Studies of selective TNF inhibitors in the treatment of brain injury from stroke and trauma: a review of the evidence to date

The brain is very actively involved in immune-inflammatory processes, and the response to several trigger factors such as trauma, hemorrhage or ischemia causes the release of active inflammatory substances such as cytokines that are the basis of second level damage . During brain ischemia and after brain trauma the intrinsic inflammatory mechanisms of the brain, as well as those of the blood, are mediated by leukocytes that communicate with each other through cytokines. A neuro-inflammatory cascade has been reported as activated after a traumatic brain injury (TBI) and this cascade is due to the release of pro- and anti-inflammatory cytokines and chemokines. Microglia are the first source of this inflammatory cascade in the brain setting. Also in ischemic stroke setting an important mediator of this inflammatory reaction is TNF-, which seems to be involved in every phase of stroke-related neuronal damage such as inflammatory and pro-thrombotic events. TNF- has been shown to have an important role within the CNS; its properties include microglia and astrocyte activation, an influence on blood brain barrier permeability, influences on glutamatergic transmission and synaptic plasticity. TNF- increases AMPA receptor density on the cell surface and simultaneously decreases expression of GABA-A receptor cells, and these effects are related to a direct neuro-toxic effect. Several endogenous mechanisms regulate TNF- activity during inflammatory responses. Among endogenous inhibitors of TNF, prostaglandins, cyclic AMP and glucocorticoids are included. Etanercept, a biologic TNF antagonist has a reported effect of decreasing microglia activation in experimental models, and it has been used therapeutically in animal models of ischemic and traumatic neuronal damage. In the studies using animal models, authors reported a limitation of TBI-induced cerebral ischemia due to etanercept action, and amelioration of brain contusion signs, and of motor and cognitive dysfunction. On this basis it appears that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed to confirm these interesting and suggestive experimental findings

Frequenza periferica delle cellule CD28null e tipizzazione degli aplotipi KIR e degli alleli HLA e in soggetti con ictus ischemico acuto

Introduction: Inflammation and T cell activation have been also described as involved in pathophysiology of some complication of atherosclerosis, nevertheless no study has yet evaluated the relationship between KIR aplotypes and HLA alleles and acute cerebrovascular disease. Material and methods : Between November 2013 and February 2016, all consecutive patients with acute ischemic stroke were recruited. As healthy controls we enrolled consecutive subjects without acute ischemic stroke. KIR aplotype and HLA allele phenotyping has been performed. Results : Subjects with acute ischemic stroke in comparison to subjects without acute ischemic stroke showed a significantly a higher frequency of 2DL3, 2DL5B, 2DS2 and 2DS4 KIR aplotypes and a significantly lower frequency of HLA-B-Bw4I allele. With regard of interaction of HLA and KIR aplotype, subjects with acute ischemic stroke showed no significant difference with regard of frequency of co-expression of any considered HLA and KIR aplotype, whereas subjects without acute ischemic stroke showed a higher frequency of 2DS2 -HLAC2 co-expression. The multiple logistic regression analysis considering variables predictive of the occurrence of acute ischemic stroke showed a protective effect of HLA-B.Bw4I and of 2DL2HLAC1, 2DS2HLAC2 and a detrimental effect of 2DL2HLAC1_A HLA-KIR interactions. We also observed an higher frequency of 2DL3 and 2 DL4 KIR aplotype in subjects with LAAS subtype . Discussion: Our findings of a higher frequency of both activating KIR haplotypes seem to be consistent with findings previously reported patients with coronary syndrome acute and unstable atherosclerotic plaques. this higher frequency of "proinflammatory"genotype in subjects with ischemic strok

Stroke subtypes and their possible implication in stroke prevention drug strategies

Thrombotic strokes can affect large or small arteries in the brain. Drugs to prevent atherosclerosis complication such as thrombotic strokes, should be drugs able to prevent the accumulation of intravascular fat, reduce vascular proliferation, decrease blood pressure levels with the resulting shear stress, reduce platelet aggregation, and possibly partially or totally reverse carotid plaques. Any of the commonly used antihypertensive drugs lower the incidence of stroke, with larger reductions in BP resulting in larger reductions in risk. Experimental and clinical data suggest that reducing the activity of the renin-angiotensin aldosterone system (RAAS) may have beneficial effects beyond the lowering of blood pressure to reduce stroke incidence. In clinical trials, statins consistently reduced the risk of ischemic stroke in patients with or without CHD whereas the data on the effects of other lipid modifying drugs on stroke risk are limited. Approximately 25% of strokes are recurrent. Antiplatelet therapy is indicated for the prevention of recurrent stroke in patients with a history of noncardioembolic minor stroke or transient ischemic attack (TIA). Although clinicians may choose acetylsalicylic acid (ASA) as first-line therapy for secondary prevention, clinical guidelines and evidence from trials suggest that ASA may not be the most effective strategy. A recent review discussed results from clinical trials that have compared the efficacy of ASA monotherapy versus ASA + extended release dipyridamole in secondary stroke prevention. Therefore it is difficult to extrapolate the real benefit of pharmacological prevention strategies against atherothrombotic subtype for excellence in the TOAST classification subtype that is represented by the LAAS and also with regard to lacunar subtype as an expression of lipohyalinosis process which is a further aspect of atherosclerosis

