Background: The inflammatory pathway in cerebrospinal fluid (CSF) leads to delayed cerebral vasospasm (DCVS) and delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH). The role of IL-1α ...has never been evaluated in a rabbit SAH model. The aim of our study is to analyze systemic and CSF changes of IL-1α, and to evaluate potential associations with the onset of DCVS in a rabbit closed cranium SAH model. Methods: 17 New Zealand white rabbits were randomized into two groups, SAH (n = 12) and sham (n = 5). In the first group, SAH was induced by extracranial-intracranial shunting from the subclavian artery into the cerebral cistern of magna under intracranial pressure (ICP) monitoring. The sham group served as a control. The CSF and blood samples for IL-1α measurement were taken at day zero before SAH induction and at day three. Results: There was a significant increase of ICP (p = 0.00009) and a decrease of cerebral perfusion pressure (CPP) (p = 0.00089) during SAH induction. At follow up, there was a significant increase of systemic IL-1α in the SAH as compared with the sham group (p = 0.042). There was no statistically significant difference in the CSF values in both groups. The CSF IL-1α values showed a correlation trend of DCVS. Conclusions: Systemic IL-1α levels are elevated after SAH induction in a rabbit SAH model.
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Nogo-A is a myelin associated protein and one of the most potent neurite growth inhibitors in the central nervous system. Interference with Nogo-A signaling has thus been investigated ...as therapeutic target to promote functional recovery in CNS injuries. Still, the finding that Nogo-A presents a fairly ubiquitous expression in many types of neurons in different brain regions, in the eye and even in the inner ear suggests for further functions besides the neurite growth repression. Indeed, a growing number of studies identified a variety of functions including regulation of neuronal stem cells, modulation of microglial activity, inhibition of angiogenesis and interference with memory formation. Aim of the present commentary is to draw attention on these less well-known and sometimes controversial roles of Nogo-A. Furthermore, we are addressing the role of Nogo-A in neuropathological conditions such as ischemic stroke, schizophrenia and neurodegenerative diseases.
•EPC-CM increases density of TH-ir neurons in rat ventral mesencephalic cultures.•EPC-CM effects on TH-ir cells are mediated by peptides but not lipids.•The increased TH-ir density is not due to ...higher proliferation.•EPC-CM is neuroprotective against MPP+ toxicity.
Transplantation of stem and progenitor cells offers a promising tool for brain repair in the context of neuropathological disorders including Parkinson’s disease. There is growing proof that the capacity of adult stem and progenitor cells for tissue regeneration relies rather on the release of paracrine factors than on their cell replacement properties. In line with this notion, we have previously reported that conditioned medium (CM) collected from cultured Endothelial Progenitor Cells (EPC) stimulated survival of striatal neurons. In the present study we investigated whether EPC-CM promotes survival of cultured midbrain progenitor cells. For that purpose primary cultures from fetal rat embryonic ventral mesencephalon (VM) were prepared and grown for 7 days in vitro (DIV). EPC-CM was administered from DIV5-7. First, we found that EPC-CM treatment resulted in significantly increased cell densities of TH-ir neurons. Interestingly, this effect was no longer seen after proteolytic digestion of the EPC-CM. EPC-CM also significantly increased densities of beta-III-tubulin positive neurons and lba-1-ir microglial cells. The effect on dopaminergic neurons was not due to higher cell proliferation as no incorporation of EdU was observed in TH-ir cells. Importantly, EPC-CM exerted neuroprotection against MPP+ induced toxicity as in vitro model of Parkinson’s disease. Taken together, our findings identified EPC-CM as a powerful tool to promote survival of cultured VM neurons and further support the importance of paracrine factors in the actions of stem and progenitor cells for brain repair.
Essential hypertension is an important risk factor for coronary artery disease and its underlying process atherosclerosis, but involved mechanisms are not fully understood. Both macrophages and ...superoxide anions have been proposed to play a major role in the pathogenesis of atherosclerosis. In the present study, we investigated whether macrophages of individuals with hypertension show higher nicotinamide adenine dinucleotide phosphate oxidase-derived superoxide anion production compared with normotensive individuals. Furthermore, we examined associations between macrophage superoxide anion production and the psychological factors depression and chronic stress independent from hypertension status.
We studied 30 hypertensive (mean standard deviation = 48.7 2.4 years) and 30 age-matched normotensive men (mean standard deviation = 48.6 2.4 years). We assessed macrophage superoxide anion production using the WST-1 assay. The assay is based on the chemical reduction of the cell-impermeative tetrazolium salt WST-1 by superoxide anions that are produced by activated human ex vivo isolated monocyte-derived macrophages. We further evaluated whether chronic stress or depressive symptom severity was associated with macrophage superoxide anion production. All analyses were adjusted for potential confounders.
