Reduced hypothalamic thermosensitivity following intraventricular injection of pyrogen in conscious rabbits

✓ Ventricular fluid pressure was measured continuously for 50 hours in conscious rabbits via a cannula implanted into the left lateral ventricle. Intraventricular injection of 25 µg reserpine (in a volume of 10 µl) resulted in increased pressure compared to that in non-injected controls during the first 7 to 10 hours. This was interpreted as depletion of noradrenaline in intracranial sympathetic nerves leading to increased cerebral blood volume and increased cerebrospinal fluid production. During the remainder of the experiment, the ventricular fluid pressure was reduced, probably due to a predominance of the central depressant effects of reserpine.

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Thermoregulation in the rabbit following intracranial injection of norepinephrine

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1975.229.3.676 ◽

1975 ◽

Vol 229 (3) ◽

pp. 676-682 ◽

Cited By ~ 7

Author(s):

E Preston

Keyword(s):

Preoptic Area ◽

Third Ventricle ◽

Intraventricular Injection ◽

Nerve Terminals ◽

Cerebral Ventricles ◽

Febrile Response ◽

Conscious Rabbits ◽

Hypothalamic Preoptic Area ◽

A Site

The release of norepinephrine (NE) from nerve terminals in the anterior hypothalamic/preoptic area (AH/POA) of the rabbit may serve to raise body temperature. To further examine the putative neurotransmitter role of NE, bilateral microinjections of 5 or 10 mug NE were made into or near the AH/POA of 44 conscious rabbits exposed to an ambient temperature of 15 degrees C. Microinjections into the AH/POS did not cause fever; they either had no influence on thermoregulation or rapidly induced ear vasocilation and increased ear temperature accompanied by slight falls in rectal temperature. The latter averaged 0.32 degrees C (range: 0.16-0.45 degrees C) in 18 rabbits in which the effects were prominent. In contrast, the injection of 100 or 250 mug NE into the lateral cerebral ventricles of conscious rabbits in the 15 degrees C environment caused mean fevers of 0.62 +/- 0.0, and 1.04 +/- 0.14 degrees C (+/- SE, n equals 6), respectively, within 70 min. The febrile response to intraventricular injection of NE may be due to an action of the drug at a site other than the AH/POA. Alternatively, the response may depend critically on the particular distribution of NE that results from its diffusion from the third ventricle into the AH/POA.

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Nimodipine pharmacokinetics after intraventricular injection of sustained-release nimodipine for subarachnoid hemorrhage

Journal of Neurosurgery ◽

10.3171/2019.9.jns191366 ◽

2021 ◽

Vol 134 (1) ◽

pp. 95-101 ◽

Cited By ~ 2

Author(s):

R. Loch Macdonald ◽

Daniel Hänggi ◽

Poul Strange ◽

Hans Jakob Steiger ◽

J Mocco ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Sustained Release ◽

Aneurysmal Subarachnoid Hemorrhage ◽

External Ventricular Drain ◽

Plasma Concentrations ◽

Intraventricular Injection ◽

World Federation ◽

Maximum Plasma ◽

Clinical Trial Registration ◽

Sustained Release Formulation

OBJECTIVEThe objective of this study was to measure the concentration of nimodipine in CSF and plasma after intraventricular injection of a sustained-release formulation of nimodipine (EG-1962) in patients with aneurysmal subarachnoid hemorrhage (SAH).METHODSPatients with SAH repaired by clip placement or coil embolization were randomized to EG-1962 or oral nimodipine. Patients were classified as grade 2–4 on the World Federation of Neurosurgical Societies grading scale for SAH and had an external ventricular drain inserted as part of their standard of care. Cohorts of 12 patients received 100–1200 mg of EG-1962 as a single intraventricular injection (9 per cohort) or they remained on oral nimodipine (3 per cohort). Plasma and CSF were collected from each patient for measurement of nimodipine concentrations and calculation of maximum plasma and CSF concentration, area under the concentration-time curve from day 0 to 14, and steady-state concentration.RESULTSFifty-four patients in North America were randomized to EG-1962 and 18 to oral nimodipine. Plasma concentrations increased with escalating doses of EG-1962, remained stable for 14 to 21 days, and were detectable at day 30. Plasma concentrations in the oral nimodipine group were more variable than for EG-1962 and were approximately equal to those occurring at the EG-1962 800-mg dose. CSF concentrations of nimodipine in the EG-1962 groups were 2–3 orders of magnitude higher than in the oral nimodipine group, in which nimodipine was only detected at low concentrations in 10% (21/213) of samples. In the EG-1962 groups, CSF nimodipine concentrations were 1000 times higher than plasma concentrations.CONCLUSIONSPlasma concentrations of nimodipine similar to those achieved with oral nimodipine and lasting for 21 days could be achieved after a single intraventricular injection of EG-1962. The CSF concentrations from EG-1962, however, were at least 2 orders of magnitude higher than those with oral nimodipine. These results supported a phase 3 study that demonstrated a favorable safety profile for EG-1962 but yielded inconclusive efficacy results due to notable differences in clinical outcome based on baseline disease severity.Clinical trial registration no.: NCT01893190 (ClinicalTrials.gov).

