scholarly journals Attenuation of Stroke Size in Rats Using an Adenoviral Vector to Induce Overexpression of Interleukin-1 Receptor Antagonist in Brain

1995 ◽  
Vol 15 (4) ◽  
pp. 547-551 ◽  
Author(s):  
A. Lorris Betz ◽  
Guo-Yuan Yang ◽  
Beverly L. Davidson
Keyword(s):  
Brain Injury ◽  
Receptor Antagonist ◽  
Recombinant Adenovirus ◽  
Infarct Volume ◽  
Interleukin 1 ◽  
Adenovirus Vector ◽  
Histochemical Staining ◽  
Artery Occlusion ◽  
Central Administration ◽  
Interleukin 1 Receptor Antagonist

Adenoviruses have been proposed as potential vectors for gene therapy in the central nervous system, but there are no reports of their use in the treatment of a brain disease. Because central administration of interleukin-1 receptor antagonist protein (IL-1ra) reduces ischemic brain damage, we determined whether a recombinant adenovirus vector carrying the human IL-1ra cDNA (Ad.RSV IL-1ra) could be used to ameliorate brain injury in permanent focal ischemia. Groups of six rats received intraventricular injections of Ad.RSV IL-1ra or a control adenovirus containing the Escherichia coli β-galactosidase gene (Ad.RSV lacZ). Histochemical staining for β-galactosidase 5 days after virus injection indicated that transgene expression was confined primarily to the cells lining the ventricle. The concentrations of IL-1ra were fivefold to 50-fold higher in the Ad.RSV IL-1ra-injected animals, achieving levels of 9.1 ± 3.3 ng/g in brain and 23.7 ± 22.5 ng/ml in CSF. In these animals, cerebral infarct volume resulting from 24 h of permanent middle cerebral artery occlusion was reduced 64%. These studies demonstrate that adenoviral vectors can be used to deliver genes that attenuate brain injury.

scholarly journals Delayed Administration of Interleukin-1 Receptor Antagonist Reduces Ischemic Brain Damage and Inflammation in Comorbid Rats

2012 ◽  
Vol 32 (9) ◽  
pp. 1810-1819 ◽  
Author(s):  
Jesus M Pradillo ◽  
Adam Denes ◽  
Andrew D Greenhalgh ◽  
Herve Boutin ◽  
Caroline Drake ◽  
...  
Keyword(s):  
Risk Factors ◽  
Brain Injury ◽  
Receptor Antagonist ◽  
Brain Damage ◽  
Infarct Volume ◽  
Interleukin 1 ◽  
Experimental Stroke ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Interleukin 1 Receptor Antagonist

Many neuroprotective agents have been effective in experimental stroke, yet few have translated into clinical application. One reason for this may be failure to consider clinical comorbidities/risk factors in experimental models. We have shown that a naturally occurring interleukin-1 receptor antagonist (IL-1Ra) is protective against ischemic brain damage in healthy animals. However, protective effects of IL-1Ra have not been determined in comorbid animals. Thus, we tested whether IL-1Ra protects against brain injury induced by experimental ischemia in aged JCR-LA (corpulent) rats, which have clinically relevant risk factors. Male, aged, lean, and corpulent rats exposed to transient (90 minutes) occlusion of the middle cerebral artery (tMCAO) were administered two doses of IL-1Ra (25 mg/kg, subcutaneously) during reperfusion. Brain injury and neuroinflammatory changes were assessed 24 hours after tMCAO. Our results show that IL-1Ra administered at reperfusion significantly reduced infarct volume measured by magnetic resonance imaging (50%, primary outcome) and blood–brain barrier disruption in these comorbid animals. Interleukin-1Ra also reduced microglial activation, neutrophil infiltration, and cytokines levels in the brain. These data are the first to indicate that IL-1Ra protects against ischemic brain injury when administered via a clinically relevant route and time window in animals with multiple risk factors for stroke.

Interleukin 1-receptor antagonist blocks interleukin 1-induced sleep and fever

1991 ◽  
Vol 260 (2) ◽  
pp. R453-R457 ◽  
Author(s):  
M. R. Opp ◽  
J. M. Krueger
Keyword(s):  
Receptor Antagonist ◽  
Eye Movement ◽  
Brain Temperature ◽  
Interleukin 1 ◽  
Central Administration ◽  
Rapid Eye Movement Sleep ◽  
Febrile Response ◽  
Purification And Characterization ◽  
Interleukin 1 Receptor Antagonist

The recent purification and characterization of an interleukin 1-receptor antagonist (IL-1ra) has provided an additional means of elucidating the mechanisms involved in the responses initiated by IL-1. Central administration of IL-1 to rabbits results in a characteristic febrile response and in increased non-rapid-eye-movement sleep (NREMS). In this study, rabbits received various doses of IL-1ra (10-1,000 micrograms) or pyrogen-free saline intracerebroventricularly, and sleep-wake activity and brain temperature (Tbr) were determined for the next 24 h. All doses of IL-1ra tested tended to reduce NREMS in the first postinjection hour with little effect on Tbr. When rabbits were pretreated with 100 micrograms IL-1ra and then injected with 10 ng IL-1, the characteristic IL-1-induced febrile and NREMS-promoting effects were completely blocked.

