Evolution of Neurotoxins: From Research Modalities to Clinical Realities

Kostrzewa, Richard M.

doi:10.1002/0471142301.ns0118s46

Cited by 9 publications

(4 citation statements)

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“…Also, it was shown that agmatine competitively inhibited the activity of all isoenzymes of NOS (Halaris & Plietz, 2007). One of the mechanisms of glutamate's neurotoxicity is an increased synthesis of NO (Montoliu et al, 2001), so the inhibition of NOS may be the way used by moxonidine in preventing the glutamate-induced neurotoxicity (Kostrzewa, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…A variety of factors including excitotoxicity, oxidative stress, growth factor withdrawal, cytokines, or toxins may cause neuronal cell damage leading to neurodegeneration. However, neuronal cell damage seems to be the most common result of excessive stimulation of ionotropic or metabotropic glutamate receptors (Kostrzewa, 2009). Glutamate is found naturally in millimolar levels in the brain and plays a dominant role in central excitatory neurotransmission.…”

Section: Introductionmentioning

confidence: 99%

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Protection in Glutamate-Induced Neurotoxicity by Imidazoline Receptor Agonist Moxonidine

Bakuridze

Savli

Gongadze

et al. 2009

International Journal of Neuroscience

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In the present study we investigated the effects of mixed imidazoline-1 and alpha(2)-adrenoceptor agonist, moxonidine, in glutamate-induced neurotoxicity in frontal cortical cell cultures of rat pups by dye exclusion test. Also, phosphorylated p38 mitogen activated protein kinases (p-p38 MAPK) levels were determined from rat frontal cortical tissue homogenates by two dimensional gel electrophoresis and semidry western blotting. Glutamate at a concentration of 10(-6) M was found neurotoxic when applied for 16 hr in cell cultures. Dead cell mean scores were 12.8 +/- 0.5 for control and 52.3 +/- 4.8 for glutamate (p < .001). On the other hand, p-p38 MAPK levels start to increase at a glutamate concentration of 10(-7) M for 20 min application. Moxonidine was found to have an U-shape neuroprotective effect in glutamate-induced neurotoxicity in neuronal cell culture experiments. Even though moxonidine did not induce neurotoxicity alone between the doses of 10(-8) to 10(-4) M concentrations in cell culture series, it caused the reduction of glutamate-induced dead cell population 23.07 +/- 3.6% in 10(-6) M and 26.7 +/- 2.1% in 10(-5) M concentrations (p <.001 for both, in respect to control values). The protective effect of moxonidine was confirmed in 10(-8) and 10(-7) M, but not in higher concentrations in glutamate neurotoxicity in gel electrophoresis and western blotting of p-p38 MAPK levels. In addition to other studies that revealed an antihypertensive feature of moxonidine, we demonstrated a possible partial neuroprotective role in lower doses for it in glutamate-mediated neurotoxicity model.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protection in Glutamate-Induced Neurotoxicity by Imidazoline Receptor Agonist Moxonidine

Bakuridze

Savli

Gongadze

et al. 2009

International Journal of Neuroscience

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“…DSP-4 is NE specific, and can readily cross the blood brain barrier [16]. While it has transient effects on peripheral NE, effects in the CNS are long-lasting [17].…”

Section: Introductionmentioning

confidence: 99%

Vagus nerve stimulation improves locomotion and neuronal populations in a model of Parkinson's disease

