Amr Abdulazim

Pannexin1 stabilizes synaptic plasticity and is needed for learning.

Pannexin 1 (Panx1) represents a class of vertebrate membrane channels, bearing significant sequence homology with the invertebrate gap junction proteins, the innexins and more distant similarities in the membrane topologies and pharmacological sensitivities with gap junction proteins of the connexin family. In the nervous system, cooperation among pannexin channels, adenosine receptors, and KATP channels modulating neuronal excitability via ATP and adenosine has been recognized, but little is known about the significance in vivo. However, the localization of Panx1 at postsynaptic sites in hippocampal neurons and astrocytes in close proximity together with the fundamental role of ATP and adenosine for CNS metabolism and cell signaling underscore the potential relevance of this channel to synaptic plasticity and higher brain functions. Here, we report increased excitability and potently enhanced early and persistent LTP responses in the CA1 region of acute slice preparations from adult Panx1−/− mice. Adenosine application and N-methyl-D-aspartate receptor (NMDAR)-blocking normalized this phenotype, suggesting that absence of Panx1 causes chronic extracellular ATP/adenosine depletion, thus facilitating postsynaptic NMDAR activation. Compensatory transcriptional up-regulation of metabotropic glutamate receptor 4 (grm4) accompanies these adaptive changes. The physiological modification, promoted by loss of Panx1, led to distinct behavioral alterations, enhancing anxiety and impairing object recognition and spatial learning in Panx1−/− mice. We conclude that ATP release through Panx1 channels plays a critical role in maintaining synaptic strength and plasticity in CA1 neurons of the adult hippocampus. This result provides the rationale for in-depth analysis of Panx1 function and adenosine based therapies in CNS disorders.

Trigeminocardiac Reflex in Neurosurgery - Current Knowledge and Prospects

Amr Abdulazim1, Martin N. Stienen1, Pooyan Sadr-Eshkevari2, Nora Prochnow1, Nora Sandu4, Benham Bohluli3 and Bernhard Schaller4 1Department of Neuroanatomy and Molecular Brain Research, Ruhr-University Bochum, Bochum, 2Farzan Clinical Research Institute,Teheran, 3Department of Oral and Maxillofacial Surgery, Tehran Azad School of Dental Medicine, Tehran, 4Department of Neurosurgery, University of Paris, Paris, 1Germany 2,3Iran 4France

Unified patch clamp protocol for the characterization of Pannexin 1 channels in isolated cells and acute brain slices

In the central nervous system, Pannexin 1 (Panx1) channels are implicated in a variety of physiological and pathological conditions. One of the prerequisites to enlighten the role of Panx1 is the development and standardization of reliable methods. Here, we address the applicability of voltage clamp protocols to identify Panx1 channel mediated currents in neurons of acutely dissected brain slices. We improved an established protocol and report on a modified paradigm that robustly evokes Panx1 channel currents. Crucial advances are the use of physiologic ion gradient conditions and a preconditioning step of depolarizing membrane potential ramps of long duration. This new paradigm provides significant impact on membrane current generation at hypo- and depolarized holding potential steps post voltage ramp preconditioning in heterologous expression systems and primary hippocampal CA1 neurons of mouse brain slices in vitro. Finally, we demonstrate that under these conditions the analysis of tail currents elicited by repolarization of the cells from preconditioning holding potential depolarization permits an independent method to isolate Panx1 mediated channel activity. In summary, this study provides a comprehensive methodological improvement in the biophysical analysis of Panx1 channels with a particular focus on investigations under physiological conditions in complex tissues.