Hypoxia-ischemia in immature rats: Interleukin-1 receptor antagonist reduces brain injury

1997 ◽  
Vol 176 (1) ◽  
pp. S170
Author(s):  
H. Hagberg ◽  
E. Gilland ◽  
E. Bona ◽  
L-Å Hanson ◽  
M. Hahn-Zoric ◽  
...  
Keyword(s):  
Brain Injury ◽  
Receptor Antagonist ◽  
Interleukin 1 ◽  
Interleukin 1 Receptor Antagonist ◽  
Immature Rats ◽  
Hypoxia Ischemia

scholarly journals Interleukin-1 Receptor Antagonist Penetrates Human Brain at Experimentally Therapeutic Concentrations

2007 ◽  
Vol 28 (2) ◽  
pp. 387-394 ◽  
Author(s):  
Simon R Clark ◽  
Catherine J McMahon ◽  
Iva Gueorguieva ◽  
Malcolm Rowland ◽  
Sylvia Scarth ◽  
...  
Keyword(s):  
Brain Injury ◽  
Receptor Antagonist ◽  
Cerebral Ischaemia ◽  
Interleukin 1 ◽  
Therapeutic Benefit ◽  
Focal Cerebral Ischaemia ◽  
Interleukin 1 Receptor Antagonist ◽  
Ischaemic Brain ◽  
Steady State Plasma Concentration ◽  
The Brain

The proinflammatory cytokine interleukin (IL)-1 mediates several forms of experimentally induced acute brain injury and has been implicated in chronic neurodegenerative disorders. The IL-1 receptor antagonist, IL-1RA, protects rodents against ischaemic brain injury, but its molecular mass (17 kDa) potentially limits the brain penetration of peripherally administered IL-1RA. We therefore sought to identify whether therapeutically effective concentrations of IL-1RA in the rat were also achieved in brain of patients with subarachnoid haemorrhage (SAH), using a peripheral administration regime that had proved to be safe and reduce peripheral inflammation in patients after stroke. An intravenous bolus of IL-1RA, followed by infusion, was administered to rats after induction of focal cerebral ischaemia. The effects of IL-1RA on brain ischaemia and the concentrations achieved in cerebrospinal fluid (CSF), were determined. Interleukin-1 receptor antagonist was similarly administered to patients with SAH, and CSF was sampled via external ventricular drains. In rats, IL-1RA significantly reduced brain injury induced by focal cerebral ischaemia. The plasma IL-1RA concentrations reached 12±2 μg/mL by 30 mins, and CSF concentrations were maintained between 91 and 232 ng/mL between 1 and 24 h of infusion. In patients with SAH, IL-1RA reached a steady-state plasma concentration of 22 ± 4 μg/mL by 15 mins, and CSF concentrations were maintained at 78 to 558 ng/mL between 1 and 24 h. Intravenous delivery of IL-1RA leads to CSF concentrations in patients comparable to those that are neuroprotective in rats, and might therefore be of therapeutic benefit.

scholarly journals Interleukin-1 Receptor Antagonist Attenuates Regional Neuronal Cell Death and Cognitive Dysfunction after Experimental Brain Injury

1999 ◽  
Vol 19 (10) ◽  
pp. 1118-1125 ◽  
Author(s):  
Kristin L. Sanderson ◽  
Ramesh Raghupathi ◽  
Kathryn E. Saatman ◽  
David Martin ◽  
Gerald Miller ◽  
...  
Keyword(s):  
Brain Injury ◽  
Total Dose ◽  
Receptor Antagonist ◽  
Motor Function ◽  
Low Dose ◽  
Interleukin 1 ◽  
High Dose ◽  
Subcutaneous Injections ◽  
Fluid Percussion ◽  
Interleukin 1 Receptor Antagonist

The effect of systemic administration of human recombinant interleukin-1 receptor antagonist (rhIL-1ra) on behavioral outcome and histopathologic damage after lateral fluid-percussion brain injury of moderate severity was evaluated. In study 1, brain-injured Sprague Dawley rats received timed subcutaneous injections beginning 15 minutes after injury of either 100 mg/kg rhIL-1ra (high dose, total dose = 1900 mg/kg), 10 mg/kg rhIL-1ra (low dose, total dose = 190 mg/kg), or vehicle over 7 days. No effect of low-dose rhIL-1ra was observed in study 1. High-dose rhIL-1ra significantly attenuated posttraumatic neuronal loss in the injured hippocampal CA3 region ( P < 0.05), dentate hilus ( P < 0.05), and cortex ( P < 0.05) but impaired recovery of motor function at 7 days after trauma ( P < 0.05). In study 2, rats were pretrained to learn a visuospatial task in a Morris water maze, subjected to fluid-percussion brain injury or sham treatment, and randomly assigned to receive multiple subcutaneous injections at timed intervals of 100 mg/kg rhIL-1ra (total dose = 900 mg/kg) or vehicle over 42 hours, followed by continuous infusion of a lower concentration of rhIL-1ra (20 mg/kg/day, total dose = 100 mg/kg), or vehicle for 5 days using subcutaneously implanted osmotic minipumps. Postinjury administration of rhIL-1ra significantly attenuated cognitive deficits compared with vehicle-treated animals at 42 hours ( P < 0.05) but did not affect motor function at 48 hours, 1 week, and 2 weeks. These results suggest that inhibitors of cytokine pathways may be therapeutically useful for the treatment of brain trauma.

CEREBROSPINAL FLUID INTERLEUKIN-1 RECEPTOR ANTAGONIST FOLLOWING SEVERE TRAUMATIC BRAIN INJURY

Shock ◽  
2006 ◽  
Vol 26 (Supplement 1) ◽  
pp. 21
Author(s):  
V. Bogner ◽  
P. Biberthaler ◽  
S. Buhmann ◽  
J. Stegmaier ◽  
K.G. Kanz ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cerebrospinal Fluid ◽  
Brain Injury ◽  
Receptor Antagonist ◽  
Severe Traumatic Brain Injury ◽  
Interleukin 1 ◽  
Interleukin 1 Receptor Antagonist
Sign in / Sign up

Export Citation Format

Share Document