Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1.

Subarachnoid hemorrhage (SAH) carries a 50% mortality rate. The extravasated erythrocytes that surround the brain contain heme, which, when released from damaged red blood cells, functions as a potent danger molecule that induces sterile tissue injury and organ dysfunction. Free heme is metabolized by heme oxygenase (HO), resulting in the generation of carbon monoxide (CO), a bioactive gas with potent immunomodulatory capabilities. Here, using a murine model of SAH, we demonstrated that expression of the inducible HO isoform (HO-1, encoded by Hmox1) in microglia is necessary to attenuate neuronal cell death, vasospasm, impaired cognitive function, and clearance of cerebral blood burden. Initiation of CO inhalation after SAH rescued the absence of microglial HO-1 and reduced injury by enhancing erythrophagocytosis. Evaluation of correlative human data revealed that patients with SAH have markedly higher HO-1 activity in cerebrospinal fluid (CSF) compared with that in patients with unruptured cerebral aneurysms. Furthermore, cisternal hematoma volume correlated with HO-1 activity and cytokine expression in the CSF of these patients. Collectively, we found that microglial HO-1 and the generation of CO are essential for effective elimination of blood and heme after SAH that otherwise leads to neuronal injury and cognitive dysfunction. Administration of CO may have potential as a therapeutic modality in patients with ruptured cerebral aneurysms.

Kinetic profile of the transcriptome changes induced in the choroid plexus by peripheral inflammation.

The choroid plexus, being part of the blood-brain barriers and responsible for the production of cerebrospinal fluid, is ideally positioned to transmit signals into and out of the brain. This study, using microarray analysis, shows that the mouse choroid plexus displays an acute-phase response after an inflammatory stimulus induced in the periphery by lipopolysaccharide (LPS). Remarkably, the response is specific to a restricted number of genes (out of a total of 24,000 genes analyzed, 252 are up-regulated and 173 are down-regulated) and transient, as it returns to basal conditions within 72 h. The up-regulated genes cluster into families implicated in immune-mediated cascades and in extracellular matrix remodeling, whereas those down-regulated participate in maintenance of the barrier function. Importantly, several acute-phase proteins, whose blood concentrations rise in response to inflammation, may contribute to the effects observed in vivo after LPS injection, as suggested by the differential response of primary choroid plexus epithelial cell cultures to LPS alone or to serum collected from animals exposed to LPS. By modulating the composition of the cerebrospinal fluid, which will ultimately influence the brain parenchyma, the choroid plexus response to inflammation may be of relevance in brain homeostasis in health and disease.

Acute phase histopathological study of spinally administered midazolam in cats.

UNLABELLED: Midazolam may be a useful analgesic when administered intrathecally. However, neurotoxicity must be excluded. The purpose of this study was to investigate whether spinally administered midazolam induces acute-phase histopathological or inflammatory reactions of the spinal cord. A lumbar laminectomy was performed on 40 cats, and their spinal cords were exposed. Midazolam 10 mg (2 mL, n = 20 cats) or saline 2 mL (20 cats) was administered directly to the spinal cord. At 1, 2, 4, or 6 h after the administration, cats were killed, and the lumbar spinal cord was removed and fixed in 10% formalin. Histology was examined using light microscopy with hematoxylin and eosin staining. Both groups showed slight to moderate changes in the spinal cord, but no severe damage was observed. Inflammatory reactions were seen in only one cat in the saline group with slight neutrophil infiltration. These changes were not different between the midazolam group and the saline group. In conclusion, up to 6 h after direct exposure to midazolam, no acute histological damage or inflammatory reaction of the spinal cord was seen in cats. IMPLICATIONS: Spinally administered midazolam, even in large doses, does not cause acute neurotoxicity or inflammation of the spinal cord.

Decreased interleukin-6 level in the cerebrospinal fluid of patients with Alzheimer-type dementia.

We examined IL-6 levels in the cerebrospinal fluid (CSF) of patients clinically diagnosed with Alzheimer-type dementia (ATD) and with vascular dementia (VD) and of age-matched normal subjects. The IL-6 levels in the CSF of ATD, but not VD patients, were significantly decreased. In the early onset ATD patients (disease onset < 65 years), IL-6 levels were reduced to 21% of the control level. The IL-6 levels in the CSF were not associated with the severity of the dementia or the duration of the disease since the identification of the first symptoms.