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Aging is closely related to the main aspects of multiple sclerosis (MS). The average age of the MS population is increasing and the number of elderly MS patients is expected to increase. In addition to neurons, N-methyl-D-aspartate receptors (NMDARs) are also expressed on non-neuronal cells, such as immune cells. The aim of this study was to investigate the role of NMDARs in experimental autoimmune encephalomyelitis (EAE) in young and aged rats. Memantine, a non-competitive NMDAR antagonist, was administered to young and aged Dark Agouti rats from day 7 after immunization. Antagonizing NMDARs had a more favourable effect on clinical disease, reactivation, and apoptosis of CD4+ T cells in the target organ of aged EAE rats. The expression of the fractalkine receptor CX3CR1 was increased in memantine-treated rats, but to a greater extent in aged rats. Additionally, memantine increased Nrf2 and Nrf2-regulated enzymes' mRNA expression in brain tissue. The concentrations of superoxide anion radicals, malondialdehyde, and advanced oxidation protein products in brain tissue were consistent with previous results. Overall, our results suggest that NMDARs play a more important role in the pathogenesis of EAE in aged than in young rats. [ABSTRACT FROM AUTHOR]

In this research, a UHPLC–MS/MS method was developed and validated for the determination of zonisamide in dried plasma spots (DPS) and dried blood spots (DBS). Detection of zonisamide and internal standard, 1-(2,3-dichlorphenyl)piperazine, was carried out in ESI+ mode by monitoring two MRM transitions per analyte. Total run time, less than 2.5 min, was achieved using Acquity UPLC BEH Amide (2.1 × 100 mm, 1.7 µm particle size) column with mobile phase comprising acetonitrile–water (85:15%, v/v) with 0.075% formic acid. The flow rate was 0.225 mL/min, the column temperature was 30 °C and the injection volume was 3 µL. Desolvation temperature, desolvation gas flow rate, ion source temperature and cone gas flow rate were set by the IntelliStart software tool in combination with tuning. All of the Guthrie cards were scanned, and DPS/DBS areas were determined by the image processing tool. The influence of hematocrit values (20–60%) on accuracy and precision was evaluated to determine the range within which method for DBSs is free from Hct or dependency is within acceptable limits. The validated method was applied to the determination of zonisamide levels in DPS and DBS samples obtained from patients confirming its suitability for clinical application. Finally, the distribution of zonisamide into the red blood cells was estimated by correlating its DPS and DBS levels. [ABSTRACT FROM AUTHOR]

Objective: The present study represents one of the largest series of pediatric multiple sclerosis (PedMS) in Western Balkan region. This is the first study aimed to evaluate the characteristics of PedMS in the Serbian population. Methods: This retrospective study on 54 PedMS, aged 7–17 years, was performed at the Clinic of Neurology and Psychiatry for Children and Youth in Belgrade, Serbia, a tertiary center for the diagnosis and treatment of children with neurological and psychiatric diseases. Results: Female to male ratio was 37 (68.5%): 17 (31.5%). Family history of MS was noted in 9.3% and autoimmune diseases in 24.1% patients. Co-occurring migraine was in 7,4%. Monofocal onset of disease was present in 77.8% patients. The most common initial symptoms were optic neuritis (37%), sensory disturbances (31.5%), motor deficit (24.1%), cerebellar (18.5%) and brainstem lesions (16.7%), pain (9.3%), acute disseminated encephalomyelitis like symptoms (1.9%), and hearing loss (3.7%). Visual evoked potentials were pathological in 75.9% of patients. Oligoclonal bands were positive in 68.5% of patients. Magnetic resonance imaging showed periventricular (94.4%), infratentorial (77.8%), juxtacortical and cortical changes (55.6%) and changes in the cervical spinal cord (33.3%). The median EDSS score was 2.0. Conclusion: Our cohort significantly differs from the literature data regarding more frequent occurrence of optic neuritis, hearing loss as a first symptom, the relapsing-remitting course of the disease, higher proportion of early onset of disease, presence of co-occurring migraine and the frequent occurrence of epilepsy and other autoimmune diseases in the family. [ABSTRACT FROM AUTHOR]

We are presenting two Leber's hereditary optic neuropathy (LHON) pedigrees with abnormal magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (H-MRS) findings but without neurological manifestation associated with LHON. The study included 14 LHON patients and 41 asymptomatic family members from 12 genealogically unrelated families. MRI showed white matter involvement and H-MRS exhibited metabolic anomalies within 12 LHON families. Main outcome measures were abnormal MRI and H-MRS findings in two pedigrees. MRI of the proband of the first pedigree showed a single demyelinating lesion in the right cerebellar hemisphere, while the proband of the second family displayed multiple supratentorial and infratentorial lesions, compatible with the demyelinating process, and both the absolute choline (Cho) concentration and Cho/creatinine ratio were increased. MRI and H-MRS profiles of both affected and unaffected mitochondrial DNA mutation carriers suggest more widespread central nervous involvement in LHON. Although even after 12 years our patients did not develop neurological symptoms, MRI could still be used to detect possible changes during the disease progression. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background There are three kinds of allosteric modulators acting through the benzodiazepine (BZ) binding site of the GABAA receptor: positive (agonist), neutral (antagonist), and negative (inverse agonist) modulators. Agonists and inverse agonists commonly exert bidirectional influences on observed behavioral parameters. In the present study we have investigated the modulation of behavioral responses to environmental novelty in two unconditioned paradigms: spontaneous locomotor activity (SLA) and forced swim test (FST), elicited by DMCM (methyl-6,7- dimethoxy-4-ethyl-beta-carboline-3-carboxylate), a nonselective inverse agonist, in the dose range that previously did not produce anxiogenic effects and convulsions. Methods SLA in the test cage (40 x 25 x 35 cm) during 30 min was recorded automatically, beginning 20 min after i.p. injections (DMCM 0.1, 0.5 and 1 mg/kg) without any habituation. FST was performed in a glass cylinder, 45 cm high, 20 cm diameter filled with water up to a height of 20 cm, with a temperature of 21–23 °C. Male Wistar rats were exposed to two swimming sessions (an initial 15-min pretest session, followed 24 h later by a 5-min test session). The animals received i.p. 0.1, 0.5 and 1 mg/kg of DMCM or vehicle, 20 min before the test session. A rat was considered immobile whenever it floated passively in the water and only made movements necessary to keep its head above the water line. Results ANOVA showed a significant effect of treatment on the total immobility time of the animals during 30 min of monitoring of spontaneous locomotor activity (p < 0.05). Namely, Dunnett’s analysis showed that the highest applied dose of DMCM (1 mg/kg) exerted the activitydecreasing effect related to vehicle. In FST during the test session, ANOVA indicated statistically significant effects of DMCM (p < 0.05) on the average immobility time of animals. Dunnett’s analysis showed that DMCM (1.0 mg/kg) significantly increased immoblity, but at the lowest applied dose DMCM (0.1 mg/kg) decreased immobility, and exerted acute antidepressant-like effects. Conclusions These data suggest that negative modulation at GABAA receptors might have triggered the acute antidepressantlike effects in rats and these effects were not confounded by locomotor influences. On the other hand, these effects are not straightforward, because they exert a kind of bimodal influence. Furthermore, these results encourage the synthesis of new BZ site ligands, aimed to possess more selective affinity/efficacy profiles. [ABSTRACT FROM AUTHOR]