All Articles

Lisa M. James^1,2,3, Apostolos P. Georgopoulos^1,2,3,4*

¹Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

²Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

³Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

⁴Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

George Stoica¹*, Heidi Martini-Stoica²

¹Texas A&M University, College Station, TX,USA

²Baylor College of Medicine, Houston, TX, USA

Hildegard M. Schuller

Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville TN, USA

Toshiyuki Mizui^{1, 2}*, Masami Kojima^1,2,3#

Biomedical Research Inst. (BMD), National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorioka, Ikeda, Osaka, 563-8577 Japan

Core Research for Evolutional Science and Technology (CREST), Science and Technology Agency (JST), Kawaguchi, 332-0012, Japan

Graduate School of Frontier Bioscience, Osaka University, Suita 565-0871, Japan

Most growth factors are initially synthesized as precursors. To produce biologically active mature peptides, the pro-domain is cleaved by proteolytic processing. However, compared with mature bioactive growth factors, the biological roles of pro-domains are poorly understood. Recent new findings on brain-derived neurotrophic factor (BDNF), a growth factor in the brain that promotes neuronal survival, differentiation, and synaptic plasticity, have been reported. Interestingly, the pro-domain (pro-peptide) of BDNF is endogenously present and localized at presynaptic termini, where it surprisingly functions as a facilitator of long-term depression (LTD). Given that BDNF elicits synaptic transmission and long-term potentiation (LTP), BDNF and its pro-peptide might exert distinct roles in synaptic plasticity in the central nervous system (CNS). In addition to reports on the BDNF pro-peptide, we review recent literature on the role of BDNF in the peripheral nervous system (PNS), and in brain-body interactions following exercise. Together, these findings provide new insight into BDNF biology.

Ido Rippin, Hagit Eldar-Finkelman*

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel

Qin Wang, Richard Grater*, Luisette Delva, Elvana Veizaj, Cheryl Black, Chris Rowbottom, Roger Rusesabagina, Ellen Rohde, Patricia Schroeder, Tonika Bohnert, Guangqing Xiao

Preclinical Pharmacokinetics and In Vitro ADME, Biogen Inc. 225 Binney St Cambridge, MA 02142, USA

Objective: The convective flow of CSF plays a crucial role for CNS to clear endogenous and xenobiotic substances. The objective of this study is to investigate the impact of modifying CSF flow with acetazolamide and arginine vasopressin (AVP) on the CNS clearance of ibuprofen and acetaminophen.

Results: Microdialysis studies indicated that acetaminophen AUC ratio (K_p,uu) between brain ISF and unbound plasma increased from 0.40 ± 0.14 in the vehicle control group to 0.60 ± 0.27 in the acetazolamide treated group (P < 0.05). Conversely, acetaminophen’s steady-state ^ISFC to ^{unbound_plasma}C ratio (K_p,uu) decreased from 0.44 ± 0.08 to 0.36 ± 0.07 upon IV infusion of 0.3 µg/hr AVP (P < 0.05). Using CSF concentration as a surrogate of unbound brain drug concentration, AVP treatment reduced the ^CSFAUC_0-5hr/^{unbound_plasma}AUC_0-5hr ratio from 1.63 to 0.85 for acetaminophen, and the ^CSFC_4hr / ^{unbound_plasma}C_4hr ratio decreased from 0.91 ± 0.27 to 0.54 ± 0.12 for ibuprofen (P < 0.05).

Conclusion: We have demonstrated that acetazolamide decreases the CNS clearance of acetaminophen, while AVP increases the CNS clearance of both acetaminophen and ibuprofen. Such changes are caused by altering the CSF production rates.