Individuals with hypertension showed higher superoxide anion production compared with normotensive individuals (F(1,58) = 11.56, p = .001). Complementary analyses using mean arterial blood pressure as a continuous measure revealed that higher mean arterial pressure correlated significantly with higher WST-1 reduction (ß = .38, p = .003, ΔR = .145). These results remained significant when controlling for potential confounding influences. Chronic stress was related to higher WST-1 reduction scores, but this association was not statistically significant (ß = .24, p = .067, ΔR = .053); depression levels were not significantly associated with WST-1 reduction scores (p = .24).
Our results indicate higher macrophage superoxide anion production in individuals with hypertension compared with normotensive individuals. This may suggest a mechanism underlying cardiovascular risk with hypertension.
Stem cells are generally believed to contain a small number of mitochondria, thus accounting for their glycolytic phenotype. We demonstrate here, however, that despite an indispensable glucose ...dependency, human dermal stem cells (hDSCs) contain very numerous mitochondria. Interestingly, these stem cells segregate into two distinct subpopulations. One exhibits high, the other low-mitochondrial membrane potentials (
ψ
). We have made the same observations with mouse neural stem cells (mNSCs) which serve here as a complementary model to hDSCs. Strikingly, pharmacologic inhibition of phosphoinositide 3-kinase (PI3K) increased the overall
ψ
, decreased the dependency on glycolysis and led to formation of TUJ1 positive, electrophysiologically functional neuron-like cells in both mNSCs and hDSCs, even in the absence of any neuronal growth factors. Furthermore, of the two, it was the
ψ
-high subpopulation which produced more mitochondrial reactive oxygen species (ROS) and showed an enhanced neuronal differentiation capacity as compared to the
ψ
-low subpopulation. These data suggest that the
ψ
-low stem cells may function as the dormant stem cell population to sustain future neuronal differentiation by avoiding excessive ROS production. Thus, chemical modulation of PI3K activity, switching the metabotype of hDSCs to neurons, may have potential as an autologous transplantation strategy for neurodegenerative diseases.
Highlights • Antagonization of the Nogo receptor 1 promotes dopaminergic parameters. • Neurotrophin-4/5 treatment promotes neuronal but not astroglial cells. • A combination of both factors is not ...superior to the single factor treatments.
Functional recovery following injury to the primary motor cortex is an uncommon phenomenon, given the limited ability of neurons of the adult central nervous system to regenerate.
We report on a ...patient with near complete functional muscle strength recovery from a marked monoparesis due to nail gun injury to the medial primary motor cortex. Besides surgical decision-making, we discuss possible related mechanisms and current challenges in the regenerative processes responsible for the functional recovery.
To achieve a favorable outcome, surgical decision-making to prevent secondary damage is of upmost importance. Lesion-induced inflammatory response may potentiate endogenous neurogenesis and neuronal plasticity and potentially contribute to the regenerative process involved.
ER stress signaling is linked to the pathophysiological and clinical disease manifestations in amyotrophic lateral sclerosis (ALS). Here, we have investigated ER stress-induced adaptive mechanisms in
...C9ORF72
-ALS/FTD, focusing on uncovering early endogenous neuroprotective mechanisms and the crosstalk between pathological and adaptive responses in disease onset and progression. We provide evidence for the early onset of ER stress-mediated adaptive response in
C9ORF72
patient-derived motoneurons (MNs), reflected by the elevated increase in GRP75 expression. These transiently increased GRP75 levels enhance ER–mitochondrial association, boosting mitochondrial function and sustaining cellular bioenergetics during the initial stage of disease, thereby counteracting early mitochondrial deficits. In
C9orf72
rodent neurons, an abrupt reduction in GRP75 expression coincided with the onset of UPR, mitochondrial dysfunction and the emergence of PolyGA aggregates, which co-localize with GRP75. Similarly, the overexpression of PolyGA in
WT
cortical neurons or
C9ORF72
patient-derived MNs led to the sequestration of GRP75 within PolyGA inclusions, resulting in mitochondrial calcium (Ca
2+
) uptake impairments. Corroborating these findings, we found that PolyGA aggregate-bearing human post-mortem
C9ORF72
hippocampal dentate gyrus neurons not only display reduced expression of GRP75 but also exhibit GRP75 sequestration within inclusions. Sustaining high GRP75 expression in spinal
C9orf72
rodent MNs specifically prevented ER stress, normalized mitochondrial function, abrogated PolyGA accumulation in spinal MNs, and ameliorated ALS-associated behavioral phenotype. Taken together, our results are in line with the notion that neurons in
C9ORF72
-ALS/FTD are particularly susceptible to ER–mitochondrial dysfunction and that GRP75 serves as a critical endogenous neuroprotective factor. This neuroprotective pathway, is eventually targeted by PolyGA, leading to GRP75 sequestration, and its subsequent loss of function at the MAM, compromising mitochondrial function and promoting disease onset.
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