Carbon Monoxide Preserves Circadian Rhythm to Reduce the Severity of Subarachnoid Hemorrhage in Mice

These earlier articles and I bet not one intervention or clinical trial came from them. Stroke survivors will continue to be screwed until we destroy the fucking failures of stroke associations and create a stroke strategy with real stroke leadership. 

Carbon Monoxide Releasing Molecule-A1 (CORM-A1) Improves Neurogenesis: Increase of Neuronal Differentiation Yield by Preventing Cell Death May 2016

Carbon monoxide may actually protect the brain from damage after subarachnoid hemorrhage  June 2015

 

 

Carbon Monoxide Preserves Circadian Rhythm to Reduce the Severity of Subarachnoid Hemorrhage in Mice

Nils Schallner, Judith-Lisa Lieberum, David Gallo, Robert H. LeBlanc, Patrick M. Fuller, Khalid A. Hanafy, Leo E. Otterbein

https://doi.org/10.1161/STROKEAHA.116.016165

Stroke. 2017;48:2565-2573

Originally published July 26, 2017

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Abstract

Background and Purpose—Subarachnoid hemorrhage (SAH) is associated with a temporal pattern of stroke incidence. We hypothesized that natural oscillations in gene expression controlling circadian rhythm affect the severity of neuronal injury. We moreover predict that heme oxygenase-1 (HO-1/Hmox1) and its product carbon monoxide (CO) contribute to the restoration of rhythm and neuroprotection.

Methods—Murine SAH model was used where blood was injected at various time points of the circadian cycle. Readouts included circadian clock gene expression, locomotor activity, vasospasm, neuroinflammatory markers, and apoptosis. In addition, cerebrospinal fluid and peripheral blood leukocytes from SAH patients and controls were analyzed for clock gene expression.

Results—Significant elevations in the clock genes Per-1, Per-2, and NPAS-2 were observed in the hippocampus, cortex, and suprachiasmatic nucleus in mice subjected to SAH at zeitgeber time (ZT) 12 when compared with ZT2. Clock gene expression amplitude correlated with basal expression of HO-1, which was also significantly greater at ZT12. SAH animals showed a significant reduction in cerebral vasospasm, neuronal apoptosis, and microglial activation at ZT12 compared with ZT2. In animals with myeloid-specific HO-1 deletion (Lyz-Cre-Hmox1^fl/fl), Per-1, Per-2, and NPAS-2 expression was reduced in the suprachiasmatic nucleus, which correlated with increased injury. Treatment with low-dose CO rescued Lyz-Cre-Hmox1^fl/fl mice, restored Per-1, Per-2, and NPAS-2 expression, and reduced neuronal apoptosis.

Conclusions—Clock gene expression regulates, in part, the severity of SAH and requires myeloid HO-1 activity to clear the erythrocyte burden and inhibit neuronal apoptosis. Exposure to CO rescues the loss of HO-1 and thus merits further investigation in patients with SAH.