Volume Articles

Karenitecin (bnp1350) and flavopridol as radiosensitizers in malignant glioma

Deepika Rajesh, H. Ian Robins*, Steven P. Howard

The poor prognosis of malignant glioma patients highlights the need to develop low toxicity, tumor specific agents with the ability to synergize with proven efficacious treatment modalities, e.g., ionizing irradiation. This paper investigates the potential of BNP1350 (karenitecin), a topoisomerase I-targeting anticancer agent, and flavopridol a cyclin-dependent kinase inhibitor as radiosensitizers at clinically relevant doses in glioblastoma cell lines. A clonogenic survival and apoptosis assays were performed to test the effect of karenitecin (0.1 nM to 10 nM), flavopridol, (50 nM to 500 nM), radiation (1 Gy to 5.5 Gy) and a combination of radiation and karenitecin or radiation and flavopridol on the glioma cell lines T986 and M059K. Cells were stained for cyclins B and D using antibodies followed by flow cytometry. Propidium Iodide staining was used to reveal the various phases of the cell cycle; cyclin staining in the G0/G1 and G2/M phase of the cell cycle was estimated as the Mean Fluorescence Intensity (MFI) after subtracting the MFI recorded by the isotype controls. Results demonstrated that in irradiated cells, pretreatment with karenitecin induced apoptosis, a transient arrest in the G2/M phase of the cell cycle and increased the expression of cyclin B1. Flavopridol treatment also induced apoptosis and a transient block in the G2/M phase of the cell cycle. The combined effects of karenitecin and flavopridol displayed synergistic effects. The unique radiosensitizing activity of orally administrable karenitecin and flavopridol is consistent with continued investigation of these compounds preclinically, as well as in the clinical setting.

Treatment of aneurysms of the extracranial carotid artery: current evidence and future perspectives

GJ de Borst*, V.E.C. Pourier

Commentary on the NeBoP score - a clinical prediction test for children with Lyme neuroborreliosis

Barbro H Skogman^1*, Johanna Sjöwall², Per-Eric Lindgren³

Enhancement of Local Retionic Acid Signaling: A Pivotal Mechanism in Fluoxetine's Pleiotropic Actions

Vera Clemens, Francesca Regen, Julian Hellmann-Regen*

Major depression (MDD) is one of the leading global causes of all non-fatal burden of disease. Involving monoaminergic imbalances, but also hormonal, structural and inflammatory alterations, the underlying pathogenesis remains incompletely understood. The antidepressant drug fluoxetine, which may be considered the “prototype” of all selective serotonin reuptake inhibitors (SSRI), appears to affect all of these processes. Interestingly, this is also the case for retinoic acid (RA), the highly potent active metabolite of vitamin A. In this review, we discuss RA signaling as a central mechanism of action – and missing link – for the multiple, pleiotropic effects of fluoxetine in the CNS, suggesting that direct inhibition of CYP-450-mediated RA catabolism by fluoxetine results in increased local concentration, and enhanced paracrine RA signaling in the CNS.

Commentary: Serotonin Receptor 2B Mediates Mechanical Hyperalgesia by Regulating Transient Receptor Potential Vanilloid 1

Yeu-Shiuan Su^1*, Wei-Hsin Sun^1,2*

Serotonin [5-hydroxytryptamine (5-HT)] is an inflammatory mediator which contributes to inflammatory pain. We previously demonstrated that 5-HT-induced mechanical hyperalgesia is mediated by 5-HT2B, but not by other 5-HT receptors. Our recent article provided further evidence how 5-HT2B regulates 5-HT-induced mechanical hyperalgesia, and suggested, that 5-HT2Bmediates mechanical hyperalgesia through Gq/11-phospholipase Cβ (PLCβ)-protein kinase Cε (PKCε) pathway. Interestingly, transient receptor potential vanilloid 1 (TRPV1) also involves in 5-HT2B-mediated hyperalgesia. It was the first evidence that 5-HT receptor regulates TRP channel to affect mechanical hyperalgesia. It is a commentary on the recent article that suggests distinct roles of peptidergic (IB4-negative) and non-peptidergic (IB4-positive) nociceptors in regulating 5-HT-induced mechanical hyperalgesia. In IB4-negative neurons, 5-HT2B in response to 5-HT mediates PLCβ-PKCε to regulate TRPV1 function. In IB4-positive neurons, 5-HT2B may control 5-HT3 or other channels to regulate mechanical hyperalgesia.