Laxminarayan Bhat*, Marc Cantillon, and Robert Ings

Reviva Pharmaceuticals, Inc., Sunnyvale, CA, USA

Schizophrenia is a condition comprising of both treatment and comorbidity factors that both complicate its management and present multiple unmet needs. Brilaroxazine (RP5063), a dopamine (D)/serotonin (5-HT) modulator, possesses a broad in vitro pharmacology profile against D_2/3/4 and 5-HT_1A/2A/2B/6/7 receptors, nicotinic acetylcholine (α₄β₂) receptors, and the serotonin transporter. In Phase 1 and 2 clinical experience in healthy volunteers, patients with schizophrenia and schizoaffective disorder, brilaroxazine was well tolerated, with the repeated 100 mg oral dose as the maximum tolerated dose. Investigators observed no cardiometabolic, cardiovascular, prolactin, or neurologic complications. Adherence in Phase 2 was good with discontinuation rates generally less than placebo. In a Phase 2 evaluation of patients with acute exacerbations in schizophrenia and schizoaffective disorders, brilaroxazine met its primary endpoint of significance versus placebo for Total Positive and Negative Symptom Scale (PANSS) Score at Day 28 as compared to baseline. In Phase 1 multi-dose pharmacodynamic evaluation, brilaroxazine displayed clinical activity in patients with stable disease and a PANSS greater than 50, as early as Day 10 of treatment. Pharmacokinetic analyses demonstrated brilaroxazine to have a substantial and relatively rapid oral absorption, linear (dose proportional) increases in maximum concentration (C_max) and area under the curve (AUC), lack of excessive accumulation, and a relatively long terminal half-life of about 60 hours. Early clinical findings with brilaroxazine in schizophrenia and schizoaffective disorders indicate that this compound appears to be effective, well tolerated, and possess a straightforward once-daily dosing pharmacokinetic profile.

Kristin A Richardson¹, Robert J Wessells^1*

¹Department of Physiology, Wayne State School of Medicine, Detroit, MI 48201, USA

Effie-Photini C. Tsilibary^1,2, Eric P. Souto¹, Lisa M. James^1,2, Brian E. Engdahl^1,2, Apostolos P. Georgopoulos^1,2*

¹Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, Minnesota, USA

²Department of Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota, USA

Gulf War Illness (GWI) is a chronic debilitating disease of unknown etiology that affects the brain and has afflicted many veterans of the 1990-91 Gulf War (GW). We showed recently¹ that blood serum from patients suffering from GWI exerts detrimental effects on neural cultures, including reduced growth, increased apoptosis, and disruption of neural network function. Remarkably, these adverse effects were prevented by the concomitant addition to the culture of serum from healthy Gulf War (GW) era veterans. We interpreted those findings¹ in the context of our hypothesis that GWI is, at least partly, due to circulating pathogenic persistent antigens², probably coming from vaccines administered to GW veterans who lacked crucial Human Leukocyte Antigen (HLA) class 2 alleles³ and, therefore, could not make antibodies against those antigens; by contrast, healthy GW veterans who received the same vaccines and possessed HLA protection³ made antibodies that neutralized the various antigens. Thus, we hypothesized that the beneficial effect of the healthy serum on preventing the adverse GWI serum effects was due to the presence of antibodies against the persistent antigens. Here we tested this hypothesis by assessing the effect of pooled human immunoglobulin G (IgG) on ameliorating the GWI adverse effects on neural growth and apoptosis in neuroblastoma N2A cultures. We tested this effect in 14 GWI patients and found that IgG exerted a potent ameliorating effect by inhibiting the reduction in growth and increased apoptosis of GWI serum. These results lend support to our persistent antigen hypothesis^1,2 and suggest an immunotherapy approach for treating GWI. This approach is further strengthened by our finding that the severity of GWI neurocognitive/mood (NCM) symptoms was positively correlated with the degree of apoptosis caused by GWI serum on the neural culture, thus validating the relevance of the apoptotic effect to NCM symptomatology. Finally, we used this relation to predict NCM scores based on the reduced apoptosis effected by IgG addition and found a predicted reduction in NCM symptom severity by ~60%. Altogether, these findings point to the possible beneficial use of IgG in treating GWI.

