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

JANUARY 30, 2018

Clinical Neuroscience - 2018;71(01-02)

DOI: https://doi.org/10.18071/isz.71.0035

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.

COMMENTS

0 comments

Further articles in this publication

Clinical Neuroscience

[Clinical neurophysiological methods in diagnosis and treatment of cerebrovascular diseases]

NAGY Ildikó, FABÓ Dániel

[Neurophysiological methods are gaining ground in the diagnosis and therapy of cerebrovascular disease. While the role of the EEG (electroencephalography) in the diagnosis of post-stroke epilepsy is constant, quantitative EEG para-meters, as new indicators of early efficiency after thrombolysis or in prognosis of patient’s condition have proved their effectiveness in several clinical studies. In intensive care units, continuous EEG monitoring of critically ill patients became part of neurointenzive care protocols. SSEP (somatosesnsory evoked potencial) and EEG performed during carotid endarterectomy, are early indicative intraoperativ neuromonitoring methods of poor outcome. Neurorehabilitation is a newly discovered area of neurophysiology. Clinical studies have demonstrated the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the rehabilitation of stroke patients. Brain computer interface mark the onset of modern rehabi-litation, where the function deficit is replaced by robotic tehnology. ]

Clinical Neuroscience

Insights into the structure and function of the hippocampal formation: Relevance to Parkinson’s disease

GYÖRFI Orsolya, NAGY Helga, BOKOR Magdolna, KÉRI Szabolcs

The link between the hippocampus and declarative memory dysfunctions following the removal of the medial temporal lobe opened unexplored fields in neuroscience. In the first part of our review, we summarized current theoretical frameworks discussing the role of hippocampus in learning and memory. Several theories are highlighted suggesting that the hippocampus is responsible for assembling stimulus elements into a unitary representation that later can be utilized to simulate future events. The hippocampal formation has been implicated in a growing number of disorders, from neurodegenerative diseases to atypical cognitive ageing and depression. Recent neuroimaging studies provided new opportunities to study in detail the hippocampal formation’s role in higher levels of the nervous system. We will present data regarding the regional specialization of the hippocampus in experimental models developed for healthy and neurological conditions with a special focus on Parkinson’s disease. Combined evidence from neuroimaging studies suggested that hippocampal volume is reduced in non-demented, newly diagnosed patients with Parkinson’s disease, which is associated with impaired memory performance. These findings proposed that, beyond the well-known striatal dopamine loss, impaired hippocampal synaptic plasticity may contribute to cognitive and affective impairments in early Parkinson’s disease.

Clinical Neuroscience

[Effects of nasal provocation with a single-dose allergen on the explicit and implicit memory of physically active and inactive patients with ragweed allergy]

TOKODI Margaréta, CSÁBI Eszter, KIRICSI Ágnes, SCHULTZ Rebeka, MOLNÁR H Andor, ROVÓ László, BELLA Zsolt

[Background and purpose - Allergy is an endemic disease and has a considerable impact on the quality of life. This study aimed to measure the effect of active allergic rhinitis on memory functions of physically active and inactive patients with ragweed allergy. Methods - Memory functions were assessed before and after allergen exposure. Participants in both groups were provoked nasally with 30 IR/mL ragweed allergen in each nostril. Explicit memory was measured with story-recalling and implicit memory was investigated with reaction time task. Results - In neuropsychological assessments athletes performed significantly better, compared with the control group after allergen provocation in short-term and long-term memory functions. There was no difference between the groups in the implicit tasks. Athletes have achieved better results after provocation, comparing to the baseline test and the tests that measured short-term and long-term memory functions. Conclusion - Short-term disturbing factors, e.g. swollen nasal mucosa, sneezing, and watery eyes after provocation did have not caused deterioration in cognitive functions. A single-shot allergen in high doses have caused an increase of mental concentration, which was more pronounced in athletes.]