Commentary: Current status of intratumoral therapy for glioblastoma

Gregory D. Arnone¹, Matt Wonais², Andreas Linninger^1,3, Ankit I. Mehta^1*

On the "Neuroscience of Ethics" - Approaching the Neuroethical Literature as a Rational Discourse on Putative Neural Processes of Moral cognition and behavior

James Giordano^1,2*, Kira Becker^1,3, John R. Shook⁴

Neuroethics is a relatively new, yet ever expanding discipline, which focuses on the “neuroscience of ethics” and the “ethics of neuroscience”. In this essay, we discuss the literature describing the “neuroscience of ethics”. Current approaches to employing neuroscientific techniques and tools to elucidate brain processes serving ethical decision making has evolved from prior psychological studies of how and why humans believe and act in ways deemed to be moral. While a number of neuroanatomical pathways have been defined as participatory in certain types of decision-making, it appears that none are exclusively dedicated to moral cognition or actions. Moreover, attempts at enhancing morality through neurological interventions are plagued by differing constructs of what constitutes moral action in various contexts. Herein, we review developments in neuroscientific studies of morality, and present a rational view of the capabilities, limitations and responsibilities that any genuine neuroethical address and discourse should regard.

An omic approach to spinal cord injury mechanisms

Erna A. van Niekerk^*

 Spinal cord injury (SCI) research continues to make substantial progress in identifying both neuron-intrinsic and neuron-extrinsic mechanisms that limit central nervous system (CNS) plasticity and regeneration. The identification of these mechanisms has in turn led to several novel strategies for therapeutically enhancing recovery of the injured CNS. Despite this progress, clinical translation remains a challenge for several reasons, including: 1) problems in projecting beneficial outcomes from small animal models to primate systems, 2) a lack of robust improvement in functional outcomes in animal models, and 3) difficulty replicating published reports in the field. Collectively, while the field has seen great progress, reconstructing the exquisite circuitry of the injured human CNS will require yet greater progress in both understanding of basic mechanisms underlying axonal growth and guidance, and testing of optimized therapies in models more predictive of potential human benefit.

Cerebral Microvascular Injury in Traumatic Brain Injury

Kimbra Kenney, Margalit Haber, Franck Amyot, Cora Davis, Angela Pronger, Carol Moore, Ramon Diaz-Arrastia*

Traumatic cerebral vascular injury (TCVI) is a frequent, perhaps universal, feature after traumatic brain injury (TBI) and may be responsible for some TBI-related chronic disability. Because there are multiple pharmacologic and non-pharmacologic therapies that promote vascular health, TCVI is an attractive target for therapeutic intervention after TBI. The cerebral microvasculature (CMV) is a component of the neurovascular unit (NVU) coupling neuronal metabolism with local cerebral blood flow. The NVU participates in the pathogenesis of TBI, either directly from physical trauma or as part of the cascade of secondary injury that occurs after TBI. Pathologically, there is extensive microvascular injury in humans and experimental animals, identified with either conventional light microscopy or ultrastructural examination. It is seen in acute and chronic TBI and even described in chronic traumatic encephalopathy (CTE). Non-invasive, physiologic measures of cerebral microvascular function show dysfunction after TBI in humans and experimental animal models of TBI. These include imaging sequences Arterial Spin Labeling (ASL), Transcranial Doppler, Near InfraRed Spectroscopy (NIRS), etc. Understanding the pathophysiology of TCVI, a relatively under-studied component of TBI, has promise for developing novel TBI therapies.

Promises and pitfalls of cannabinoids as agents with potential anticancer efficacy

Lara A. Haeusser, Lothar Kanz, Marcus M. Schittenhelm, Kerstin M. Kampa-Schittenhelm^*

The endocannabinoid system is extensively studied in neuroscience and clinical use of cannabinoid derivatives as substances with remarkable spasmolytic effects in multiple sclerosis and antiemetic potential in cancer therapy as well as pain-relieving properties is broadly acknowledged.

However, it becomes increasingly apparent, that in addition cannabinoids exert manifold functions in various organ systems, such as the immune system, the reproductive or cardiovascular system among others. Moreover, interactions with signaling pathways involved in programmed cell death, angiogenesis, metastasis or anti-tumor immunity make it highly suggestive that cannabinoids may have therapeutic potential in the treatment of cancer. Indeed, detailed reports have repeatedly shown anticancer efficacy in solid and hematologic tumor models, best characterized in human gliomas.

