Inflammasomes link vascular disease with neuroinflammation and brain disorders

The role of inflammation in neurological disorders is increasingly recognised. Inflammatory processes are associated with the aetiology and clinical progression of migraine, psychiatric conditions, epilepsy, cerebrovascular diseases, dementia and neurodegeneration, such as seen in Alzheimer's or Parkinson's disease. Both central and systemic inflammatory actions have been linked with the development of brain diseases, suggesting that complex neuro-immune interactions could contribute to pathological changes in the brain across multiple temporal and spatial scales. However, the mechanisms through which inflammation impacts on neurological disease are improperly defined. To develop effective therapeutic approaches, it is imperative to understand how detrimental inflammatory processes could be blocked selectively, or controlled for prolonged periods, without compromising essential immune defence mechanisms. Increasing evidence indicates that common risk factors for brain disorders, such as atherosclerosis, diabetes, hypertension, obesity or infection involve the activation of NLRP3, NLRP1, NLRC4 or AIM2 inflammasomes, which are also associated with various neurological diseases. This review focuses on the mechanisms whereby inflammasomes, which integrate diverse inflammatory signals in response to pathogen-driven stimuli, tissue injury or metabolic alterations in multiple cell types and different organs of the body, could functionally link vascular- and neurological diseases and hence represent a promising therapeutic target

Systemic inflammatory challenges compromise survival after experimental stroke via augmenting brain inflammation, blood- brain barrier damage and brain oedema independently of infarct size

<p>Abstract</p> <p>Background</p> <p>Systemic inflammation impairs outcome in stroke patients and experimental animals via mechanisms which are poorly understood. Circulating inflammatory mediators can activate cerebrovascular endothelium or glial cells in the brain and impact on ischaemic brain injury. One of the most serious early clinical complications of cerebral ischaemia is brain oedema, which compromises survival in the first 24-48 h. It is not understood whether systemic inflammatory challenges impair outcome after stroke by increasing brain injury only or whether they have direct effects on brain oedema, cerebrovascular inflammation and blood-brain barrier damage.</p> <p>Methods</p> <p>We used two different systemic inflammatory stimuli, acute endotoxin treatment and anaphylaxis to study mechanisms of brain injury after middle cerebral artery occlusion (MCAo). Ischaemic brain injury, blood-brain barrier damage and oedema were analysed by histological techniques. Systemic cytokine responses and inflammatory changes in the brain were analysed by cytometric bead array, immunofluorescence, <it>in situ </it>hibridization and quantitative real-time PCR.</p> <p>Results</p> <p>Systemic inflammatory challenges profoundly impaired survival in the first 24 h after experimental stroke in mice, independently of an increase in infarct size. Systemic lipopolysaccharide (LPS) dose-dependently increased mortality (50-100%) minutes to hours after cerebral ischaemia. Acute anaphylactic challenge in ovalbumin-sensitised mice affected stroke more seriously when induced via intraperitoneal administration compared to intravenous. Both LPS and anaphylaxis induced inflammatory changes in the blood and in the brain prior to experimental stroke. Plasma cytokine levels were significantly higher after LPS, while increased IL-10 levels were seen after anaphylaxis. After MCAo, both LPS and anaphylaxis increased microglial interleukin-1α (IL-1α) expression and blood-brain barrier breakdown. LPS caused marked granulocyte recruitment throughout the ipsilateral hemisphere. To investigate whether reduction of ischaemic damage can improve outcome in systemic inflammation, controlled hypothermia was performed. Hypothermia reduced infarct size in all treatment groups and moderately improved survival, but failed to reduce excess oedema formation after anaphylaxis and LPS-induced neuroinflammation.</p> <p>Conclusions</p> <p>Our results suggest that systemic inflammatory conditions induce cerebrovascular inflammation via diverse mechanisms. Increased brain inflammation, blood-brain barrier injury and brain oedema formation can be major contributors to impaired outcome in mice after experimental stroke with systemic inflammatory stimuli, independently of infarct size.</p