Clinical Neuroscience

Electroclinical and prognostic characteristics of epilepsy patients with photosensitivity

YAZAR Olgun Hülya, GUL Gunay, YAZAR Tamer, EREN Fulya, KUSCU Yandım Demet, KIRBAS Dursun

Background - Epilepsy with photosensitivity (PSE) is one of the reflex epilepsy types with pathophysiology still unexplained. In our study we aimed to evaluate the clinical, electroencephalogram (EEG) and prognosis of patients with PSE diagnosis. Method - A total of 44 patients with PSE diagnosis according to international classification were included in this retrospective and cross-sectional study. The age, gender, syndrome, clinical and EEG characteristics of patients, and treatment response were investigated. Results - The mean age was 22.09±6.49 years for 28 females and 16 males included in the study. Of patients, 17 had idiopathic photosensitive occipital lobe epilepsy (IPOLE), 11 had juvenile myoclonic epilepsy (JME), 11 had other PSE and 5 had juvenile absence epilepsy (JAE), with the most common visual trigger factors television and sunlight. In terms of seizure type, the most common was generalized tonic clonic seizure (GTCS), with myoclonus, absence and other seizure types observed. There was family history present in 17 patients and valproic acid was most commonly used for treatment. Conclusion - As noted in the literature, our data show that PSE has defined age group and clinical presentation, good prognosis but requires correct choice of medication for treatment. It is thought that good description of these epilepsy types will reduce misdiagnosis and mistreatment rates.

Clinical Neuroscience

Alteration of mean platelet volume in the pathogenesis of acute ischemic stroke: cause or consequence?

AYAS Özözen Zeynep, CAN Ufuk

Introduction - Platelets have a crucial role on vascular disease which are involved in pathogenesis of ischemic stroke. Platelet size is measured as mean platelet volume (MPV) and is a marker of platelet activity. Platelets contain more dense granules as the size increases and produce more serotonin and tromboglobulin (b-TG) than small platelets. In this study, the alteration of MPV values were investigated in patients with acute stroke, who had MPV values before stroke, during acute ischemic stroke and 7 days after the stroke. The relationship between this alteration and risk factors, etiology and localization of ischemic stroke were also investigated. Methods - Sixty-seven patients with clinically and radiologically established diagnoses of ischemic stroke were enrolled into the study and stroke etiology was classified by modified Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification and, modified Bamford classification was used for localization and stroke risk factors were also evaluated. The platelet counts and MPV values from patient files in patients who had values before stroke (at examination for another diseases), within 24 hours of symptom onset and after 7 further days were analysed. Results - MPV values increased after stroke (10.59±2.26) compared with acute stroke values (9.84±1.64) and the values before stroke (9.59±1.72) (p<0.0001); this alteration of MPV values occured 7 days after stroke (p<0.016). There was a positive correlation between age and MPV values during acute stroke (r=0.270; p<0.05). Patients with atrial fibrillation had higher alteration in the time of MPV compared with patients without atrial fibrillation (p>0.006). We assessed for gender, men (n=38) had a higher alteration in the time of MPV compared with women (n=29) (p=0.013). Conclusion - Although there was no alteration of platelet counts, MPV values were increased 7 days after stroke in patients with acute ischemic stroke.

All articles in the issue

Related contents

Clinical Neuroscience

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 Oncology

[Prevention of drug-related neuropathy in the clinical practice]

VAJDICS Tímea

[There was a revolution of oncological treatments in the last fi ve years caused by introduction of immuncheckpoint inhibitors. Platinum and taxane based chemotherapies are the standard of care of the most frequent malignancies such as colon and breast cancer. Signifi cant improvement was achieved concerning side effects of chemotherapy in the few past decades. Preventive treatment of vomiting, neutropenia, aneamia are now based on clinical evidences. Meanwhile, there remained side effects (including chemotherapy induced neuropathy) which are diffi cult to treat. This article provides overwiev of the pharmacological therapies, vitamins and non-pharmacological procedures aimed to prevent chemotherapy induced neuropathy. Unfortunately still there are no drugs that are highly effective of preventing of chemotherapy induced periferial neuropathy validated in randomized clinical trials.]

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

[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.]

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

[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.]