Nobuko Inoue^{1, 2}, Hitoshi Sakano²*

¹Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

²Department of Brain Function, University of Fukui School of Medicine, 23-3 Shimo-aizuki, Matsuoka, Fukui 910-1193, Japan

Odorant molecules are detected by olfactory sensory neurons (OSNs) in the olfactory epithelium. Odor information is then transmitted to the olfactory cortex through synapses with mitral/tufted (M/T) cells. We recently analyzed a pair of signaling molecules, Semaphorin (Sema) 7A expressed in OSN axons and its receptor Plexin (Plxn) C1 localized to M/T-cell dendrites. In the knockout mice for Sema7A or PlxnC1, initiation of synapse formation is perturbed. Rescue and reconstitution experiments demonstrated that interactions of Sema7A and PlxnC1 are essential to induce the post-synaptic assembly. Pharmacological blocking of NMDA receptors indicated that synaptic transmission induces primary-dendrite selection after the synapses are formed. We conclude that Sema7A/PlxnC1 signaling is key for initiating synapse formation followed by dendrite selection in M/T cells. Since other Sema molecules are known to regulate targeting of OSN axons without involving neuronal activities, Sema7A is a unique example of Sema family proteins that regulates synapse formation and dendrite selection in an activity-dependent manner. Possible roles of Sema7A/PlxnC1 signaling will be discussed in the context of olfactory circuit formation in neonates.

A. S. M. Ali Reza¹, Mst. Samima Nasrin¹, A. H. M. Khurshid Alam²*

¹Department of Pharmacy, Faculty of Science and Engineering, International Islamic University, Chittagong, Bangladesh

²Department of Pharmacy, University of Rajshahi, Bangladesh

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder of the brain characterized by memory loss and, impaired judgment and language use. As AD incidence increases with age, AD has become a large socioeconomic burden that will only continue growing as populations age. Natural compounds that possess polyphenolic (phenolics and flavonoids) content and antioxidant property have the capacity to reduce the progression and symptoms of neurodegenerative diseases, including AD. In this mini-review, we emphasize the pathomechanisms of AD, including oxidative stress and modulatory roles of natural antioxidants in preventing AD. We discuss the antioxidant, phytochemical, and anticholinesterase properties of the plant Elatostema papillosum, which are relevant to the management of AD.

Bernhard J. Mitterauer*

Volitronics-Institute for basic research and psychopathology, Salzburg, Austria

A model of imbalances in tripartite synapses responsible for the pathophysiology of mental disorders and epilepsy is reviewed. A tripartite synapse consists of the presynapse and the postsynapse as the neuronal component and the astrocyte as the glial component. Based on a formalism of system-balancing it is hypothesized that the expression of astroglial receptors determines imbalances of neurotransmission. In depression, tripartite synapses are imbalanced since neurotransmitters cannot activate the overexpressed astroglial receptors in the time leading to a prolonged neurotransmission. Inversely, in mania the imbalance of tripartite synapses is caused by a surplus of neurotransmitters overactivating underexpressed astroglial receptors causing a shortened neurotransmission. If astroglial receptors are non-functional, they cannot be activated by neurotransmitters leading to an unconstrained neurotransmission responsible for schizophrenia. In epilepsy, astroglial receptors are overexpressed, but glutamatergic synapses are hyperactivated and GABAergic synapses are hypoactivated causing an imbalance between excitatory and inhibitory tripartite synapses responsible for epileptogenesis. It is suggested that common imbalances of astroglia-synapse interactions may be responsible for mental disorders and epilepsy.

