Clinical Neuroscience

[Assessment of the role of multidrug resistance-associated proteins in MPTP neurotoxicity in mice]

PLANGÁR Imola, ZÁDORI Dénes, SZALÁRDY Levente, VÉCSEI László, KLIVÉNYI Péter

NOVEMBER 30, 2013

Clinical Neuroscience - 2013;66(11-12)

[Goals - The available scientific data indicate that the pathomechanism of Parkinson's disease (PD) involves the accumulation of endogenous and exogenous toxic substances. The disruption of the proper functioning of certain transporters in the blood-brain barrier and in the blood-cerebrospinal fluid barrier in PD would accompany to that accumulation. Although there is an emerging role of the dysfunction of multidrug resistance-associated proteins (MRPs), members of ATP-binding cassette (ABC) transporter superfamily, in neurodegenerative disorders, there is only a few available data as regards PD. So the aim of our study was the assessment of the role of certain MRPs (1,2,4 and 5) in neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Methods - Following the intraperitoneal administration of silymarin (with MRP1, 2, 4 and 5 inhibitory effects), naringenin (with MRP1, 2 and 4 stimulatory effects), sulfinpyrazone (with MRP1, 4 and 5 inhibitory and MRP2 stimulatory effects) and allopurinol (with MRP4 stimulatory effect) in doses of 100 mg/kg, 100 mg/kg, 100 mg/kg and 60 mg/kg, respectively, for one week before and after the administration of MPTP in C57B/6 mice in acute dosing regimen, the striatal concentrations of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid has been measured using high-performance liquid chromatography. Results - Although the results of these experiments showed that neither of these substances exerted significant influence on MPTP-induced striatal depletion of dopamine and its metabolites, naringenin exerted a slight prevention of dopamine decrease, while allopurinol considerably enhanced the MPTP-induced lethality in mice. The explanation of these findings would be that the stimulation of MRP1- and MRP2-mediated transport of glutathione conjugates of toxic substances may have slight beneficial effects, while stimulation of MRP4-mediated efflux of brain urate, which has an important antioxidant potency, may worsen the effects of oxidative stress.]

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Clinical Neuroscience

[Status epilepticus and its treatment - Update 2013]

GYIMESI Csilla, JUHOS Vera, HORVÁTH Réka, BÓNÉ Beáta, TÓTH Márton, FOGARASI András, KOMOLY Sámuel, JANSZKY József

[Our study provides an overview of the results and guidelines published on the treatment of status epilepticus in the last five years. In recent years, as a result of scientific observations and collected data, the definition of and treatment approach to status epilepticus have been refined and novel therapeutic methods have been developed. The updated guidelines provide guidance in everyday medical practice. However, only a relatively small number of randomized studies are available on status epilepticus, especially in second-line treatment and third-line treatment, thus it is difficult to transfer the newest methods into clinical practice and into updates to treatment protocols. Due to the nature and epidemiology of the disease, the treatment of status epilepticus remains a daily challenge for healthcare providers. The key points of an effective treatment are: expeditiously initiating appropriate therapy, concurrent causal treatment and anticonvulsant therapy, early detection of nonconvulsive status epilepticus, as well as avoiding "overtreatment" and side effects.]

Clinical Neuroscience

[Comparative efficacy of different muscle relaxants in the rehabilitation of post-stroke patients with spasticity]

LIPTÁK Judit

Clinical Neuroscience

[Post-operative management of primary glioblastoma multiforme in patients over 60 years of age]

DARÓCZI Borbála, SZÁNTÓ Erika, TÓTH Judit, BARZÓ Pál, BOGNÁR László, BAKÓ Gyula, SZÁNTÓ János, MÓZES Petra, HIDEGHÉTY Katalin

