Effects of Therapeutic Hypothermia on Inflammasome Signaling after Traumatic Brain Injury

Tomura, Satoshi; Vaccari, Juan Pablo de Rivero; Keane, Robert W.; Bramlett, Helen M.; Dietrich, W. Dalton

doi:10.1038/jcbfm.2012.99

Cited by 73 publications

(60 citation statements)

References 42 publications

(78 reference statements)

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“…Of importance is the finding that the NLRP1 inflammasome was present in motor neurons of the spinal cord, indicating that neurons express an inflammatory complex. 6 Similar findings regarding inflammasome activation in neurons have been obtained after traumatic brain injury 5,74 and stroke. 4 Increased levels of NLRP1, ASC, and caspase-1 have also been reported in the CSF of traumatic brain injury patients and are associated with poor prognosis.…”

Section: Inflammasome Activation After Brain and Spinal Cord Injurysupporting

confidence: 63%

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

Vaccari¹,

Dietrich²,

Keane

2014

J Cereb Blood Flow Metab

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271

222

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The inflammasome is an intracellular multiprotein complex involved in the activation of caspase-1 and the processing of the proinflammatory cytokines interleukin-1b (IL-1b) and IL-18. The inflammasome in the central nervous system (CNS) is involved in the generation of an innate immune inflammatory response through IL-1 cytokine release and in cell death through the process of pyroptosis. In this review, we consider the different types of inflammasomes (NLRP1, NLRP2, NLRP3, and AIM2) that have been described in CNS cells, namely neurons, astrocytes, and microglia. Importantly, we focus on the role of the inflammasome after brain and spinal cord injury and cover the potential activators of the inflammasome after CNS injury such as adenosine triphosphate and DNA, and the therapeutic potential of targeting the inflammasome to improve outcomes after CNS trauma.

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Section: Inflammasome Activation After Brain and Spinal Cord Injurysupporting

confidence: 63%

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

Vaccari¹,

Dietrich²,

Keane

2014

J Cereb Blood Flow Metab

Self Cite

271

222

View full text Add to dashboard Cite

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“…TH appears to have tremendous potential as a treatment for a variety of neurological injuries including ischemic stroke (4,9,42,48). However, TH has yet to be evaluated for the treatment of stroke in large-scale clinical trials (1).…”

Section: Discussionmentioning

confidence: 99%

Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion

Cao

Balasubramanian

Marrelli

2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Cao Z, Balasubramanian A, Marrelli SP. Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 minutes after reperfusion. Am J Physiol Regul Integr Comp Physiol 306: R149-R156, 2014. First published December 4, 2013; doi:10.1152/ajpregu.00329.2013.-Traditional methods of therapeutic hypothermia show promise for neuroprotection against cerebral ischemia-reperfusion (I/R), however, with limitations. We examined effectiveness and specificity of pharmacological hypothermia (PH) by transient receptor potential vanilloid 1 (TRPV1) channel agonism in the treatment of focal cerebral I/R. Core temperature (Tcore) was measured after subcutaneous infusion of TRPV1 agonist dihydrocapsaicin (DHC) in conscious C57BL/6 WT and TRPV1 knockout (KO) mice. Acute measurements of heart rate (HR), mean arterial pressure (MAP), and cerebral perfusion were measured before and after DHC treatment. Focal cerebral I/R (1 h ischemia ϩ 24 h reperfusion) was induced by distal middle cerebral artery occlusion. Hypothermia (Ͼ8 h) was initiated 90 min after start of reperfusion by DHC infusion (osmotic pump). Neurofunction (behavioral testing) and infarct volume (TTC staining) were measured at 24 h. DHC (1.25 mg/kg) produced a stable drop in Tcore (33°C) in naive and I/R mouse models but not in TRPV1 KO mice. DHC (1.25 mg/kg) had no measurable effect on HR and cerebral perfusion but produced a slight transient drop in MAP (Ͻ6 mmHg). In stroke mice, DHC infusion produced hypothermia, decreased infarct volume by 87%, and improved neurofunctional score. The hypothermic and neuroprotective effects of DHC were absent in TRPV1 KO mice or mice maintained normothermic with heat support. PH via TRPV1 agonist appears to be a well-tolerated and effective method for promoting mild hypothermia in the conscious mouse. Furthermore, TRPV1 agonism produces effective hypothermia in I/R mice and significantly improves outcome when initiated 90 min after start of reperfusion. cerebral ischemia-reperfusion; hypothermia; neuroprotection; TRPV1 STROKE is the second highest cause of death in the world and the main cause of long-term disability in the United States (43). However, current treatment options for stroke are quite limited (51). Thrombolysis is the only approved method for stroke therapy (41), but it can be applied to less than 10% of the patients due to the stringent treatment criteria (26) and in some cases may even produce further reperfusion injury (2). Mild hypothermia (32-34°C) has been demonstrated to reduce stroke injury and improve neurofunctional recovery in animal studies and has shown promise in small-scale clinical trials (20,25,37,49,50). At present, most clinical therapeutic hypothermia (TH) protocols involve methods of forced cooling such as with cold blankets and ice baths or intravenous methods of cooling (25). Although TH seems to have significant promise in stroke therapy, current protocols are accompanied by many adverse complications, which reduce effectiveness...