Deborah R. Gustafson^1,2*

¹Department of Neurology, State University of New York, Downstate Medical Center, New York, USA

²Department of Health and Education, University of Skövde, Sweden

Michaela T. Haindl¹, Muammer Ücal², Franz Fazekas¹, Sonja Hochmeister^1*

¹Department of Neurology, Medical University Graz, Auenbruggerplatz 22, 8036 Graz, Austria

²Research Unit of Experimental Neurotraumatology, Department of Neurosurgery, Medical University Graz, Auenbruggerplatz 29, 8036 Graz, Austria

Success in developing new drugs for diseases often depends on laboratory research usually involving animal models. For the early disease phases of multiple sclerosis (MS) this prerequisite was given by experimental autoimmune encephalomyelitis (EAE), an animal model which reflects the pathophysiological mechanisms of the disease quite well. Only a few models resemble cellular features of the progressive disease form of MS (like cortical demyelination) and if they do observable lesions are rather sparse and short lived. The lack of suitable animal models delayed and complicated drug development. Recently a few promising animal models reassembling many characteristics of progressive MS have been described aiming at both a better understanding of cellular mechanisms of this disease phase as well as the development of new therapeutic options. The authors of new rat models postulate novel findings of cortical pathology summarized in this article. The models differ in their focus and not all distinct models are reflecting all features of progressive MS but together they allow research on different aspects of the disease and offer the opportunity to expand our knowledge and clear the way for drug development.

Karla Cervantes Gracia¹, Holger Husi^2,3*

¹University of Monterrey, Health Sciences Division, Monterrey, 66238, Mexico

²Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, G12 8TA, UK

³Department of Diabetes and Cardiovascular Science, University of the Highlands and Islands, Centre for Health Science, Inverness, IV2 3JH, UK

William K. Summers^1*, Roy L. Martin¹, Yimeng Liu², Bernice Peña¹, Gary M. Marsh²

¹Alzheimer’s Corporation,6000 Uptown Blvd, Suite 308, Albuquerque, NM 87110, USA

²Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, University of Pittsburgh, A410 Crabtree Hall, 130 DeSoto St, Pittsburgh, PA 15261, USA

Curtis Osborne*, John Paul Taylor, Alan J. Thomas

Institute of Neuroscience, Biomedical Research Building, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK

Melita Salkovic-Petrisic*

Department of Pharmacology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia

Incretin-based drugs originally developed for the treatment of type 2 diabetes mellitus are currently under investigation for their therapeutic potential in sporadic Alzheimer’s disease (AD). Two major incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which both additionally have neuroprotective, neurotrophic and neurogenesis-promoting effects upon the stimulation of GLP-1 and GIP receptors in the brain. This review points out another approach to the incretin-related sAD therapy based on the therapeutic potential of oral galactose in a streptozotocin-induced rat model of sporadic AD (STZ-icv model). Chronic oral galactose treatment prevents the development and ameliorates already developed cognitive deficits in the early stage of sAD-like pathology in STZ-icv rat model. The underlying mechanism(s) of these beneficial effects might be related to stimulation of endogenous GLP-1-mediated central effects and normalization of cerebral glucose hypometabolism as well as other oral galactose-induced effects along the oro-gastro-intestinal tract. The beneficial effects on cognitive impairment seem to depend on galactose exposure, presence and stage of sAD-like pathology. Further research is needed to clarify therapeutic potential and safety profile of oral galactose treatment as well as its possible advantages over or synergistic activity with the GLP-1 analogues and inhibitors of dipeptidyl peptidase-4.

Martin Berli*, Lazaros Vlachopoulos, Sabra Leupi, Thomas Boeni, Charlotte Vlachopoulos-Baltin

Department of Orthopedicsn University Hospital Balgrist Zurich, Switzerland

A brief review of the above-mentioned article: forty patients with 43 affected feet and 60 cases of osteomyelitis were included in this study. They were split into two groups, one with osteomyelitis outside and another one with osteomyelitis within the active Charcot region. The results showed that the amputation rate did not differ between the two groups, although in group 1 – osteomyelitis outside the active Charcot region.

amputations were exclusively performed at the forefoot and in group 2 – with osteomyelitis within the active Charcot region – exclusively in the mid- and hindfoot. Amputations in group 2 were, therefore, more high level. The duration of immobilization and antibiotic treatment was significantly longer in group 2. We conclude, that patients treated for osteomyelitis in an active Charcot foot should be considered and treated as separate entities, depending on whether the osteomyelitis is located within or outside the active Charcot region. If osteomyelitis occurs outside the active Charcot region, primary amputation may be preferred to internal resection.