[Background and purpose - Optimal treatment for elderly patients with glioblastoma multiforme is not well defined. We evaluated the efficacy of post-operative radiotherapy with or without concomitant and/or adjuvant temozolomide in patients aged ≥60 years to assess survival and identify prognostic factors of survival. Methods - A retrospective analysis of overall survival and progression-free survival in patients with newly diagnosed glioblastoma multiforme aged ≥60 years treated with postoperative radiotherapy with or without temozolomide chemotherapy was conducted at our institutions. Prognostic factors were determined by univariate and multivariate analyses. Results - Of 75 study participants (54.7% male; median age at first diagnosis, 65.1 years), 29 (38.7%) underwent gross total resection, whereas others underwent partial resection or biopsy only. All but 1 patient received radiotherapy. Twenty patients received concomitant temozolomide only. Adjuvant temozolomide (1-50 cycles) was administered in 42 patients; 16 received ≥6 cycles. Median overall survival was 10.3 months. One- and 2-year overall survival rates were 42.6% and 6.7%, respectively. Median progression-free survival was 4.1 months. Radiochemotherapy was generally well tolerated. Median overall survival was 15.3 and 29.6 months for patients who received 6-12 cycles and >12 cycles of adjuvant temozolomide, respectively. There were no significant differences in overall survival between age groups (60-64, 65-69, and ≥70 years). Adjuvant temozolomide, Karnofsky performance status ≥70, and additional surgery after progression were significant prognostic factors of longer overall survival (p<0.05). Conclusions: Radiochemotherapy, including ≥6 cycles of adjuvant temozolomide, was safe and prolonged survival of glioblastoma patients aged ≥60 years. Aggressive therapy should not be withheld from patients aged ≥60 years with good performance status because of age.]

Clinical Neuroscience

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Clinical Neuroscience

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KOZÁK Lajos Rudolf

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A case with reversible neurotoxicity induced by metronidazole

EREN Fulya, ALDAN Ali Mehmet, DOGAN Burcu Vasfiye, GUL Gunay, SELCUK Hatem Hakan, SOYSAL Aysun

Background - Metronidazole is a synthetic antibiotic, which has been commonly used for protozoal and anaerobic infections. It rarely causes dose - and duration - unrelated reversible neurotoxicity. It can induce hyperintense T2/FLAIR MRI lesions in several areas of the brain. Although the clinical status is catastrophic, it is completely reversible after discontinuation of the medicine. Case report - 36-year-old female patient who had recent brain abscess history was under treatment of metronidazole for 40 days. She admitted to Emergency Department with newly onset myalgia, nausea, vomiting, blurred vision and cerebellar signs. She had nystagmus in all directions of gaze, ataxia and incompetence in tandem walk. Bilateral hyperintense lesions in splenium of corpus callosum, mesencephalon and dentate nuclei were detected in T2/FLAIR MRI. Although lumbar puncture analysis was normal, her lesions were thought to be related to activation of the brain abscess and metronidazole was started to be given by intravenous way instead of oral. As lesions got bigger and clinical status got worse, metronidazole was stopped. After discontinuation of metronidazole, we detected a dramatic improvement in patient’s clinical status and MRI lesions reduced. Conclusion - Although metronidazole induced neurotoxicity is a very rare complication of the treatment, clinicians should be aware of this entity because its adverse effects are completely reversible after discontinuation of the treatment.

Clinical Neuroscience

Functional neurotoxicity and tissue metal levels in rats exposed subacutely to titanium dioxide nanoparticles via the airways

HORVÁTH Tamara, VEZÉR Tünde, KOZMA Gábor, PAPP András

Introduction and aims - Nanoparticles of titanium dioxide are suspected neurotoxic agents and have numerous applications possibly resulting in human exposure by several ways including inhalation. In the present work, rats were exposed to spherical TiO2 nanoparticles of two different sizes by the intratracheal route. It was investigated how the neuro-functional alterations, detected by electrophysiological and behavioral methods, were related to the concentration of Ti in the tissue samples and what the influence of the size of the NPs was. Materials and methods - Rats (young adult Wistar males, 10/group) were exposed to TiO2 nanoparticles of ca. 10 and 100 nm diameter (suspension medium: neutral PBS with 1% hydroxyethyl cellulose) by intratracheal instillation in 5 and 18 mg/kg b.w. dose; 5 days per week for 6 weeks. Controls were instilled with saline, and vehicle controls, with the suspension medium. To see general toxicity, body weight was checked daily, and organ weights were measured at the end of experiment. Grip strength test, to assess motor function damage, was done before and after the 6-week treatment. Finally, the rats were anesthetized with urethane, spontaneous cortical activity and sensory evoked potentials were recorded, then the rats were dissected and tissue samples were taken for Ti level measurement. Results - Body weight gain indicated no general toxicity, and no significant change in the relative organ weights, except that of the lungs, was seen. However, change of time-to-fall in the grip strength test, and latency of cortical evoked po­tentials, were altered in the treated groups, indicating functional damage. Correlation of these alterations with the cortical Ti level was dissimilar for the two sizes of nanoparticles. Conclusion - The results provided further support to the functional neurotoxicity of TiO2 nanoparticles. The exact role of particle size, and the mechanisms involved, remain to be elucidated.