Mitochondrial Ultrastructure is Coupled to Synaptic Performance at Axonal Release Sites

Mitochondrial function in neurons is tightly linked with metabolic and signaling mechanisms that ultimately determine neuronal performance. The subcellular distribution of these organelles is dynamically regulated as they are directed to axonal release sites on demand, but whether mitochondrial internal ultrastructure and molecular properties would reflect the actual performance requirements in a synapse-specific manner, remains to be established. Here, we examined performance-determining ultrastructural features of presynaptic mitochondria in GABAergic and glutamatergic axons of mice and human. Using electron-tomography and super-resolution microscopy we found, that these features were coupled to synaptic strength: mitochondria in boutons with high synaptic activity exhibited an ultrastructure optimized for high rate metabolism and contained higher levels of the respiratory chain protein cytochrome-c (CytC) than mitochondria in boutons with lower activity. The strong, cell type-independent correlation between mitochondrial ultrastructure, molecular fingerprints and synaptic performance suggests that changes in synaptic activity could trigger ultrastructural plasticity of presynaptic mitochondria, likely to adjust their performance to the actual metabolic demand

A stresszválasz hipotalamikus szabályozása = Hypothalamic regulation of the stress response

Vizsgálatainkban funkcionális neuroanatómiai és molekuláris biológiai technikák kombinációjával vizsgáltuk különböző stresszorok hatását a hipotalamusz paraventrikuláris magjának (PVN) a neuroendokrin és a vegetativ szabályozásban szerepet játszó neuroncsoportjaira. Elektronmikroszkópos technikákkal kimutattuk, hogy a neuroendokrin stresszválasz elindításáért felelős kortikotropin-releasing hormont (CRH) termelő idegsejteken GABAerg axonok végződnek és ezek száma, elhelyezkedési mintázata változik krónikus stresszben. A CRH neuronok szomszédságában hisztaminerg axonokat is feltérképeztünk, de ezek nem képeznek szinaptikus kapcsolatot a stresszel kapcsolatos hipotalamikus neuronokkal. A hisztamin hiány hisztidin dekarboxylase génkiütött egerek (HDC-KO) esetében nem okoz eltérést sem a stressz-, sem az anyagcsere szabályozásában szereplő hipotalamikus neuropeptidek expressziójában, mégis az állatokon olyan metabolikus fenotípus alakul ki, melynek jellemzői az elhízás, a glükóz intolerancia és a hiperleptinémia. Leírtuk, hogy a GABAerg gátló tónus felfüggesztése, valamint fizikális-, metabolikus- és immunstresszorok eltérő módon aktiválják a paraventrikuláris mag funkcionálisan különböző neuroncsoportjait és a CRH valamint az arginin vazopresszin (AVP) gének időben és térben eltérő indukcióját eredményezik a PVN-ben. Organotipikus hipotalamusz szelet tenyészeteken igazoltuk, hogy a szteroidok CRH expressziót gátló hatása közvetlenül a parvocelluláris neuronokon érvényesül | The effect of different stress challenges on the functionally distinct cell population in the hypothalamic paraventricular nucleus (PVN) has been studied by combination of anatomical and molecular biological methods. GABAergic terminals have been revealed on the corticotropin-releasing hormone (CRH) synthesizing neurons. The number and spatial distribution of these terminals has been changed after chronic stress. Histaminergic boutons have been identified in close apposition to CRH neurons without any synaptic contact. Lack of histamine in histidine decarboxylase knockout (HDC-KO) mice results in a metabolic phenotype with visceral obesity, glucose intolerance and hiperleptinemia without any detectable changes in the expression of neuropeptides involved in stress or metabolic regulation. We have revealed that suspension of inhibitory GABAergic tone, as well as physical, immune and metabolic challenges differentially recruit functionally distinct domains of the PVN and result in spatially and temporally different upregulation pattern of CRH and AVP genes. Using organotypic hypothalamic slice cultures we have provided evidence for the direct inhibitory effect of corticosteroid hormones on the CRH gene expression in the parvocellular neurons