All Articles

Hannah C. Saternos¹ and Wissam A. AbouAlaiwi¹*

¹University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology and Experimental Therapeutics, Toledo, Ohio, USA

Lisa M. James^1,2,3, Brian E. Engdahl^1,2,4, Rachel A. Johnson¹, Apostolos P. Georgopoulos^1,2,3,4,5*

¹Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 5541, 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 Psychology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

⁵Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Gulf War Illness (GWI) is a chronic multi-system condition that has affected one-third of U.S. veterans who served in the Persian Gulf. Although GWI etiology remains unclear, mounting evidence points to immune system involvement and inflammation, in particular, as underlying the host of symptoms associated with the condition. Here we investigated the association between GWI symptoms and C-reactive protein (CRP), a marker of inflammation, in 76 veterans with GWI. Results indicated a highly significant positive association between CRP and mean GWI symptom severity. At the symptom domain level, CRP was significantly and positively associated with Pain, Neurocognitive/Mood, Fatigue, and Respiratory symptom severity but not with Skin or Gastrointestinal symptom severity. These results support the premise that GWI symptoms, particularly those implicating brain involvement, are a result of neuroinflammation. The cause for inflammation is not known. We have hypothesized that at the root of GWI are harmful persistent antigens stemming from environmental exposures associated with service during the Gulf War that could not be successfully eliminated due to lack of specific immunity^1,2. Work is underway in our laboratory to identify and eliminate persistent antigens in veterans with GWI which we anticipate will result in reduced inflammation and reduced GWI symptoms.

Ashutosh Gupta¹*, Suman Kushwaha²

¹Department of Neurology, Institute of Human Behavior and Allied Sciences, Delhi, India

F. Haour¹*, E. Dobbelaere^1,2, C. de Beaurepaire³

¹EMDR France Association, 9 rue Papillon, 75009 Paris, France

²Université Paris 5, 75006 Paris, France

³EPS of Maison-Blanche, 6-10, Pierre-Bayle Street, 75020 Paris, France

Palalle G. Tharushi Perera¹, Olha Bazaka², Kateryna Bazaka³, Dominique Appadoo⁴, Rodney J. Croft⁵, Russell J. Crawford², Elena P. Ivanova²*

¹Faculty of Science, Engineering and Technology, Swinburne University of Technology, PO Box 218, Hawthorn, Vic 3122, Australia

²School of Science, RMIT University, PO Box 2476, Melbourne, Vic 3001, Australia

³Institute for Future Environments, Queensland University of Technology, GPO Box 2434. Brisbane, QLD 4001, Australia

⁴THz/Far-Infrared Beamline, Australian Synchrotron, Clayton, VIC 3168, Australia

⁵School of Psychology, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia

Pheochromocytoma PC 12 cell line is an established model system for neurosecretion and neuronal differentiation, particular to study cellular responses to nerve growth factors (NGF) and how these lead to expression of differentiation-specific proteins and differentiation. More recently, PC 12 has become a model system for investigating cell membrane permeabilization and cell attachment on different substrata. Of particular interest is the use of PC 12 to study the fundamental responses of cells to electromagnetic fields (EMFs) of 18 GHz and THz in the range of 0.3-19.5×1012 Hz, a type of radiation treatment shown to induce membrane depolarization and transient increase in permeability with no changes in cell viability, morphology, proliferation and cellular physiology. This makes EMFs of 18 GHz and THz radiation a promising alternative to conventional poration techniques for drug and gene delivery applications. This article will review recent progress in the use of PC 12 to investigate EMF radiation-induced cell membrane permeability, as well as to study mammalian cell attachment preferences and differentiation on polymer surfaces, including those coated with high molecular weight proteins of the extracellular matrix, e.g. laminins, poly-l-lysine, fibronectin, and on novel metallic surfaces of nanostructured titanium.

Yoshikuni Mizuno

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan

In 2018, we wrote a paper on the drug treatment of Parkinson's disease. In this article, we obtained that the wearing off was observed in 77%, but the incidence of dyskinesia was 37.7% for the Parkinson?s disease patients from the onset of the disease 16-20 years. In this review article, we will discuss some of the newer treatments of Parkinson?s disease first, i.e., transplantation with induced pluripotent stem cell-derived cells, gene therapy, deep brain stimulation, levodopa/ carbidopa intrajejunal gel infusion, MRI-supported focused ultrasound, and IPX066. Then, we will discuss our opinion on the mechanism of wearing off and dyskinesia, and modifications of levodopa treatment after the wearing off sets in.

