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Parkinson's disease (PD) is a progressive age-related neurodegenerative disorder affecting millions of people worldwide. Essentially, it is characterised by selective degeneration of dopamine neurons of the nigro-striatal pathway and intraneuronal aggregation of misfolded α-synuclein with formation of Lewy bodies and Lewy neurites. Moreover, specific small molecules of intermediary metabolism may have a definite pathophysiological role in PD. These include dopamine, levodopa, reduced glutathione, glutathione disulfide/oxidised glutathione, and the micronutrients thiamine and ß-Hydroxybutyrate. Recent research indicates that these small molecules can interact with α-synuclein and regulate its folding and potential aggregation. In this review, we discuss the current knowledge on interactions between α-synuclein and both the small molecules of intermediary metabolism in the brain relevant to PD, and many other natural and synthetic small molecules that regulate α-synuclein aggregation. Additionally, we analyse some of the relevant molecular mechanisms potentially involved. A better understanding of these interactions may have relevance for the development of rational future therapies. In particular, our observations suggest that the micronutrients ß-Hydroxybutyrate and thiamine might have a synergistic therapeutic role in halting or reversing the progression of PD and other neuronal α-synuclein disorders.

Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and declare that this report is consistent with those guidelines.

On the basis that similar biochemical and histological sequences of events occur in the brain during thiamine deficiency and hypoxia/ischemia related brain damage, we have planned this review to discuss the possible therapeutic role of thiamine and its derivatives in the management of neonatal hypoxic-ischemic encephalopathy (HIE). Among the many benefits, thiamine per se as antioxidant, given intravenously (IV) at high doses, defined as dosage greater than 100 mg IV daily, should counteract the damaging effects of reactive oxygen and nitrogen species in the brain, including the reaction of peroxynitrite with the tyrosine residues of the major enzymes involved in intracellular glucose metabolism, which plays a key pathophysiological role in HIE in neonates. Accordingly, it is conceivable that, in neonatal HIE, the blockade of intracellular progressive oxidative stress and the rescue of mitochondrial function mediated by thiamine and its derivatives can lead to a definite neuroprotective effect. Because therapeutic hypothermia and thiamine may both act on the latent period of HIE damage, a synergistic effect of these therapeutic strategies is likely. Thiamine treatment may be especially important in mild HIE and in areas of the world where there is limited access to expensive hypothermia equipment.

Human endogenous retrovirus (HERV)-K env-su glycoprotein has been documented in amyotrophic lateral sclerosis (ALS), where HERV-K env-su 19-37 antibody levels significantly correlated with clinical measures of disease severity. Herein, we investigated further the humoral and cell-mediated immune response against specific antigenic peptides derived from HERV-K in ALS. HERV-K env glycoprotein expression on peripheral blood mononuclear cells (PBMCs) membrane and cytokines and chemokines after stimulation with HERV-K env 19-37 and HERV-K env 109-126 were quantified in patients and healthy controls (HCs). HERV-K env glycoprotein was more expressed in B cells and NK cells of ALS patients compared to HCs, whereas HERV-K env transcripts were similar in ALS and HCs. In ALS patients, specific stimulation with HERV-K env 109-126 peptide showed a higher expression of IL-6 by CD19/B cells. Both peptides, however, were able to induce a great production of IFN-γ by stimulation CD19/B cells, and yielded a higher expression of MIP-1α and a lower expression of MCP-1. HERV-K env 19-37 peptide induced a great production of TNF-α in CD8/T cells. In conclusion, we observed the ability of HERV-K to modulate the immune system, generating mediators mainly involved in proinflammatory response.