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“…20 Hypothermic treatment by manipulation of body temperature at 33°C 30 minutes after traumatic brain injury could provide neuroprotection by decreasing inflammasome signaling-mediated injury. 21 It is unknown whether GLP-1R activation affects cerebral microcirculation. Although hypoglycemic, cardiovasoprotective, and neuroprotective effects of Ex-4 have been reported, [10][11][12][13] the drug is also limited by a short half-life, high burst release, and lower bioactivity.…”

Section: Introductionmentioning

confidence: 99%

Exendin-4-Loaded PLGA Microspheres Relieve Cerebral Ischemia/Reperfusion Injury and Neurologic Deficits through Long-Lasting Bioactivity-Mediated Phosphorylated Akt/eNOS Signaling in Rats

Chien

Jou

Cheng

et al. 2015

J Cereb Blood Flow Metab

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Glucagon-like peptide-1 (GLP-1) receptor activation in the brain provides neuroprotection. Exendin-4 (Ex-4), a GLP-1 analog, has seen limited clinical usage because of its short half-life. We developed long-lasting Ex-4-loaded poly(D,L-lactide-co-glycolide) microspheres (PEx-4) and explored its neuroprotective potential against cerebral ischemia in diabetic rats. Compared with Ex-4, PEx-4 in the gradually degraded microspheres sustained higher Ex-4 levels in the plasma and cerebrospinal fluid for at least 2 weeks and improved diabetes-induced glycemia after a single subcutaneous administration (20 μg/day). Ten minutes of bilateral carotid artery occlusion (CAO) combined with hemorrhage-induced hypotension (around 30 mm Hg) significantly decreased cerebral blood flow and microcirculation in male Wistar rats subjected to streptozotocin-induced diabetes. CAO increased cortical O 2 − levels by chemiluminescence amplification and prefrontal cortex edema by T2-weighted magnetic resonance imaging analysis. CAO significantly increased aquaporin 4 and glial fibrillary acidic protein expression and led to cognition deficits. CAO downregulated phosphorylated Akt/endothelial nitric oxide synthase (p-Akt/p-eNOS) signaling and enhanced nuclear factor (NF)-κBp65/ intercellular adhesion molecule-1 (ICAM-1) expression, endoplasmic reticulum (ER) stress, and apoptosis in the cerebral cortex. PEx-4 was more effective than Ex-4 to improve CAO-induced oxidative injury and cognitive deficits. The neuroprotection provided by PEx-4 was through p-Akt/p-eNOS pathways, which suppressed CAO-enhanced NF-κB/ICAM-1 signaling, ER stress, and apoptosis.

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Effects of Therapeutic Hypothermia on Inflammasome Signaling after Traumatic Brain Injury

Cited by 73 publications

References 42 publications

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion

Exendin-4-Loaded PLGA Microspheres Relieve Cerebral Ischemia/Reperfusion Injury and Neurologic Deficits through Long-Lasting Bioactivity-Mediated Phosphorylated Akt/eNOS Signaling in Rats

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