone on Thromboxane and Prostacyclin Synthesis in Rabbits

10.1055/s-0038-1665775 ◽

1979 ◽

Author(s):

J McDonald ◽

A Cerskus ◽

M Ali

Keyword(s):

Arachidonic Acid ◽

Platelet Aggregation ◽

Low Dose ◽

High Dose ◽

Prostacyclin Synthesis

Arachidonic acid (AA) or collagen were infused into rabbits causing intravascular platelet aggregation with thrombocytopenia, hypotension and death. Thromboxane and prostacyclin synthesis were measured by radioimmunoassay of plasma TXB2 and 6-keto-PGF1α. The effects of pretreatement with aspirin (ASA) or sulfinpyrazone(SPZ) were assessed.Death in drug-treated rabbits was always associated with elevations of plasma TXB2(1-40 ng/ml) and of 6-keto-PGF1α(1-20 ng/ml). Collagen produced only small elevations of plasma TXB2 compared to AA but protection by ASA correlated better with inhibition of TXB2 and 6-keto-PGF1α synthesis than with inhibition of aggregation. Low dose ASA produced less inhibition of prostacyclin synthesis than high dose ASA but was less effective in preventing thromboxane synthesis and death.

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