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FGF10 Attenuates Experimental Traumatic Brain Injury through TLR4/MyD88/NF-κB Pathway

Cells Tissues Organs ◽

10.1159/000511381 ◽

2021 ◽

pp. 1-9

Author(s):

Qinhan Hou ◽

Hongmou Chen ◽

Quan Liu ◽

Xianlei Yan

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Protein Expression ◽

Water Content ◽

Neurological Deficit ◽

Neuronal Apoptosis ◽

Neuronal Damage ◽

Intraventricular Injection ◽

Brain Water Content ◽

Brain Water

Traumatic brain injury (TBI) can induce neuronal apoptosis and neuroinflammation, resulting in substantial neuronal damage and behavioral disorders. Fibroblast growth factors (FGFs) have been shown to be critical mediators in tissue repair. However, the role of FGF10 in experimental TBI remains unknown. In this study, mice with TBI were established via weight-loss model and validated by increase of modified neurological severity scores (mNSS) and brain water content. Secondly, FGF10 levels were elevated in mice after TBI, whereas intraventricular injection of Ad-FGF10 decreased mNSS score and brain water content, indicating the remittance of neurological deficit and cerebral edema in TBI mice. In addition, neuronal damage could also be ameliorated by stereotactic injection of Ad-FGF10. Overexpression of FGF10 increased protein expression of Bcl-2, while it decreased Bax and cleaved caspase-3/PARP, and improved neuronal apoptosis in TBI mice. In addition, Ad-FGF10 relieved neuroinflammation induced by TBI and significantly reduced the level of interleukin 1β/6, tumor necrosis factor α, and monocyte chemoattractant protein-1. Moreover, Ad-FGF10 injection decreased the protein expression level of Toll-like receptor 4 (TLR4), MyD88, and phosphorylation of NF-κB (p-NF-κB), suggesting the inactivation of the TLR4/MyD88/NF-κB pathway. In conclusion, overexpression of FGF10 could ameliorate neurological deficit, neuronal apoptosis, and neuroinflammation through inhibition of the TLR4/MyD88/NF-κB pathway, providing a potential therapeutic strategy for brain injury in the future.

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Lipopolysaccharide induces neuroinflammation in microglia by activating the MTOR pathway and downregulating Vps34 to inhibit autophagosome formation

Journal of Neuroinflammation ◽

10.1186/s12974-019-1644-8 ◽

2020 ◽

Vol 17 (1) ◽

Cited By ~ 8

Author(s):

Xiaoxia Ye ◽

Mingming Zhu ◽

Xiaohang Che ◽

Huiyang Wang ◽

Xing-Jie Liang ◽

...

Keyword(s):

Inflammatory Response ◽

Microglial Activation ◽

Adaptor Protein ◽

Mtor Pathway ◽

Microglial Cells ◽

Inflammatory Factors ◽

Intraventricular Injection ◽

Enzyme Linked Immunosorbent Assay ◽

Autophagic Flux

Abstract Background Microglial activation is a prominent feature of neuroinflammation, which is present in almost all neurodegenerative diseases. While an initial inflammatory response mediated by microglia is considered to be protective, excessive pro-inflammatory response of microglia contributes to the pathogenesis of neurodegeneration. Although autophagy is involved in the suppression of inflammation, its role and mechanism in microglia are unclear. Methods In the present study, we studied the mechanism by which lipopolysaccharide (LPS) affects microglial autophagy and the effects of autophagy on the production of pro-inflammatory factors in microglial cells by western blotting, immunocytochemistry, transfection, transmission electron microscopy (TEM), and real-time PCR. In a mouse model of neuroinflammation, generated by intraventricular injection of LPS (5 μg/animal), we induced autophagy by rapamycin injection and investigated the effects of enhanced autophagy on microglial activation by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. Results We found that autophagic flux was suppressed in LPS-stimulated N9 microglial cells, as evidenced by decreased expression of the autophagy marker LC3-II (lipidated form of MAP1LC3), as well as increased levels of the autophagy adaptor protein SQSTM1. LPS significantly decreased Vps34 expression in N9 microglial cells by activating the PI3KI/AKT/MTOR pathway without affecting the levels of lysosome-associated proteins and enzymes. More importantly, overexpression of Vps34 significantly enhanced the autophagic flux and decreased the accumulation of SQSTM1 in LPS-stimulated N9 microglial cells. Moreover, our results revealed that an LPS-induced reduction in the level of Vps34 prevented the maturation of omegasomes to phagophores. Furthermore, LPS-induced neuroinflammation was significantly ameliorated by treatment with the autophagy inducer rapamycin both in vitro and in vivo. Conclusions These data reveal that LPS-induced neuroinflammation in N9 microglial cells is associated with the inhibition of autophagic flux through the activation of the PI3KI/AKT/MTOR pathway, while enhanced microglial autophagy downregulates LPS-induced neuroinflammation. Thus, this study suggests that promoting the early stages of autophagy might be a potential therapeutic approach for neuroinflammation-associated diseases.