et al. 2017

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Background Parkinson’s disease (PD) is a progressive, neurodegenerative disorder with no disease-modifying therapies, and symptomatic treatments are often limited by debilitating side effects. In PD, locus coeruleus noradrenergic (LC-NE) neurons degenerate prior to substantia nigra dopaminergic (SN-DA) neurons. Vagus nerve stimulation (VNS) activates LC neurons, and decreases pro-inflammatory markers, allowing improvement of LC targets, making it a potential PD therapeutic. Objective To assess therapeutic potential of VNS in a PD model. Methods To mimic the progression of PD degeneration, rats received a systemic injection of noradrenergic neurotoxin DSP-4, followed one week later by bilateral intrastriatal injection of dopaminergic neurotoxin 6-hydroxydopamine. At this time, a subset of rats also had vagus cuffs implanted. After eleven days, rats received a precise VNS regimen twice a day for ten days, and locomotion was measured during each afternoon session. Immediately following final stimulation, rats were euthanized, and left dorsal striatum, bilateral SN and LC were sectioned for immunohistochemical detection of monoaminergic neurons (tyrosine hydroxylase, TH), α-synuclein, astrocytes (GFAP) and microglia (Iba-1). Results VNS significantly increased locomotion of lesioned rats. VNS also resulted in increased expression of TH in striatum, SN, and LC; decreased SN α-synuclein expression; and decreased expression of glial markers in the SN and LC of lesioned rats. Additionally, saline-treated rats after VNS, had higher LC TH and lower SN Iba-1. Conclusions Our findings of increased locomotion, beneficial effects on LC-NE and SN-DA neurons, decreased α-synuclein density in SN TH-positive neurons, and neuroinflammation suggest VNS has potential as a novel PD therapeutic.

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“…In addition to being sensitive to their surroundings, neurons are vulnerable to a wide range of toxins. This includes metabolites, chemicals or xenobiotics that may be present in the blood [51]. …”

Section: Barriers To Cns Drug Deliverymentioning

confidence: 99%

NanoART, NeuroAIDS and CNS Drug Delivery

2009

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A broad range of nanomedicines is being developed to improve drug delivery for CNS disorders. The structure of the blood-brain barrier (BBB), the presence of efflux pumps and the expression of metabolic enzymes pose hurdles for drug-brain entry. Nanoformulations can circumvent the BBB to improve CNS-directed drug delivery by affecting such pumps and enzymes. Alternatively, they can be optimized to affect their size, shape, and protein and lipid coatings to facilitate drug uptake, release and ingress across the barrier. This is important as the brain is a sanctuary for a broad range of pathogens including HIV-1. Improved drug delivery to the CNS would affect pharmacokinetic and drug biodistribution properties. This article focuses on how nanotechnology can serve to improve the delivery of antiretroviral medicines, termed nanoART, across the BBB and affect the biodistribution and clinical benefit for HIV-1 disease. Keywords BBB; CNS; drug delivery; HIV; nanoparticles; nanotechnologyTo maximize treatment of CNS diseases, drugs must cross the blood-brain barrier (BBB) and show limited systemic toxicities. This task is by no means simple. Owing to its structural and functional complexities, the BBB represents one of the greatest challenges impeding drug penetration for combating nervous system diseases [1]. For example, drugs, nucleic acids, proteins, imaging agents and other low-molecular-weight compounds and macromolecules are restricted in brain entry. Thus, the means to improve delivery of compounds across the BBB in an efficient, safe and site-specific manner remain a primary goal to achieve optimal therapeutics in the battle against neuroinflammatory and neurodegenerative diseases [2][3][4][5].The major bottleneck in the development of both diagnostic tools and therapies aimed at combating CNS disorders is in modulating BBB structure, function and biophysiology. With regards to structure, the ability of the barrier to effectively limit transport is attributed, in part, to brain microvessel endothelial cells (BMVECs) that form brain capillaries. Without question, BMVECs are a principal means for limiting transport and solute passage from blood to the CNS [1,[6][7][8][9]. The function and biophysiology of the barrier is also linked to its tight intercellular junctions, low pinocytic potentials and the presence of high levels of drug efflux transporters and metabolizing enzymes. †Author for correspondence: Department of Pharmacology & Experimental Neuroscience, Center for Neurovirology & Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA, Tel.: +1 402 559 8920, Fax: +1 402 559 3744, hegendel@unmc.edu. Financial & competing interests disclosure:The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.For r...

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Evolution of Neurotoxins: From Research Modalities to Clinical Realities

Cited by 9 publications

References 99 publications

Protection in Glutamate-Induced Neurotoxicity by Imidazoline Receptor Agonist Moxonidine

Protection in Glutamate-Induced Neurotoxicity by Imidazoline Receptor Agonist Moxonidine

Vagus nerve stimulation improves locomotion and neuronal populations in a model of Parkinson's disease

NanoART, NeuroAIDS and CNS Drug Delivery

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