The Role of the Amygdala in Regulating the Hypothalamic-Pituitary-Adrenal Axis

We investigated the regulatory role of the amygdala upon the function of the hypothalamic-pituitary-adrenal (HPA) axis as measured by median eminence corticotrophin releasing hormone (CRH) content and serum levels of adrenocorticotrophic hormone (ACTH) and corticosterone. Our findings showed that (1) lesions of the central amygdala inhibited the HPA axis responses to a variety of stressful stimuli. (2) Depletion of norepinephrine or serotonin in the amygdala and hypothalamus and local injections of norepinephrine and serotonin receptor antagonists into the central amygdala inhibited the HPA axis responses to neural stress. Norepinephrine and serotonin agonists injected into the amygdala caused an increase in HPA axis activity. The activation of the amygdala facilitated the in vivo release of serotonin from the paraventricular nucleus following electrical stimulation of the brainstem raphe nuclei. (3) Electrical stimulation of the amygdala impaired the glucocorticoid negative feedback action following neural stressful stimuli probably via a decrease in hippocampal corticosteroid receptors

Early postoperative serum S100β levels predict ongoing brain damage after meningioma surgery: a prospective observational study

INTRODUCTION: Elevated serum levels of S100β, an astrocyte-derived protein, correlate with unfavourable neurological outcomes following cardiac surgery, neurotrauma, and resuscitation. This study evaluated whether pre-/postoperative serum S100β levels correlate with unfavourable clinical and radiological findings in patients undergoing elective meningioma resection. METHODS: In 52 consecutive patients admitted for meningioma surgery, serum S100β levels were determined upon admission and immediately, 24 hours, and 48 hours after surgery. All patients underwent complete pre- and postoperative neurological examination and mini-mental state examination. Radiological evaluation included preoperative magnetic resonance imaging (MRI) and postoperative computed tomography. Tumour volume, brain edema, and bleeding volume were calculated using BrainSCAN™ software. RESULTS: Preoperative S100β levels did not correlate with the tumour characteristics demonstrated by preoperative MRI (for example, tumour volume, edema volume, ventricular asymmetry, and/or midline shift). Preoperative serum S100β levels (0.065 ± 0.040 μg/l) were significantly lower than the levels measured immediately (0.138 ± 0.081 μg/l), 24 hours (0.142 ± 0.084 μg/l), and 48 hours (0.155 ± 0.119 μg/l) postoperatively (p < 0.0001). Significantly greater postcraniotomy S100β levels were observed with prolonged surgery (p = 0.039), deterioration in the mini-mental state examination (p = 0.005, 0.011, and 0.036 for pre versus immediate, 24 hours, and 48 hours postsurgery, respectively), and with postoperative brain computed tomography evidence of brain injury; bleeding was associated with higher serum S100β levels at 24 and 48 hours after surgery (p = 0.046, 95% confidence interval [CI] -0.095 to -0.001 and p = 0.034, 95% CI -0.142 to -0.006, respectively) as was the presence of midline shift (p = 0.005, 95% CI -0.136 to -0.025 and p = 0.006, 95% CI -0.186 to -0.032, respectively). Edema was associated with higher serum S100β levels immediately (p = 0.022, 95% CI -0.092 to -0.007) and at 48 hours after surgery (p = 0.017, 95% CI -0.142 to -0.026). The degree of elevation in S100β levels at 24 and 48 hours after surgery also correlated with the severity of midline shift and edema. CONCLUSION: In patients with meningioma, serum S100β levels perform poorly as an indicator of tumour characteristics but may suggest ongoing postcraniotomy injury. Serum S100β levels may serve as a potentially useful early marker of postcraniotomy brain damage in patients undergoing elective meningioma resection

MTADV 5-MER peptide suppresses chronic inflammations as well as autoimmune pathologies and unveils a new potential target-Serum Amyloid A.

