Abstract 212: Effects of Therapeutic Hypothermia on Glymphatic Clearance

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_4) ◽  
Author(s):  
Padmesh Rajput ◽  
Jessica Lamb ◽  
Patrick D Lyden
Keyword(s):  
Molecular Weight ◽  
Clinical Trials ◽  
Therapeutic Hypothermia ◽  
Blood Gases ◽  
Brain Parenchyma ◽  
Sprague Dawley ◽  
Small Molecular Weight ◽  
Nih Image ◽  
Clinical Models ◽  
Inflammatory Molecules

Objectives: Therapeutic hypothermia is the most potent protective therapy for cerebral ischemia in pre-clinical models, however clinical trials have failed to show a significant benefit in patient outcomes. We sought to reconcile this discrepancy by investigating whether hypothermia impaired glymphatic system mediated waste clearance from brain parenchyma in a rat model. Methods: Sprague -Dawley rats were divided into normothermia and hypothermia groups. Hypothermia was achieved using a perivascular closed-loop cooling circuit implanted one week before the experiments in both the groups. Animals in the normothermia group were kept at 37C while the hypothermia animals were cooled to 33C. Once the targeted temperature was reached, two fluorescent tracers, small molecular weight (Texas Red-Dextran 3KdA) and large molecular weight (FITC -Dextran 2MdA) were injected intracisternally in each animal. Animals in both the groups were monitored for blood pressure and blood gases. Thirty minutes after injection, animals were perfused with 4% paraformaldehyde and 50 micron sections were cut using Leica vibratome. Brain sections were mounted on slides and cover slipped using antifade Fluro gold. Sections were imaged on Carl-Zeiss apotome microscope. For each animal 12 sections were imaged, data was analyzed using NIH Image J software. Results and Discussion: Cerebrospinal fluid tracer efflux in brain was significantly reduced in the hypothermia group compared to the normothermia group. This experiment helps provide insight as to a potential reason clinical trials have failed to show benefit in stroke patients, as hypothermia may have an untoward effect of hindering the brain’s natural clearance system from clearing inflammatory molecules and other waste from brain parenchyma.

scholarly journals Posttraumatic therapeutic hypothermia alters microglial and macrophage polarization toward a beneficial phenotype

2016 ◽  
Vol 37 (8) ◽  
pp. 2952-2962 ◽  
Author(s):  
Jessie S Truettner ◽  
Helen M Bramlett ◽  
W Dalton Dietrich
Keyword(s):  
Brain Injury ◽  
Therapeutic Hypothermia ◽  
Macrophage Polarization ◽  
Temperature Sensitive ◽  
Sprague Dawley ◽  
Rt Pcr ◽  
M2 Microglia ◽  
Sprague Dawley Rats ◽  
Inflammatory Processes ◽  
Clinical Models

Posttraumatic inflammatory processes contribute to pathological and reparative processes observed after traumatic brain injury (TBI). Recent findings have emphasized that these divergent effects result from subsets of proinflammatory (M1) or anti-inflammatory (M2) microglia and macrophages. Therapeutic hypothermia has been tested in preclinical and clinical models of TBI to limit secondary injury mechanisms including proinflammatory processes. This study evaluated the effects of posttraumatic hypothermia (PTH) on phenotype patterns of microglia/macrophages. Sprague-Dawley rats underwent moderate fluid percussion brain injury with normothermia (37℃) or hypothermia (33℃). Cortical and hippocampal regions were analyzed using flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR) at several periods after injury. Compared to normothermia, PTH attenuated infiltrating cortical macrophages positive for CD11b+ and CD45high. At 24 h, the ratio of iNOS+ (M1) to arginase+ (M2) cells after hypothermia showed a decrease compared to normothermia. RT-PCR of M1-associated genes including iNOS and IL-1β was significantly reduced with hypothermia while M2-associated genes including arginase and CD163 were significantly increased compared to normothermic conditions. The injury-induced increased expression of the chemokine Ccl2 was also reduced with PTH. These studies provide a link between temperature-sensitive alterations in macrophage/microglia activation and polarization toward a M2 phenotype that could be permissive for cell survival and repair.

Pharmacology and Safety of SB-497115-GR, an Orally Active Small Molecular Weight TPO Receptor Agonist, in Chimpanzees, Rats and Dogs.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2063-2063 ◽  
Author(s):  
Teresa Sellers ◽  
Timothy Hart ◽  
Michael Semanik ◽  
Krishna Murthy
Keyword(s):  
Molecular Weight ◽  
Clinical Trials ◽  
Receptor Agonist ◽  
Fold Increase ◽  
Distinct Species ◽  
In Vivo Studies ◽  
Small Molecular Weight ◽  
Platelet Counts