Clinical Neuroscience

Electrophysiological alterations and general toxic signs obtained by subacute administration of titanium dioxide nanoparticles to the airways of rats

HORVÁTH Tamara, PAPP András, KOVÁCS Dávid, KÁLOMISTA Ildikó, KOZMA Gábor, VEZÉR Tünde

Introduction and aims - Particles of titanium dioxide (TiO2) with typical size below 100 nm have gained a broad range of application by now, partly involving direct human exposure. Their known properties - high specific surface, mobility within the organism, induction of oxidative stress, release of inflammation mediators etc. - raise the possibility of nervous system damage but the available data regarding this are scarce and contradictory. Based on that, and the experiences with other metal oxide nanoparticles, the aim of the present study was to investigate certain general end nervous system toxic effects of TiO2 nanoparticles applied in the airways of rats. Materials and methods - Young adult Wistar rats (5 groups of 10 rats each) received, daily for 28 days, intratracheal instillations of titanium dioxide nanoparticles of ca. 10 nm diameter, suspended in 1% hydroxyethyl cellulose dissolved in phosphate-buffered saline, in the doses of 1, 3, and 10 mg/kg b. w. Vehicle controls received the suspension medium and there was also an untreated control group. During treatment, the rats’ body weight was measured, and their clinical state observed, daily. After the 28 days, spontaneous cortical activity, sensory evoked potentials and tail nerve action potential was recorded in urethane anesthesia, then the rats were dissected and tissue samples were taken for Ti level determination and biochemical measurements of some oxidative stress indicators. Results - The two higher doses reduced the rate of body weight gain significantly. Sensory evoked potentials and tail nerve action potential were significantly slowed, but the change in the spectrum of spontaneous cortical activity was not significant. Correlation of moderate strength was found between certain evoked potential parameters and brain Ti level and oxidative stress data. Conclusion - Our results underlined the possible neurotoxicity of TiO2 NPs but also the need for further investigations.

Clinical Neuroscience

[EFFECTS OF KETAMINE ON THE DEVELOPING CENTRAL NERVOUS SYSTEM]

VUTSKITS László, GASCON Eduardo, KISS Zoltán József

[Ketamine is a widely used drug in pediatric anesthesia practice, acting primarily through the blockade of the Nmethyl- D-aspartate (NMDA) type of glutamate receptors. A growing body of laboratory evidence, accumulated during the past few years, suggests that this drug could have potential adverse effects on the developing central nervous system. The goal of this short review is to give a brief synopsis of experimental work indicating ketamine-induced developmental neurotoxicity as well as to discuss potential limitations concerning extrapolation of these studies to clinical practice.]

Clinical Neuroscience

[Thallium poisoning induced polyneuropathy - clinical and electrophysiological data]

LUKÁCS Miklós

[Introduction - The aim of the study was the electrophysiological investigation of thallium induced polyneuropathy. Beyond the rarity of the illness, the motivation of this work was the possibility of following up the pattern of neuronal damage. Thallium is one of the most toxic heavy metal and its wide use increases the chance of chronic or accidental acute poisoning. The entero-hepatic circulation makes the accumulation of this toxic agent in tissues possible, mostly in neurons, in the epithelial cells of the digestive tract, in the germinative cells of the skin and testicles. In addition to alopecia and digestive complaints, the clinical picture of thallium poisoning is dominated by neurological signs. Severe axonal polyneuropathy develops in almost all cases, with further damage to the retina and impairment of cognitive functions being not unusual. The diagnosis is confirmed by finding high levels of thallium in body fluids, especially in saliva and urine. Case report - Electrophysiological examination of our accidentally poisoned patient revealed severe, sensory-motor, predominant motor axonal polyneuropathy and pointed out some aspects of the pattern of neurotoxic process: the initially distal lesion, the dying-back course and the capacity for regeneration. Conclusion - Because thallium has the same molecular targets as potassium ion thus impairing the energetical supply of the nerve cell, the most effective treatment is carefully loading with potassium. If recognized and treated early, thallium poisoning has a favourable prognosis.]