Despite the existence of potent anti-inflammatory biological drugs e.g., anti-TNF and anti IL-6 receptor antibodies, for treating chronic inflammatory and autoimmune diseases, these are costly and not specific. Cheaper oral available drugs remain an unmet need. Expression of the acute phase protein Serum Amyloid A (SAA) is dependent on release of pro-inflammatory cytokines IL-1, IL-6 and TNF-α during inflammation. Conversely, SAA induces pro-inflammatory cytokine secretion, including Th17, leading to a pathogenic vicious cycle and chronic inflammation. 5- MER peptide (5-MP) MTADV (methionine-threonine-alanine-aspartic acid-valine), also called Amilo-5MER, was originally derived from a sequence of a pro-inflammatory CD44 variant isolated from synovial fluid of a Rheumatoid Arthritis (RA) patient. This human peptide displays an efficient anti-inflammatory effects to ameliorate pathology and clinical symptoms in mouse models of RA, Inflammatory Bowel Disease (IBD) and Multiple Sclerosis (MS). Bioinformatics and qRT-PCR revealed that 5-MP, administrated to encephalomyelytic mice, up-regulates genes contributing to chronic inflammation resistance. Mass spectrometry of proteins that were pulled down from an RA synovial cell extract with biotinylated 5-MP, showed that it binds SAA. 5-MP disrupted SAA assembly, which is correlated with its pro-inflammatory activity. The peptide MTADV (but not scrambled TMVAD) significantly inhibited the release of pro-inflammatory cytokines IL-6 and IL-1β from SAA-activated human fibroblasts, THP-1 monocytes and peripheral blood mononuclear cells. 5-MP suppresses the pro-inflammatory IL-6 release from SAA-activated cells, but not from non-activated cells. 5-MP could not display therapeutic activity in rats, which are SAA deficient, but does inhibit inflammations in animal models of IBD and MS, both are SAA-dependent, as shown by others in SAA knockout mice. In conclusion, 5-MP suppresses chronic inflammation in animal models of RA, IBD and MS, which are SAA-dependent, but not in animal models, which are SAA-independent

Targeting of prion-infected lymphoid cells to the central nervous system accelerates prion infection

BACKGROUND: Prions, composed of a misfolded protein designated PrP(Sc), are infectious agents causing fatal neurodegenerative diseases. We have shown previously that, following induction of experimental autoimmune encephalomyelitis, prion-infected mice succumb to disease significantly earlier than controls, concomitant with the deposition of PrP(Sc) aggregates in inflamed white matter areas. In the present work, we asked whether prion disease acceleration by experimental autoimmune encephalomyelitis results from infiltration of viable prion-infected immune cells into the central nervous system. METHODS: C57Bl/6 J mice underwent intraperitoneal inoculation with scrapie brain homogenates and were later induced with experimental autoimmune encephalomyelitis by inoculation of MOG(35-55) in complete Freund's adjuvant supplemented with pertussis toxin. Spleen and lymph node cells from the co-induced animals were reactivated and subsequently injected into naïve mice as viable cells or as cell homogenates. Control groups were infected with viable and homogenized scrapie immune cells only with complete Freund's adjuvant. Prion disease incubation times as well as levels and sites of PrP(Sc) deposition were next evaluated. RESULTS: We first show that acceleration of prion disease by experimental autoimmune encephalomyelitis requires the presence of high levels of spleen PrP(Sc). Next, we present evidence that mice infected with activated prion-experimental autoimmune encephalomyelitis viable cells succumb to prion disease considerably faster than do mice infected with equivalent cell extracts or other controls, concomitant with the deposition of PrP(Sc) aggregates in white matter areas in brains and spinal cords. CONCLUSIONS: Our results indicate that inflammatory targeting of viable prion-infected immune cells to the central nervous system accelerates prion disease propagation. We also show that in the absence of such targeting it is the load of PrP(Sc) in the inoculum that determines the infectivity titers for subsequent transmissions. Both of these conclusions have important clinical implications as related to the risk of prion disease contamination of blood products

Serum S100B levels after meningioma surgery: A comparison of two laboratory assays

