GCS-CNS-IS

Pro-inflammatory and anti-inflammatory effects of glucocorticosteroids in the Central Nervous System

 Partecipanti

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'Glucocorticoids (GCs), the adrenal steroid hormones released during stress, can have an array of adverse effects in the nervous system, including disruption of hippocampal-dependent plasticity and cognition. Of relevance to this proposal, GCs can also compromise the ability of hippocampal and cortical neurons to survive an array of necrotic neurological insults. Amid this picture of deleterious effects, there is the accepted paradigm in which GCs are seemingly protective in the context of necrotic insults, namely concerning the well-known anti-inflammatory effects of the hormone. There has been a growing appreciation for the extent to which inflammation can worsen the neurotoxicity of necrotic insults, and the anti-inflammatory capacity of GCs has long been exploited pharmacologically to protect against circumstances of post-insult edema. This proposal is therefore designed to address this paradox of how and why GCs can have adverse effects on neuronal survival given the well-accepted anti-inflammatory effects of the hormone.

The purpose of this project is to better understand when GCs are classically anti-inflammatory, and when unexpected pro-inflammatory effects occur in the challenged nervous system, and to explore the mechanisms underlying such unexpected effects. This represents an innovative and fascinating question (i.e., understanding how a signaling molecule such as GCs can have diametrically opposite and simultaneous effects. At the same time, understanding this phenomenon is of great potential clinical relevance, given the common use of GCs.'

Introduzione (Teaser)

Glucocorticoids (GCs) are commonly used for their anti-inflammatory action. Paradoxically, GCs can have an opposite effect in the brain, compromising the ability of neurons to survive an array of necrotic neurological insults.

Descrizione progetto (Article)

GCs, the adrenal steroid hormones released during stress, can have an array of adverse effects in the nervous system, including disruption of hippocampal-dependent plasticity and cognition. This contradicts the accepted paradigm in which GCs are seemingly protective in necrotic insults.

The EU-funded project GCS-CNS-IS (Pro-inflammatory and anti-inflammatory effects of glucocorticosteroids in the central nervous system) aimed to resolve this paradox. The project explored when the stress-released GCs are classically anti-inflammatory, and when unexpected pro-inflammatory effects occur in the challenged nervous system.

Partners investigated gene expression patterns under conditions where GCs are pro-inflammatory, and examined the cellular specificity of GC-induced pro-inflammatory gene expression profiles. The effects were studied 24 hours after terminating the immune challenge, at a time point when GCs in blood were back to baseline.

Researchers compared gene expression patterns for multiple inflammatory markers in the different regions of the brain. While the pro-inflammatory effects of stress were present in the hippocampus and hypothalamus, they were the opposite in amygdala. Comparing additional regions (striatum, prefrontal cortex, frontal cortex, brain stem, cerebellum, pituitary and liver) revealed a different inflammatory pattern in different brain structures. The parts of the brain traditionally most sensitive to GCs (hippocampus, amygdala and frontal cortex) were affected the most.

The most interesting findings involved interleukin-1 beta (IL-1b). Stress was pro-inflammatory and potentiated the effect of lipopolysaccharides on IL-1b in the hippocampus, hypothalamus, frontal cortex, prefrontal cortex and pituitary. However, this effect was absent in the amygdala, brainstem, cerebellum and striatum. The mRNA expression of the neuronal activation marker C-fos was decreased in the amygdala but not in the hippocampus.

GCS-CNS-IS impacted the classic concept of GCs as anti-inflammatory and showed that the effects of GCs are not uniform, can be pro-inflammatory and are regional-dependent. Understanding how signalling molecules such as GCs can have diametrically opposite and simultaneous effects is of great potential clinical relevance, given their common use.