Early high-dosage atorvastatin treatment improved serum immune-inflammatory markers and functional outcome in acute ischemic strokes classified as large artery atherosclerotic stroke: A randomized trial

Statins have beneficial effects on cerebral circulation and brain parenchyma during ischemic stroke and reperfusion. The primary hypothesis of this randomized parallel trial was that treatment with 80 mg/day of atorvastatin administered early at admission after acute atherosclerotic ischemic stroke could reduce serum levels of markers of immune-inflammatory activation of the acute phase and that this immune-inflammatory modulation could have a possible effect on prognosis of ischemic stroke evaluated by some outcome indicators. We enrolled 42 patients with acute ischemic stroke classified as large arteries atherosclerosis stroke (LAAS) randomly assigned in a randomized parallel trial to the following groups: Group A, 22 patients treated with atorvastatin 80mg (once-daily) from admission day until discharge; Group B, 20 patients not treated with atorvastatin 80mg until discharge, and after discharge, treatment with atorvastatin has been started. At 72 hours and at 7 days after acute ischemic stroke, subjects of group A showed significantly lower plasma levels of tumor necrosis factor-a, interleukin (IL)-6, vascular cell adhesion molecule-1, whereas no significant difference with regard to plasma levels of IL-10, E-Selectin, and P-Selectin was observed between the 2 groups. At 72 hours and 7 days after admission, stroke patients treated with atorvastatin 80mg in comparison with stroke subjects not treated with atorvastatin showed a significantly lower mean National Institutes of Health Stroke Scale and modified Rankin scores. Our findings provide the first evidence that atorvastatin acutely administered immediately after an atherosclerotic ischemic stroke exerts a lowering effect on immune-inflammatory activation of the acute phase of stroke and that its early use is associated to a better functional and prognostic profile

Arterial stiffness, endothelial and cognitive function in subjects with type 2 diabetes in accordance with absence or presence of diabetic foot syndrome

Abstract Background Endothelial dysfunction is an early marker of cardiovascular disease so endothelial and arterial stiffness indexes are good indicators of vascular health. We aimed to assess whether the presence of diabetic foot is associated with arterial stiffness and endothelial function impairment. Methods We studied 50 subjects with type 2 diabetes mellitus and diabetic foot syndrome (DFS) compared to 50 diabetic subjects without diabetic foot, and 53 patients without diabetes mellitus, by means of the mini mental state examination (MMSE) administered to evaluate cognitive performance. Carotid-femoral pulse wave velocity (PWV) and augmentation index (Aix) were also evaluated by Applanation tonometry (SphygmoCor version 7.1), and the RH-PAT data were digitally analyzed online by Endo-PAT2000 using reactive hyperemia index (RHI) values. Results In comparison to diabetic subjects without diabetic foot the subjects with diabetic foot had higher mean values of PWV, lower mean values of RHI, and lower mean MMSE. At multinomial logistic regression PWV and RHI were significantly associated with diabetic foot presence, whereas ROC curve analysis had good sensitivity and specificity in arterial PWV and RHI for diabetic foot presence. Conclusions Pulse wave velocity and augmentation index, mean RHI values, and mean MMSE were effective indicators of diabetic foot. Future research could address these issues by means of longitudinal studies to evaluate cardiovascular event incidence in relation to arterial stiffness, endothelial and cognitive markers

HLA and killer cell immunoglobulin-like receptor (KIRs) genotyping in patients with acute ischemic stroke