<p>Abstract</p> <p>Background</p> <p>S100B protein is a potential biomarker of central nervous system insult. This study quantitatively compared two methods for assessing serum concentration of S100B.</p> <p>Methods</p> <p>A prospective, observational study performed in a single tertiary medical center. Included were fifty two consecutive adult patients undergoing surgery for meningioma that provided blood samples for determination of S100B concentrations. Eighty samples (40 pre-operative and 40 postoperative) were randomly selected for batch testing. Each sample was divided into two aliquots. These were analyzed by ELISA (Sangtec) and a commercial kit (Roche Elecsys^®) for S100B concentrations. Statistical analysis included regression modelling and Bland-Altman analysis.</p> <p>Results</p> <p>A parsimonious linear model best described the prediction of commercial kit values by those determined by ELISA (y = 0.045 + 0.277*x, x = ELISA value, R²= 0.732). ELISA measurements tended to be higher than commercial kit measurements. This discrepancy increased linearly with increasing S100B concentrations. At concentrations above 0.7 μg/L the paired measurements were consistently outside the limits of agreement in the Bland-Altman display. Similar to other studies that used alternative measurement methods, sex and age related differences in serum S100B levels were not detected using the Elecsys^®(p = 0.643 and 0.728 respectively).</p> <p>Conclusion</p> <p>Although a generally linear relationship exists between serum S100B concentrations measured by ELISA and a commercially available kit, ELISA values tended to be higher than commercial kit measurements particularly at concentrations over 0.7 μg/L, which are suggestive of brain injury. International standardization of commercial kits is required before the predictive validity of S100B for brain damage can be effectively assessed in clinical practice.</p

Nitric Oxide Interaction with the Eye

Nitric oxide (NO) is acknowledged as a vital intercellular messenger in multiple systems in the body. Medicine has focused on its functions and therapeutic applications for decades, especially in cardiovascular and nervous systems, and its role in immunological responses. This review was composed to demonstrate the prevalence of NO in components of the ocular system, including corneal cells and multiple cells in the retina. It discussed NO’s assistance during the immune, inflammation and wound-healing processes. NO is identified as a vascular endothelial relaxant that can alter the choroidal blood flow and prompt or suppress vascular changes in age-related macular degeneration and diabetes, as well as the blood supply to the optic nerve, possibly influencing the progression of glaucoma. It will provide a deeper understanding of the role of NO in ocular homeostasis, the delicate balance between overproduction or underproduction and the effect on the processes from aqueous outflow and subsequent intraocular pressure to axial elongation and the development of myopia. This review also recognized the research and investigation of therapies being developed to target the NO complex and treat various ocular diseases

Antineoplastic effect of decoy oligonucleotide derived from MGMT enhancer.

Silencing of O(6)-methylguanine-DNA-methyltransferase (MGMT) in tumors, mainly through promoter methylation, correlates with a better therapeutic response and with increased survival. Therefore, it is conceivable to consider MGMT as a potential therapeutic target for the treatment of cancers. Our previous results demonstrated the pivotal role of NF-kappaB in MGMT expression, mediated mainly through p65/NF-kappaB homodimers. Here we show that the non-canonical NF-KappaB motif (MGMT-kappaB1) within MGMT enhancer is probably the major inducer of MGMT expression following NF-kappaB activation. Thus, in an attempt to attenuate the transcription activity of MGMT in tumors we designed locked nucleic acids (LNA) modified decoy oligonucleotides corresponding to the specific sequence of MGMT-kappaB1 (MGMT-kB1-LODN). Following confirmation of the ability of MGMT-kB1-LODN to interfere with the binding of p65/NF-kappaB to the NF-KappaB motif within MGMT enhancer, the efficacy of the decoy was studied in-vitro and in-vivo. The results of these experiments show that the decoy MGMT-kB1-LODN have a substantial antineoplastic effect when used either in combination with temozolomide or as monotherapy. Our results suggest that MGMT-kB1-LODN may provide a novel strategy for cancer therapy