Anecdotal evidence of blast control in a young patient with acute myeloid leukemia has led us to systematically investigate the potential use of cannabinoids in the treatment of acute leukemia.

Owing to the critical cellular role of lysosomes in the myelination, mounting studies focus on the mechanisms underlying exocytosis of lysosome in nervous system has emerged. In this paper, we briefly introduce the recent advances in this respect.

These data are summarized herein in the context of key data regarding anticancer efficacy of cannabinoids.

Primary age-related tauopathy and the amyloid cascade hypothesis: the exception that proves the rule?

John F. Crary

Extensive data supports the amyloid cascade hypothesis, which states that Alzheimer’s disease (AD) stems from neurotoxic forms of the amyloid-beta(Aβ)peptide. But the poor correlation between Aβ plaques and neurodegeneration/cognitive impairment, the spaciotemporal disparity between Aβ and tau pathology, and the disappointing results following several large clinical trials using Aβ-targeting agents are inconsistent with this explanation. The most perplexing inconsistency is the existence of AD-type dementia patients that develop abundant neurofibrillary tangles that are indistinguishable from those in early to moderate-stage AD in the absence of compelling evidence of amyloid toxicity. This neuropathological phenotype, which is distinct from other diseases with tangles, represents a conceptual disconnect, because it does not fall within any previously established category of tauopathy and ostensibly invalidates the amyloid cascade hypothesis. Instead, recent efforts have led to consensus criteria for a new alternative diagnostic category, which presupposes that these tangle-only dementia patients represent extreme examples of a distinct primary age-related tauopathy (PART) that is universally observed, albeit to varying degrees, in the aging brain. The cause of PART is unknown, but sufficient evidence exists to hypothesize that it stems from an Aβ-independent mechanism, such as mechanical injury. Should the PART hypothesis withstand further experimental testing, it would represent a shift in the way a subset of subjects with AD neuropathological change are classified and has the potential to focus and reaffirm the amyloid cascade hypothesis.

Clinical commentary: Systemic and subclinical adverse effects of repeated botulinum toxin a injections to decrease spasticity in adults affected by stroke undergoing rehabilitation

Maria Amelia Chang

This is a clinical commentary that expands on an initial attempt to classify possible adverse effects (AE) of repeated and long-term use of Botox A (BTX) to manage post-stroke spasticity into three types, local, systemic and subclinical AE. Clinical manifestations of non-local, systemic AE from widespread diffusion of BTX are presented to help clinicians and researchers recognize changes that may develop in post-stroke patients. Subclinical AE of muscle atrophy and bone degradation may hinder return of motor control and increase certain risk factors. Even with increased trend in the use of BTX, very little is written about long term effects of repeated BTX injections for post-stroke spasticity coupled by fewer clinicians who report what they find in actual practice. Although published studies infrequently report AE, it will be an error if it is attributed to an extension of the disease process in stroke.

Biochemical and anatomical basis of brain dysfunctions caused by cytochrome b5 reductase deficiency or dysregulation

Alejandro K. Samhan-Arias^1*, Carmen López-Sánchez^2*, Dorinda Marques-da-Silva¹, Ricardo Lagoa^1,2,3Virginio Garcia-Lopez^2,4, Virginio García-Martínez²Carlos Gutierrez-Merino^1,#

Cytochrome b5 reductase (Cb5R) and cytochrome b5 (Cb5) are coupled redox systems with a high potential as biomarkers of health and disease in the brain because they regulate metabolic pathways that are essential to maintain normal neuronal function, like lipid biosynthesis, steroid and xenobiotics metabolism, neuronal bioenergetics and production of reactive oxygen species. Mutations of the Cb5R reported in humans produce recessive congenital methemoglobinemia of type II, a disease with severe clinical neurological dysfunctions. The isoform 3 of Cb5R (Cb5R3) and Cb5 are highly expressed in pyramidal neurons of the primary and secondary motor areas of frontoparietal cerebral cortex, hippocampus, vestibular, reticular and motor nuclei of the cerebellum and brain stem, and also in Purkinje and granule neurons of the cerebellum cortex. These brain areas are highly prone to undergo oxidative stress-induced neurodegeneration and their functional impairment can account for neurological deficits reported in type II congenital methemoglobinemia.

An Overview of Arachnoid Webs

Rohit Aiyer^1*, Lynne Voutsinas², Yasir El-Sherif³