Increased expression of the retroviruses of HERV-W family has been linked to multiple sclerosis (MS) pathophysiology; nothing is known at the moment about MOG-IgG associated disorders. We compared antibody response against HERV-W peptides among patients with MOG-IgG associated disorders, multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG positive neuromyelitis optica spectrum disorder (NMOSD). A total of 102 serum samples were retrospectively analyzed. Antibody reactivity against HERV-W env peptides was similar in MOG-IgG associated disorders and MS, but different from AQP4-IgG positive NMOSD. Our findings expand the diagnostic role of HERV-W antibodies to the spectrum of demyelinating disorders associated with MOG-IgG., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Myasthenia gravis (MG) is an autoimmune disease leading to varying degrees of skeletal muscle weakness. It is caused by specific antibodies directed against definite components in the postsynaptic membrane at the neuromuscular junction (NMJ), such as the acetylcholine receptor (AChR) and the muscle-specific kinase (MUSK) receptor. In clinical practice, MG patients may be classified into three main subgroups based on the occurrence of serum autoantibodies directed against AChR or MUSK receptor or antibody-negative. As the MG subgroups differ in terms of clinical characteristics, disease pathogenesis, prognosis, and response to therapies, they could benefit from targeted treatment as well as the detection of other possible disease biomarkers. We performed proteomics on plasma fractions enriched in low-abundance proteins to identify potential biomarkers according to different autoimmune responses. By this approach, we evidenced a significant reduction of vitronectin in MG patients compared to healthy controls, irrespective of the autoantibodies NMJ target. The obtained results were validated by mono- and two-dimensional Western blotting analysis. Vitronectin is a multifunctional glycoprotein involved in the regulation of several pathophysiological processes, including complement-dependent immune response, coagulation, fibrinolysis, pericellular proteolysis, cell attachment, and spreading. The pathophysiological significance of the reduction of plasma vitronectin in MG patients has yet to be fully elucidated. It could be related either to a possible deposition of vitronectin at NMJ to counteract the complement-mediated muscle damage at this level or to a parallel variation of this glycoprotein in the muscle extracellular matrix with secondary induced alteration in clustering of AChRs at NMJ, as it occurs with variation in concentrations of agrin, another extracellular matrix component. The clinical value of measuring plasma vitronectin has yet to be defined. According to present findings, significantly lower plasma values of this glycoprotein might be indicative of an impaired complement-dependent immune response., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Trigeminal nerve stimulation (TNS) is a non-invasive neuromodulation method which is increasingly used for its beneficial effects on symptoms of several neuropsychiatric disorders such as drug-resistant epilepsy. Sites and mechanisms of its action are still unknown. The present study was aimed at investigating the physiological effects of acute TNS on rest electroencephalographic (EEG) activity. EEG was recorded with a 19-channel EEG system from 18 healthy adults who underwent 20 min of sham- and real-TNS (cycles of 30 s ON and 30 s OFF) in two separate sessions. EEG was continuously acquired in the 10-min preceding TNS, during TNS in the "OFF" period and throughout 10 min after TNS. Mean frequency, total power over the 0.5-48 Hz frequency range and absolute power for delta, theta, alpha, beta and gamma bands were analyzed by a discrete Fast Fourier Transform algorithm. Interhemispheric and intrahemispheric coherences were also analyzed for each band at different time points. Intra- and interhemispheric coherences were significantly reduced for the beta frequencies only during real-TNS (p = 0.002 and p = 0.006, respectively). No TNS effect on the power spectra of any band was detected. A trend of increase in the mean EEG frequency total power during real-TNS (p = 0.03) and of decrease in interhemispheric gamma coherence after real-TNS (p = 0.01) was observed. Acute TNS may induce a spatially diffuse desynchronization of fast EEG rhythms in healthy adults, this desynchronization may underpin the antiepileptic effect of TNS described by clinical studies.

Parkinson's disease is a neurodegenerative disorder and its etiology is unknown, numerous studies show how different environmental factors can influence the development of disease. miRNAs are involved in several pathologies and their dysregulation contribute to different pathologies, also in neurodegenerative such as Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic lateral sclerosis. In this study, we profiled the expression of different candidate miRNAs: miR-155, miR-26a, miR-146a, and miR132, in PBMCs of L-dopa treated Parkinson patients and unaffected controls (HCs).We investigated the expression of miRNAs by RT-real time PCR, the results were subjected to statistical analysis. miRNA-155-5p was generally up-regulated in PD patients compared to HCs whereas miRNA-146a-5p was down-regulated in PD patients in comparison to HCs. It is interesting to point out that the expression of miR-155-5p was modified by levodopa treatment, in fact a down-regulation of miR-155-5p in PD patients with the highest dosage was observed. In conclusion, miRNA 155 could not only be a promising target for the anti-inflammatory therapy in PD but also a good candidate as a disease progression biomarker. The role of levodopa in modulating the levels of miRNA 155 requires further studies.