Abstract SB 497115-GR is a small molecular weight Tpo receptor (TpoR) agonist that has properties similar to thrombopoietin (TPO), primarily inducing proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. SB-497115-GR is being developed for the treatment of thrombocytopenias, such as immune thrombocytopenic purpura. In vitro and in vivo studies have demonstrated that SB-497115-GR has very distinct species specificity. SB-497115 or other molecules in this class induced dose dependent STAT activation in platelets from humans and chimpanzees but not in platelets from laboratory animal species commonly used in drug safety studies. In order to demonstrate in vivo activity of SB-497115-GR, a single dose and 5 daily dose pharmacology and safety study in chimpanzees was conducted. To support initiation of clinical trials, a comprehensive package of toxicology studies was conducted including studies up to 14 days duration in rats and dogs. All procedures involving the care and use of animals in these studies were reviewed and approved by the appropriate Institutional Animal Care and Use Committees. Female chimpanzees (1–3/group) were administered vehicle or SB-497115-GR at doses of 0.1 to 10 mg/kg/day by oral gavage. For toxicology studies, SB-497115-GR was administered orally to rats (10/sex/group) by gavage at doses of 3 to 40 mg/kg/day and to dogs (3/sex/group) by capsule at doses of 3 to 30 mg/kg/day for 14 days. SB-497115-GR was well tolerated in chimpanzees, rats and dogs at all doses tested. In chimpanzees, no treatment related increases in platelet counts were observed after administration of single doses of up to 10 mg/kg or 5 daily doses of up to 3 mg/kg/day. However, following 5 daily doses of 10 mg/kg/day SB-497115-GR, there was a 1.3- to 2.4-fold increase in circulating platelet counts in 3 chimpanzees. A similar change in reticulated platelet counts was observed preceding this increase. In contrast, there was no effect of treatment for up to 14 days on platelet counts in rats or dogs. In conclusion, SB-497115-GR, an orally bioavailable small molecular weight agonist of the TpoR, has been shown to increase platelet counts in chimpanzees. These in vivo data confirm the in vitro data demonstrating the unique species-specific effects of this novel Tpo receptor agonist on platelets and were predictive of a pharmacodynamic effect currently being observed in human clinical trials.

Low Molecular Weight Heparin Therapy: Is Monitoring Needed?

1994 ◽  
Vol 72 (03) ◽  
pp. 330-334 ◽  
Author(s):  
B Boneu
Keyword(s):  
Molecular Weight ◽  
Clinical Trials ◽  
Plasma Proteins ◽  
Bleeding Risk ◽  
Heparin Therapy ◽  
Low Molecular Weight ◽  
Vein Thrombosis ◽  
Meta Analyses ◽  
Deep Vein ◽  
Initial Check

SummaryRecent meta-analyses indicate that low molecular weight heparins (LMWH) are more effective than unfractionated heparin (UH) in preventing and treating deep vein thrombosis. This article presents the arguments for and against the need for laboratory monitoring. At the present time, the only tests currently available for monitoring LMWH therapy are those which measure the anti Xa activity in the plasma. Due to lower binding to plasma proteins and to cell surfaces,the plasma anti Xa activity generated by a given dose of LMWH is more predictable than for UH.Some clinical trials suggest that LMWH delivered at the recommended dose expose the patient to less bleeding risk than UH. Several . meta-analyses indicate comparable risk while any overdose unaccept-ably increases the haemorrhagic risk. The lowest dose of LMWH still effective in treating established DVT is presently unknown; some reports indicate that inadequate doses of LMWH are associated with a lack of efficacy for prevention. An overview of the published clinical trials indicates that the LMWH dose has never been monitored for prevention of DVT. In the treatment of established DVT, several trials have been performed without any monitoring, while in others the dose was adapted to target a given anti Xa activity. These considerations suggest that in prevention of DVT, monitoring the dose is not required. In the treatment of established DVT, considering the haemorrhagic risk of LMWH, the risk of undertreating the patient and the absence of large clinical trials comparing the advantages of monitoring the dose or not, it might be useful to check anti Xa activity at least once at the beginning of the treatment but the need for this initial check remains to be established. Because a large proportion of patients will be in the desired range, dose adjustments will be far less frequent than for UH.

Hemostatically potent small molecular weight serine protease from Maclura spinosa (Roxb. ex Willd.) accelerates healing of subcutaneous dermal wounds in Swiss albino mice

Biologia ◽  
2019 ◽  
Vol 75 (1) ◽  
pp. 139-149
Author(s):  
Venkatesh Bommalapura Kulkarni ◽  
Raghu Ram Achar ◽  
Maheshwari Mahadevappa ◽  
Dinesh Sosalagere Manjegowda ◽  
Priya Babu Shubha ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Serine Protease ◽  
Small Molecular Weight ◽  
Swiss Albino Mice ◽  
Albino Mice

Biosynthesis of the Diguanosine Nucleotides. I. Purification and Properties of an Enzyme from Yolk Platelets of Brine Shrimp Embryos

1974 ◽  
Vol 52 (3) ◽  
pp. 231-240 ◽  
Author(s):  
A. H. Warner ◽  
P. C. Beers ◽  
F. L. Huang
Keyword(s):  
Molecular Weight ◽  
Brine Shrimp ◽  
Artemia Salina ◽  
Temperature Optimum ◽  
Small Molecular Weight ◽  
Ph Optimum ◽  
Optimal Activity ◽  
Purification And Properties

An enzyme that catalyzes the synthesis of P1P4-diguanosine 5′-tetraphosphate (Gp4G) has been isolated and purified from yolk platelets of encysted embryos of the brine shrimp, Artemia salina. The enzyme GTP:GTP guanylyltransferase (Gp4G synthetase) utilizes GTP as substrate, has a pH optimum of 5.9–6.0, a temperature optimum of 40–42 °C, and requires Mg2+ and dithiothreitol for optimal activity. The synthesis of Gp4G is inhibited markedly by pyrophosphate, whereas orthophosphate has no effect on the reaction. In the presence of GDP the enzyme also catalyzes the synthesis of P1,P3-diguanosine 5′-triphosphate (Gp3G), but the rate of synthesis is low compared with Gp4G synthesis and dependent upon other small molecular weight components of yolk platelets.

The role of small molecular weight compounds to increase vacuolation induced by VacA toxin in vitro

2010 ◽  
Vol 24 (5) ◽  
pp. 1373-1378 ◽  
Author(s):  
Juan Sun ◽  
Yan Wu ◽  
Zhuang Su ◽  
Zhifang Liu ◽  
Bingzhong Su ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Small Molecular Weight
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