Friederike Auer*

¹Department of Animal Physiology, Centre for Organismal Studies, University of Heidelberg, Heidelberg, Germany

Cerebellar ataxias are characterized by a disturbance of motor coordination and learning. To understand the molecular mechanisms underlying especially hereditary cerebellar ataxias, many mouse models, often with altered Purkinje cell firing, have been studied in the past decades. Of particular interest were mouse lines with mutations in ion channels or their ligands. In this context, a recently described ANO2^-/- mouse line has been reported to show a variety of ataxic symptoms, ranging from gait abnormalities and problems in motor coordination to severely impaired motor learning. These mice lack the calcium-gated chloride channel Anoctamin 2 (ANO2). First studies, focusing on the molecular mechanisms underlying the ataxic phenotype of ANO2^-/- mice, indicate an involvement of ANO2 in two different processes in the neuronal network of the cerebellar cortex. Both mechanisms are thought to modulate the firing pattern of cerebellar Purkinje cells and could, therefore, explain the ataxic phenotype of ANO2^-/- mice. This review summarizes the so far obtained data regarding the role of ANO2 in the coordination and learning of movements.

Pawan Agarwal^1*, Dhananjaya Sharma²

Plastic Surgery Unit, Department of Surgery, NSCB Government Medical College, Jabalpur, MP, India

Acontractile bladder is very common after spinal cord injury which may lead to morbidity and even renal failure. The standard treatment options to facilitate bladder emptying include clean intermittent catheterization (CIC) or indwelling catheter (IC), which is also not free of complications. The purpose of this article is to review the treatment options for acontractile bladder; especially feasibility and effectiveness of muscle wrap around urinary bladder to improve voluntary voiding. We performed Rectus Abdominis Detrusor Myoplasty (RADM) in 5 patients of acontractile bladder following spinal cord injury. Postoperatively, all 5 patients could void urine immediately after removal of per-urethral catheter after 3 weeks. After RADM, Post Void Residual Volume, Bladder Contractility Index, Detrusor Pressure and urine flow rate (V-max) improved significantly (p < 0.05) in all patients. Rectus Abdominis Detrusor Myoplasty is a promising surgical option in a patient having hypocontractile or acontractile urinary bladder. In this mini review RADM and other treatment options for acontractile bladder have been reviewed.

Felipe Ortega^1,2,3*

¹Biochemistry and Molecular Biology Department, Faculty of Veterinary medicine, Complutense University, Madrid, Spain

²Institute of Neurochemistry (IUIN), Madrid, Spain

³Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Spain

Live imaging and single cell tracking enables researchers to monitor crucial aspects of the biology of neural populations. In this commentary, we highlight the requirements, applications, and limitations of a protocol recently published by our research group. This protocol involves adapting the culture of several types of neural cells to time-lapse video microscopy, and the post-processing of the data to track distinct cell populations.

Mario Gonzalez-Gronow^{1, 2*}, Salvatore V. Pizzo²

¹Department of Biological Sciences, Laboratory of Environmental Neurotoxicology, Faculty of Medicine, Universidad Católica del Norte, Coquimbo, Chile