Background: A specific humoral immune response against HERV-W envelope surface (env-su) glycoprotein antigens has been reported in serum of patients with multiple sclerosis (MS). However, it has not been evaluated to date in patients with neuromyelitis optica spectrum disorder (NMOSD)., Objective: The objective of this paper is to investigate whether antibody (Ab) response against HERV-W env-su antigenic peptides differs between NMOSD and MS., Methods: Serum samples were collected from 36 patients with NMOSD, 36 patients with MS and 36 healthy control individuals (HCs). An indirect ELISA was set up to detect specific Abs against HERV-W env-su peptides., Results: Our data showed that two antigenic peptides, particularly HERV-Wenv 93-108 and HERV-Wenv 248-262, were statistically significantly present only in serum of MS compared to NMOSD and HCs. Thus, the specific humoral immune response against HERV-W env-su glycoprotein antigens found in MS is widely missing in NMOSD., Conclusion: Increased circulating serum levels of these HERV-W Abs may be suitable as additional biomarkers to better differentiate MS from NMOSD.

Environmental factors are implicated in the development of Parkinson's disease (PD). The aim of this study is to investigate the role of cell-mediated immunity upon a specific immune-stimulation with HSV-1 and human alpha-synuclein homologues peptides by using the intracellular cytokine method on Parkinson's patients and healthy controls. The study showed, for the first time, a specific response to TNF-α CD8, CD4 and NK cells after stimulation in PD patients. Our data show a possible role of the immune system in the pathogenesis of Parkinson's disease, and that HSV-1 infections may lead to a progression of the disease., (Copyright © 2017. Published by Elsevier B.V.)

While the genetic origin of Fabry disease (FD) is well known, it is still unclear why the disease presents a wide heterogeneity of clinical presentation and progression, even within the same family. Emerging observations reveal that mitochondrial impairment and oxidative stress may be implicated in the pathogenesis of FD. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of FD, we have genotyped European mtDNA haplogroups in 77 Italian FD patients and 151 healthy controls. Haplogroups H and I, and haplogroup cluster HV were significantly more frequent in patients than controls. However, no correlation with gender, age of onset, organ involvement was observed. Our study seems to provide some evidence of a contribution of mitochondrial variation in FD pathogenesis, at least in Italy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

MicroRNAs fine-tune the regulation of Th1/Th17 lymphocyte subsets in multiple sclerosis. We investigated the expression of miRNAs (previously associated with mycobacterial and viral infections) in MS patients and healthy donors (HD) following 6 months natalizumab therapy. In addition, Th1/Th17 cytokines and the presence of anti-EBNA1/VCA IgG in MS patients with different pattern of miRNA expression have been evaluated. MiR-155, miR-26a, miR-132, miR-146a and Th1/Th17 cytokines expression was detected by RT-real time PCR; moreover anti-EBNA1 and VCA IgG titres were measured by ELISA. We observed an up-regulation of miR-155 (p value = 0.009) and miR-132 (p value = 0.04) in MS patients compared to HD. In MS patients, IL-17a (p = 0.037), IFN γ (p = 0.012) and TNFα (p = 0.015) but not IL-6 were over-expressed compared to HD. Two different miRNAs patterns associated to the expression of different cytokines were observed in the MS cohort. Moreover, a down-regulation of miR-155 and miR-26a was seen in MS patients during and after natalizumab therapy. MS patients that over-expressed miR-155 showed a higher EBNA1 IgG titer than MS patients with high levels of miR-26a. In conclusions the expression of particular miRNAs modulates the pro-inflammatory cytokine expression and the humoral response against EBV and this expression is natalizumab regulated.