Introduction: In humans, a major component of natural killer (NK) and T cell target recognition depends on the surveillance of human leukocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIRs). Aims: To implement the knowledge about the immunological genetic background of acute ischemic stroke susceptibility in relation to the frequency of the KIR genes and HLA alleles. Methods: Subjects with acute ischemic stroke and subjects without stroke were genotyped for the presence of KIR genes and of the three major KIR ligand groups, HLA-C1, HLA-C2, and HLA-Bw4, both HLA-B and HLA-A loci. Results: Between November 2013 and February 2016, consecutive patients with acute ischemic stroke were recruited. As healthy controls, we enrolled subjects without acute ischemic stroke. Subjects with acute ischemic stroke in comparison with controls showed a higher frequency of 2DL3, 2DL5B, 2DS2, and 2DS4 KIR genes and a lower frequency of HLA-B-Bw4 I alleles. Subjects without acute ischemic stroke showed a higher frequency of interaction between KIR 2DS2 and HLAC2. We also observed a higher frequency of 2DL3 and 2 DL4 KIR genes in subjects with atherosclerotic (LAAS) subtype. Multiple logistic regression analysis showed a protective effect towards stroke of HLA-B-Bw4 I and interaction between KIR 2DL2 and HLAC1 and 2DS2-HLAC2 and a detrimental effect of 2DL2-HLA-C1-A interactions. Conclusion: Our findings of a higher frequency of activating KIR genes seem to be consistent with findings previously reported patients with coronary syndrome. This higher frequency of "proinflammatory" genes in subjects with ischemic stroke could also explain the immunoinflammatory activation of the acute phase of stroke

HLA and killer cell immunoglobulin-like receptor (KIRs) genotyping in patients with acute viral encephalitis

Introduction: The HLA genes, as well as the innate immune KIR genes, are considered relevant determinants of viral outcomes but no study, to our knowledge, has evaluated their role in the clinical setting of acute viral encephalitis. Results: Subjects with acute viral encephalitis in comparison to subjects without acute viral encephalitis showed a significantly higher frequency of 2DL1 KIR gene and AA KIR haplotypes and of HLA-C2 and HLA-A-Bw4 alleles. Subjects without acute viral encephalitis showed a higher frequency of interaction between KIR2DL2 and HLAC1. Multiple logistic regression analysis showed the detrimental effect of HLA-A haplotype and HLA-C1, HLA-A-BW4 HLA-B-BW4T alleles, whereas multiple logistic regression showed a protective effect of AB+BB KIR haplotype and a detrimental effect of interaction between KIR3DL1 and HLA-A-Bw4. Discussion: Our findings of a lower frequency of activating receptors in patients with acute encephalitis compared to controls could result in a less efficient response of NK cells. This finding could represent a possible pathogenetic explanation of susceptibility to acute symptomatic encephalitis in patients with viral infection from potentially responsible viruses such as Herpes virus. Materials and Methods: 30 Consecutive patients with symptomatic acute viral encephalitis and as controls, 36 consecutive subjects without acute encephalitis were analyzed. The following KIR genes were analyzed, KIR2DL1, 2DL2, 2DL3, 2DL5, 3DL1, 3DL2, 3DL3, 2DL4, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DS1, 2 pseudogenes (2DP1 and 3DP1) and the common variants of KIR2DL5 (KIR2DL5A, KIR2DL5B)

Cross-Talk between Neurohormonal Pathways and the Immune System in Heart Failure: A Review of the Literature

Heart failure is a complex clinical syndrome involving a multitude of neurohormonal pathways including the renin-angiotensin-aldosterone system, sympathetic nervous system, and natriuretic peptides system. It is now emerging that neurohumoral mechanisms activated during heart failure, with both preserved and reduced ejection fraction, modulate cells of the immune system. Indeed, these cells express angiotensin I receptors, adrenoceptors, and natriuretic peptides receptors. Ang II modulates macrophage polarization, promoting M2 macrophages phenotype, and this stimulation can influence lymphocytes Th1/Th2 balance. -AR activation in monocytes is responsible for inhibition of free oxygen radicals production, and together with 2-AR can modulate TNF- receptor expression and TNF- release. In dendritic cells, activation of 2-AR inhibits IL-12 production, resulting in the inhibition of Th1 and promotion of Th2 differentiation. ANP induces the activation of secretion of superoxide anion in polymorphonucleated cells; reduces TNF- and nitric oxide secretion in macrophages; and attenuates the exacerbated TH1 responses. BNP in macrophages can stimulate ROS production, up-regulates IL-10, and inhibits IL-12 and TNF- release by dendritic cells, suggesting an anti-inflammatory cytokines profile induction. Therefore, different neurohormonal-immune cross-talks can determine the phenotype of cardiac remodeling, promoting either favorable or maladaptive responses. This review aims to summarize the available knowledge on neurohormonal modulation of immune responses, providing supportive rational background for further research