Marianna Stamou¹, Pamela J Lein²

¹1Department of Molecular Biosciences, School of Veterinary Medicine, 1089 Veterinary Medicine Drive, University of California, Davis, CA 95616

²2ETH Zurich, Department of Health Sciences and Technology, Institute of Molecular Systems Biology, 8093 Zürich, Switzerland

Monica Ines¹, Joao Costa^1,2,3*

¹Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal

²Laboratório de Farmacologia Clínica e Terapêutica, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal

³Centro de Estudos de Medicina Baseada na Evidência, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal

Transthyretin-associated familial amyloid polyneuropathy (TTR-FAP) is a neurological disease that affects severely patients and their families and caregivers over generations. It is a rare, progressive, and if untreated fatal autosomal dominant hereditary disorder. The disease may affect multiple organ systems and if untreated progress rapidly to death. TTR-FAP affects nearly 10,000 people worldwide, with known endemic regions in Portugal, Sweden, and Japan. Until recently only liver transplantation and tafamidis were treatment options across several world regions. Despite the worldwide use of these disease-modifying treatments to delay disease progression, challenges in clinical assessment and management remain because of disease heterogeneity, phenotypic diversity, small patient populations, incomplete natural history and uncertainty of treatment effect in survival. The two new treatment options (inotersen and patisiran) appear to provide important benefits for patients, based on clinical trials short-term evidence. In this review, we discuss the disease natural survival course and currently available treatments impact on survival. We also discuss the importance of treatment choice (and or sequence of treatments) to maximize survival, while preserving the patient’s health-related quality of life.

Tehila Beiser, Rami Yaka*

Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel

Cocaine is a powerfully addictive psychostimulant that elevates dopamine (DA) levels in the mesolimbic system and causes a feeling of wellbeing. At the same time, cocaine leads to toxic effects in many essential organs, including the brain. The harmful effects of cocaine on the brain are the basis for the development of compulsive and irrational behaviors, an integral part of cocaine addiction. Over the last two decades, it has been suggested that the damage and reinforcing properties of cocaine are associated with increased reactive oxygen species (ROS) production. This increase impairs the endogenous defense antioxidant system, either directly by cocaine metabolites, or indirectly via increased DA metabolites, resulting in oxidative stress (OS). It was thus plausible to seek an exogenous, stable and non-toxic antioxidant, which can penetrate the blood brain barrier and counteract the oxidative damage in the brain caused by drugs of abuse such as cocaine. In this mini-review we describe studies that explore the role of antioxidants in reducing the OS state in the brain reward system and consequently reversing negative behavioral outcomes induced by cocaine.

John Grizzanti¹, Rachel Corrigan¹, Spencer Servizi¹, Gemma Casadesus^1,2*

¹School of Biomedical Sciences, Kent State University, Ohio, USA

²Department of Biological Sciences, Kent State University, Ohio, USA

Growing evidence highlights the intimate relationship between type II diabetes (T2D) and Alzheimer’s disease (AD). Importantly, these two diseases share a number of pathological similarities, including amyloid accumulation, oxidative stress, inflammation, and cell death. To date, drug therapies for AD and T2D are lacking and there is a crucial need for the discovery and development of novel therapeutics for these diseases. A number of human and rodent studies have given evidence that metabolic hormone supplementation is highly valuable for improving cognitive function and overall metabolic health in both T2D and AD. The pancreatic hormone amylin has arisen as a crucial component of the disease etiology of both T2D and AD, though the exact role that amylin plays in these diseases is not yet well understood. Here, we critically review the current literature that utilizes human amylin or its synthetic analogue, pramlintide, as well as amylin receptor antagonists for the treatment of AD.

Genki Tohnai¹, Ryoichi Nakamura¹, Masahiro Nakatochi², Naoki Atsuta¹, Masahisa Katsuno¹, Gen Sobue^1,3*

¹Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

²Statistical Analysis Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan

³Research Division of Dementia and Neurodegenerative Disease, Nagoya University Graduate School of Medicine, Nagoya, Japan

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, and the etiology of sporadic ALS is unknown. The TANK-binding kinase 1 (TBK1) gene identified as an ALS gene, contributes towards a predisposition for ALS. In this review, we analyzed variants of TBK1 found in ALS cohort studies belonging to various regions and ethnic populations. TBK1 variants tend to be enriched in patients with ALS compared to patients without ALS. The frequency of TBK1 variants is more in the familial Caucasian than that in the Asian population. However, loss of function (LoF) variant associated with sporadic ALS is almost similar among the Asian group, including Japanese population. LoF variants were frequently reported to be associated with the TBK1 biology. These findings indicate that TBK1- LoF variants are pathogenic for ALS, regardless of race or region.

Renata M. Lataro¹, Helio C. Salgado²*

¹Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil

²Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

There is a consensus in the literature that the autonomic dysfunction in arterial hypertension involves the increase of sympathetic activity and, also, reduction of vagal tone. In the last years, the role played by inflammation in the development of hypertension and target organs injuries, such as heart and blood vessels, has been emphasized. Although the clinical importance of sympathetic hyperactivity and its treatment of arterial hypertension is recognized, the therapeutic benefit of increasing parasympathetic activity in hypertensive patients still requires an in-depth investigation. The increased vagal activity may produce beneficial effects on cardiovascular modulation and inflammation, preventing target organ damage. Parasympathetic neurotransmission can be improved by the inhibition of acetylcholinesterase action. Anticholinesterase agents prevent the hydrolysis of acetylcholine by acetylcholinesterase, prolonging its availability within the cholinergic cleft. This article will highlight the key concepts of the cardiac autonomic imbalance and the increase of acetylcholine availability under inflammation and control of arterial hypertension. In conclusion, significant evidence exists associating the reduction of parasympathetic activity and the occurrence of inflammation involving the pathophysiology of hypertension; suggesting that the improvement of vagal activity by the increased availability of acetylcholine has a remarkable potential for the therapeutic intervention on arterial hypertension.

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