Vol 3-5 Commentary

A Future Direction for Treatment of Alzheimer's Disease via the Oxidative Injury Theory

William K. Summers1*, 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

DOI: 10.29245/2572.942X/2018/5.1215 View / Download Pdf
Vol 3-5 Commentary

Commentary: Integrative Analysis of Multiple Sclerosis Using a Systems Biology Approach

Karla Cervantes Gracia1, Holger Husi2,3*

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

DOI: 10.29245/2572.942X/2018/5.1210 View / Download Pdf
Vol 3-5 Mini Review

Overview of Promising Rat Models for Cortical Lesion Research- 2006 Until Now

Michaela T. Haindl1, Muammer Ücal2, Franz Fazekas1, Sonja Hochmeister1*

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.

DOI: 10.29245/2572.942X/2018/5.1218 View / Download Pdf
Vol 3-5 Opinion Article

Epidemiology Informs Randomized Clinical Trials of Cognitive Impairments and Late-Onset, Sporadic Dementias

Deborah R. Gustafson1,2*

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

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

DOI: 10.29245/2572.942X/2018/5.1220 View / Download Pdf
Vol 3-5 Mini Review

Phytochemicals, Antioxidants, and Cholinesterase Inhibitory Profiles of Elatostema Papillosum Leaves: An Alternative Approach for Management of Alzheimer's Disease

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.

DOI: 10.29245/2572.942X/2018/5.1211 View / Download Pdf
Vol 3-5 Research Article

Human Immunoglobulin G (IgG) Neutralizes Adverse Effects of Gulf War Illness (GWI) Serum in Neural Cultures: Paving the Way to Immunotherapy for GWI

Effie-Photini C. Tsilibary1,2, Eric P. Souto1, Lisa M. James1,2, Brian E. Engdahl1,2, Apostolos P. Georgopoulos1,2*

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 hypothesis1,2 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.

DOI: 10.29245/2572.942X/2018/5.1219 View / Download Pdf
Vol 3-5 Commentary

Commentary: Octopamine Drives Endurance Exercise Adaptations in Drosophila

Kristin A Richardson1, Robert J Wessells1*

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

DOI: 10.29245/2572.942X/2018/5.1224 View / Download Pdf
Vol 3-5 Mini Review

Sema7A Signaling is Essential for Activity-Dependent Synapse Formation in the Mouse Olfactory Bulb

Nobuko Inoue1, 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.

DOI: 10.29245/2572.942X/2018/5.1223 View / Download Pdf
Vol 3-5 Review Article

Brilaroxazine (RP5063) Clinical Experience in Schizophrenia: "A New Option to Address Unmet Needs"

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 D2/3/4 and 5-HT1A/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 (Cmax) 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.

DOI: 10.29245/2572.942X/2018/5.1225 View / Download Pdf
Vol 3-5 Short Communication

The Effects of Arginine Vasopressin and Acetazolamide on CNS Clearance of Acetaminophen and Ibuprofen in Rats

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 (Kp,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_plasmaC ratio (Kp,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 CSFAUC0-5hr/unbound_plasmaAUC0-5hr ratio from 1.63 to 0.85 for acetaminophen, and the CSFC4hr / unbound_plasmaC4hr 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.

DOI: 10.29245/2572.942X/2018/5.1217 View / Download Pdf
Vol 3-5 Mini Review

Imbalances of Tripartite Synapses Responsible for the Pathophysiology of Mental Disorders and Epilepsy

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.

DOI: 10.29245/2572.942X/2018/5.1216 View / Download Pdf