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Thiamine transport in the central nervous system

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1976.230.4.1101 ◽

1976 ◽

Vol 230 (4) ◽

pp. 1101-1107 ◽

Cited By ~ 39

Author(s):

R Spector

Keyword(s):

Choroid Plexus ◽

Intraventricular Injection ◽

Simple Diffusion ◽

Thiamine Transport ◽

Choroid Plexuses ◽

The Central Nervous System ◽

The Brain ◽

Thiamine Phosphates

Total thiamine (free thiamine and thiamine phosphates) transport into the cerebrospinal fluid (CSF), brain, and choroid plexus and out of the CSF was measured in rabbits. In vivo, total thiamine transport into CSF, choroid plexus, and brain was saturable. At the normal plasma total thiamine concentration, less than 5% of total thiamine entry into CSF, choroid plexus, and brain was by simple diffusion. The relative turnovers of total thiamine in choroid plexus, whole brain, and CSF were 5, 2, and 14% per h, respectively, when measured by the penetration of 35S-labeled thiamine injected into blood. From the CSF, clearance of [35S]thiamine relative to mannitol was not saturable after the intraventricular injection of various concentrations of thiamine. However, a portion of the [35S]thiamine cleared from the CSF entered brain by a saturable mechanism. In vitro, choroid plexuses, isolated from rabbits and incubated in artificial CSF, accumulated [35S]thiamine against a concentration gradient by an active saturable process that did not depend on pyrophosphorylation of the [35S]thiamine. The [35S]thiamine accumulated within the choroid plexus in vitro was readily released. These results were interpreted as showing that the entry of total thiamine into the brain and CSF from blood is regulated by a saturable transport system, and that the locus of this system may be, in part, in the choroid plexus.

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Stimulation of LH and FSH secretion following intraventricular injection of cysteic acid but not taurine

Brain Research ◽

10.1016/0006-8993(80)90778-7 ◽

1980 ◽

Vol 201 (1) ◽

pp. 99-106 ◽

Cited By ~ 12

Author(s):

J. Scheibel ◽

T. Elsasser ◽

J.G. Ondo

Keyword(s):

Cysteic Acid ◽

Intraventricular Injection ◽

Stimulation Of

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Intraventricular injection of antibodies to β1-integrins generates pressure gradients in the brain favoring hydrocephalus development in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00307.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. R1312-R1321 ◽

Cited By ~ 8

Author(s):

Gurjit Nagra ◽

Lena Koh ◽

Isabelle Aubert ◽

Minhui Kim ◽

Miles Johnston

Keyword(s):

Fluid Pressure ◽

Active Role ◽

Intraventricular Injection ◽

Pressure Gradients ◽

Tissue Pressure ◽

Before And After ◽

The Matrix ◽

System 2 ◽

Periventricular Area ◽

The Brain

In some tissues, the injection of antibodies to the β1-integrins leads to a reduction in interstitial fluid pressure, indicating an active role for the extracellular matrix in tissue pressure regulation. If perturbations of the matrix occur in the periventricular area of the brain, a comparable lowering of interstitial pressures may induce transparenchymal pressure gradients favoring ventricular expansion. To examine this concept, we measured periventricular (parenchymal) and ventricular pressures with a servo-null micropipette system (2-μm tip) in adult Wistar rats before and after anti-integrin antibodies or IgG/IgM isotype controls were injected into a lateral ventricle. In a second group, the animals were kept for 2 wk after similar injections and after euthanization, the brains were removed and assessed for hydrocephalus. In experiments in which antibodies to β1-integrins ( n = 10) but not isotype control IgG/IgM ( n = 7) were injected, we observed a decline in periventricular pressures relative to the preinjection values. Under similar circumstances, ventricular pressures were elevated ( n = 10) and were significantly greater than those in the periventricular interstitium. We estimated ventricular to periventricular pressure gradients of up to 4.3 cmH2O. In the chronic preparations, we observed enlarged ventricles in many of the animals that received injections of anti-integrin antibodies (21 of 29 animals; 72%) but not in any animal receiving the isotype controls. We conclude that modulation/disruption of β1-integrin-matrix interactions in the brain generates pressure gradients favoring ventricular expansion, suggesting a novel mechanism for hydrocephalus development.

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