²Department of Pathology, Duke University Medical Center, Durham, NC, USA

Catalytic autoantibodies with proteinase enzymatic activity against myelin basic protein (MBP) are a distinctive feature of several autoimmune disorders. These autoantibodies, named abzymes (Abz), have both antibody and proteinase activity in a single molecule. Abz targeting MBP (MBP Abz) are commonly found in sera from multiple sclerosis (MS) and systemic lupus erythematosus (SLE) patients, and only recently have been identified in sera from autism spectrum disorder (ASD) patients. Their activities and specificity are similar in MS and SLE; however, although they recognize the same substrate, MBP, the catalytic activity of the Abz from autism spectrum disorder patients is controlled by different proteinase inhibitors. MBP Abz are generated as part of a process started by loss of compaction of myelin due to changes in charge after deamination of arginyl residues in MBP by the enzyme peptidylarginine deiminase. This exposes a normally hidden surface of MBP to T-cells initiating the autoimmune response. A large body of evidence suggests that MBP Abz play an important role in the pathogenesis not only of MS and SLE, but also of ASD. Many autoantibodies found in MS and SLE are also observed in healthy individuals at ranges usually considered pathological; however, clinical signs of the disease are not manifested, suggesting that expression of single autoantibodies may be inconsequential to develop the disease. However, it is the expression of hundreds of different autoantibodies, in addition to MBP Abz, that collectively lead to the clinical development of MS and SLE.

Roberto Rodriguez-Jimenez^1,2,3*, Eugenio Blázquez⁴, Antonio Lobo^2,5, José Luis Santos^2,6

¹Department of Psychiatry, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain

²CIBERSAM (Biomedical Research Networking Centre in Mental Health), Spain

³CogPsy-Group, Universidad Complutense de Madrid (UCM), Madrid, Spain

4Department of Oftalmology, Hospital Universitario 12 de Octubre, Madrid, Spain

⁵Department of Psychiatry, Universidad Zaragoza, Instituto de Investigación Sanitaria Aragón

⁶Department of Psychiatry, Hospital Virgen de La Luz, Cuenca, Spain

Optical coherence tomography (OCT) is a non-invasive imaging technique recently used to investigate neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease or multiple sclerosis. Over the last years it has been used in schizophrenia research due to the potential utility of its measurements as biomarkers of the disease. From the first publication by Ascaso et al. (Eur J Psychiat. 2010) until now, a number of papers have been published regarding this topic. Although the majority of them have found a reduction in the thickness or the volume of some retinal and optic nerve structures, there have also been some results with contradictory data. These could be due on the one hand to methodological factors such as the use of different OCT devices or the inclusion/exclusion criteria. On the other hand, there could be an important limitation due to the fact that the different stages of the disorder and their different neurobiological correlates and biomarkers were not taken into consideration. Future longitudinal studies, that begin the assessments in the first psychotic episode (or even before, in ultra-high risk population) are needed in order to clarify the potential role of some OCT measures as biomarkers in schizophrenia.

Jong Han Lee^1,2, Sahar Eshghjoo³, Jon Davis⁴, Robert C. Alaniz³, Yuxiang Sun^2,5*

¹College of Pharmacy, Gachon University, Incheon, Gyeonggi, Korea

²Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

³Department of Microbial Pathogenesis and Immunology, Texas A&M University, Health Science Center, College Station, TX, USA

⁴Integrative Physiology and Neuroscience, Washington State University, Pullman WA, USA

⁵Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA

Obesity is defined as excessive fat accumulation caused by the imbalance of energy intake versus expenditure. Low-grade chronic inflammation is a hallmark of obesity, and it is closely linked to insulin resistance. Obesity-induced inflammation and its associated metabolic dysfunctions underlay pathological processes of many chronic diseases such as insulin resistance, diabetes, sarcopenia and cardiovascular disease. Ghrelin is the only known circulating orexigenic hormone; it stimulates growth hormone release, and increases adiposity and insulin resistance. Ghrelin’s functions are mediated through its receptor, growth hormone secretagogue receptor (GHS-R). The brain plays a critical role in energy homeostasis and energy metabolism. GHS-R is primarily expressed in the brain; the brain is a key ghrelin targeting site. The current review discusses the insights we have gained from global GHS-R knockout mice and neural conditional GHS-R knockout mice, specifically involving the roles of GHS-R in food intake, feeding adaptation, thermogenesis, meta-inflammation, and physical activity.