In Parkinson's disease (PD) ZnT proteins play an important role. Zinc is a co-factor of numerous enzymes and stabilizes the tertiary structure of several proteins. Nothing is known about previous infections mediated by Mycobacterium avium subsp. paratuberculosis (MAP). We evaluated if a previous infection with MAP could induce the production of antibodies that cross-reacted with the Znt homologous antigenic peptides associated to Parkinson. The humoral response toward MAP3865c peptides, ZnT3 and ZnT10 was evaluated. The hypothesis of cross-reactivity needs to be confirmed; we have observed the presence of MAP in PD patients by PCR, positivity to MAP3865c peptides, therefore MAP infection but not cross-reaction with human homologous Znt proteins., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Environmental factors are implicated in the development of Parkinson's disease (PD). We have investigated on the role of molecular mimicry between HSV1 and α-synuclein that could foster the progression of PD. The antibody response against homologous peptides in PD patients and healthy controls was evaluated, showing that these antibodies are highly prevalent among PD patients to healthy controls. The competitive assay demonstrated cross-reactivity between HSV1 and human α-synuclein peptides. The results may suggest the hypothesis of the involvement of HSV1 in stimulating the immune cells against the neurons of the substantia nigra as a consequence of the cross reactivity., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Multiple Sclerosis (MS) is a heterogeneous disorder of the central nervous system (CNS) that begins as an inflammatory autoimmune disorder mediated by auto-reactive lymphocyte followed by microglial activation and chronic degeneration. The etiology of Multiple Sclerosis (MS) is unknown but several data support the hypothesis of possible infectious agents which may act as a trigger for the pathogenic cascade. Human endogenous retrovirus (HERV-W/MSRV), Epstein Barr Virus (EBV) and Mycobacterium avium ss. paratuberculosis (MAP) have been associated to Multiple Sclerosis. In this study, we evaluated the humoral response against different peptides: the human endogenous retrovirus HERV-Wenv73-88, MAP106c121-132 from MAP, EBNA1 400-413 from EBV and the homologous human peptide MBP85-98 in a cohort of MS patients treated with natalizumab. Results showed a statistically significant difference in the response against the HERV-W peptide in MS patients after two years of natalizumab treatment., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The identification of a hot spot of exceptional longevity, the Longevity Blue Zone (LBZ), in the mountain population of Sardinia has aroused considerable interest toward its traditional food as one of the potential causal factors. This preliminary study on the traditional Sardinian diet has been supported by the literature available, which has been carefully reviewed and compared. Up to a short time ago, the LBZ population depended mostly upon livestock rearing, and consumption of animal-derived foods was relatively higher than in the rest of the island. The nutrition transition (NT) in urbanized and lowland areas began in the mid-1950s, fueled by economic development, whereas in the LBZ it started later owing to prolonged resistance to change by a society organized around a rather efficient pastoral economy. Even nowadays a large proportion of the population in this area still follows the traditional diet based on cereal-derived foods and dairy products. The LBZ cohorts comprising individuals who were of a mature age when NT began may have benefited both from the high-quality, albeit rather monotonous, traditional diet to which they had been exposed most of their life and from the transitional diet, which introduced positive changes such as more variety, increased consumption of fruits and vegetables and moderate meat intake. It could be speculated that these changes may have brought substantial health benefits to this particular aging group, which was in need of nutrient-rich food at this specific time in life, thereby resulting in a decreased mortality risk and, in turn, life-span extension.

Thiocolchicoside is a myorelaxant drug with anti-inflammatory and analgesic properties as well as pronounced convulsant activity. To characterize the mechanisms of action of this drug at the molecular level, we examined its effects on the function of various recombinant neurotransmitter receptors expressed in Xenopus oocytes. Electrophysiological recordings from recombinant human gamma-aminobutyric acid type A (GABA(A)) receptors consisting of alpha1beta1gamma2L, alpha1beta2gamma2L, or alpha2beta2gamma2L subunit combinations revealed that thiocolchicoside inhibited GABA-evoked Cl(-) currents with similar potencies (median inhibitory concentrations of 0.13 to 0.2 microM) and in a competitive manner. Consistent with previous observations, thiocolchicoside also inhibited the binding of GABA to rat cerebral cortical membranes. Thiocolchicoside inhibited the function of recombinant human strychnine-sensitive glycine receptors composed of the alpha1 subunit with a potency (median inhibitory concentration of 47 microM) lower than that apparent with recombinant GABA(A) receptors. It also inhibited the function of human nicotinic acetylcholine receptors composed of the alpha4 and beta2 subunits, but this effect was only partial and apparent at high concentrations. In contrast, thiocolchicoside had no effect on the function of 5-HT(3A) serotonin receptors. Our results thus provide molecular evidence that the epileptogenic activity of thiocolchicoside might be due to inhibition of the function of inhibitory receptors in the central nervous system, especially that of GABA(A) receptors.

Neurological syndromes caused by Mycoplasma pneumoniae (MP) infection are occasionally reported in adults, usually in the post-infectious period, and three computed tomography documented cases have recently appeared in this journal. Here we present the cases of three young women with recent respiratory tract infection caused by MP some weeks prior to neurological complication documented by magnetic resonance imaging. Two cases suffered from demyelinating disorders of the central nervous system (CNS). The other case had a middle cerebral artery thrombosis, a rare complication of MP infection. Another potential risk factor for stroke in the latter case was the use of oral contraceptives. Recent infection with MP is discussed as a risk factor for cerebrovascular disorders and CNS demyelinating diseases.

To evaluate possible cause-effect relationships between hyperostosis frontalis interna and cognitive dysfunction, we performed a neurophysiological (event-related potentials, ERPs) and neuropsychological study in a case of Morgagni-Stewart-Morel (MSM) syndrome associated with frontal lobe compression. Neuropsychological evaluation evidenced selective impairment of executive function. Visual and auditory oddball ERPs revealed delayed P300 latency and reduced auditory P300 amplitude with multi-peaked morphology. ERP abnormalities and cognitive dysfunction could be due to the frontal bone-cortex conflict documented by neuroradiological investigations.