Intramedullary spinal cord metastasis and multiple brain metastases from urothelial carcinoma

Intramedullary spinal cord metastases (ISCM) are rare spinal cord neoplasms associated with severe neurological deterioration and poor life expectancy. However, their incidence is expected to increase as a result of advances in diagnostic techniques and longer survival of patients with cancer due to improvements in cancer therapy. Reports on ISCM from primary urothelial carcinoma are virtually non existent. We report a 74-year-old male patient with a significant history of a high-grade urothelial carcinoma who presented with progressive back pain and concomitant weakness, grade 3-4/5 proximally and 0-1/5 distally, and distal hyperesthesia and hyperalgesia, particularly of the left lower limb. MRI revealed a contrast-enhancing intramedullary lesion at Th11/Th12. Laminectomies of Th11/Th12 and lesion resection were performed. Postoperative histopathological examinations confirmed the metastatic nature of the lesion. Subsequently the patient developed multiple brain metastases. Radiation therapy was refused by the patient. We conclude that ISCM are devastating complications of systemic cancer. Early and thorough diagnosis, as well as carefully considered and prompt therapy, is important for minimizing the patients functional deficit, thus improving quality of life.

Bisphosphonates and Connexin 43: A Critical Review of Evidence

Abstract Bisphosphonates (BPs) are drugs commonly used in the treatment of various disease arising or affecting bone tissue. There is a standard use in bone neoplasia and metastasis, hormonal and developmental disorders as well as for compensation of adverse effects in several medical therapies. Many in-vivo and in-vitro studies have assessed the efficacy of this drug and its function in cellular scale. In this concern, BPs are described to inhibit the resorptive function of osteoclasts and to prevent apoptosis of osteoblasts and osteocytes. They can preserve the osteocytic network, reduce fracture rate, and increase the bone mineral content, which is therapeutically used. Connexin 43 (Cx43) is a crucial molecule for basal regulation of bone homeostasis, development, and differentiation. It is described for signal transduction in many physiological and pathological stimuli and recently to be involved in BP action.

The role of the immunoinflammatory response after cardiac arrest

Cardiac arrest is a good (experimental) model for research in ischaemic tolerance [1], so it has been used often during the last 20 years in animal models. The (global) ischaemic event induced by cardiac arrest is followed by a phase of ischaemic preconditioning if the initial phase was of shorter or even stroke/complete ischaemia if the initial phase was of longer duration [2]. During the last years, there has been great effort in different research groups all over the world to find out the underlying pathophysiological mechanisms involved after these events or at least to find out some risk factors either in the brain or in the whole body [3, 4]. In the present issue of Archives of Medical Science, Anna Samborska-Sablik et al. present an interesting manuscript that deals with the role of the immunoinflammatory response after cardiac arrest in humans [5]. It is one of the very few studies in humans after cardiac arrest and is therefore of special interest [6]. The authors could find a significant correlation of the post-cardiac-arrest immunoinflammatory response (hs-CRP and IL-6) with the patients’ clinical state and also with the prediction of survival [5]. Such data are in line with previous research in the brain [7, 8] and open the door to so-called “immunomodulatory therapy”. In the brain such research is advanced, but we need a better understanding of the brain and immune system after such ischaemic events [9]. For the whole body, nearly no data exist so far. However, Anna Samborska-Sablik et al. have now provided a better insight into the clinical relevance of such research [5]: They show the relevance of this immunoinflammatory response for Glasgow Coma Scale (GCS) and Acute Physiology and Chronic Health Evaluation II (APACHE II) score: two of the major scores used in clinical daily practice. Therefore the immunoinflammatory response after ischaemic events is not only an experimental phenomenon (as many others), but also of great clinical importance [10, 11]. What are now the therapeutic implications of these findings? In experimental studies, preventive antibiotic treatment dramatically improved survival and outcome after ischaemic events, and even reduced the organ’s infarct size area [9, 12]. Apart from these experimental studies there are several clinical trials with promising results in this direction [12]. Smaller events of shorter duration can be protective – for example in the postoperative period – for further ischaemic events [7]. In this context, the oxygen-conserving reflex has gained more interest [13, 14] and can explain – at least partly – why the brain is only damaged after a very long duration of cardiac arrest. Nevertheless, the article of Samborska-Sablik et al. [5] goes deep into the pathophysiology of different organs. Further clinical research on this topic will open widely the doors to interesting therapeutic modalities and will help to resolve one of the great problems in internal medicine. Let’s go on this way!