The physicochemical properties of the whole-brain interstitial fluid (IF) are unknown. A volume of whole-brain IF sufficient for analysis was obtained through a small, hollow, multiperforated polypropylene sphere implanted for 4-5 weeks into the dog brain parenchyma. The main physicochemical properties of the whole-brain IF were characterized, in comparison with the physicochemical properties of cerebrospinal fluid and blood/serum.

A double-blind controlled trial was performed on 6 patients affected with Steinert's disease in order to evaluate the efficacy of two different dosages of diphenylhydantoin (PHT, 200 and 300 mg/day) and carbamazepine (CBZ, 600 and 800 mg/day) on the myotonic afterdischarge. Both dosages of PHT and CBZ induced a significant improvement of myotonia. For PHT a trend towards decreased efficacy is pointed out at toxic or at high dosages.

Carbamazepine (CBZ) brain distribution was studied in cats rendered epileptic by penicillin topically applied on neocortex. CBZ penetration into the focus did not differ significantly from penetration into the other areas of the brain, with the drug rapidly entering the cerebral tissue (peak at 30 min). As no difference was found between CBZ brain concentrations at 15 and 90 min, substantial early binding of the drug was confirmed in this experimental model of epilepsy. As CBZ was able to decrease rapidly the spike frequency of the penicillin focus, it may be speculated that it was also able to prevent the metabolic alterations associated with severe epileptogenesis that would have caused an impaired CBZ brain distribution.

Three patients with dystrophia myotonica and echocardiographic signs of subclinical cardiopathy had cardiac side effects during oral treatment with phenytoin sodium or carbamazepine. These side effects were dose related: ventricular tachycardia appeared at a toxic serum phenytoin level in one patient and disappeared as the concentration fell within the therapeutic range, and atrioventricular block grade 1 developed in two patients at low serum carbamazepine levels, its severity increasing with the drug level. Given the risk of dangerous side effects, cardiac status needs to be carefully assessed before administration of phenytoin or carbamazepine in the treatment of dystrophia myotonica.

We describe two patients in whom clonazepam withdrawal status epilepticus occurred in spite of therapeutic levels of carbamazepine in plasma and cerebrospinal fluid. The failure of carbamazepine to prevent clonazepam withdrawal status epilepticus is discussed.

The penetration of phenobarbital (PB) into cerebral tissue was determined in cats rendered epileptic by parenteral penicillin and in cats with focal penicillin-induced epilepsy. The results were compared with those from normal controls. In both kinds of experimental models of epilepsy, PB penetration was impaired, although a gradual and progressive accumulation of the drug in the brain tissue was observed in all three groups of cats (binding occurring from time 30 min on). Similar to the events with other substances, such as carbamazepine, the prolonged epileptic activity may have contributed to the impaired penetration of PB, because of severe metabolic alterations secondary to seizures. The present data confirm previous reports indicating that epileptic seizures alter the pharmacokinetics of drugs.

A case of Behr's disease (complicated optic atrophy) associated with epilepsy and with imbalance of the free amino acid pool in plasma and cerebrospinal fluid, quite similar to that identified in patients with hereditary ataxias, is reported. The latter finding stands for a closer correlation between the two clinical entities.

Acute or chronic treatment of epileptic patients with phenytoin is often associated with the appearance of disturbances such as postural impairment and ocular nystagmus, probably due to high toxic plasma levels of the drug. We describe the changes in spontaneous electrical activity of vestibular units in cerebellectomized rats following an acute nontoxic dose of phenytoin, in static conditions and after macular stimulation. Administration of phenytoin induced an inhibition of Deiters cells and a drug level-dependent biphasic effect (excitation followed by inhibition) on medial and superior vestibular cells. The experiments pointed to a direct action of phenytoin on the vestibular nuclear complex, indicating that postural and motor disturbances are not only cerebellar but also vestibular in origin.

Reports of epileptic seizures evoked by eating are very scarce in the literature. A review of the reported cases suggests that various mechanisms may act as triggering factors in this form of reflex epilepsy. We studied a 17-year-old boy in whom the seizures precipitated by eating had been prevented by giving him some alerting stimuli during the meal. The attention-arousal coupling sustained by the meal seems to play a role in triggering the attacks.