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Noninvasive brain stimulation techniques can be used to study in vivo the changes of cortical activity and plasticity in subjects with Parkinson's disease (PD). Also, an increasing number of studies have suggested a potential therapeutic effect of these techniques. High-frequency repetitive transcranial magnetic stimulation (rTMS) and anodal transcranial direct current stimulation (tDCS) represent the most used stimulation paradigms to treat motor and nonmotor symptoms of PD. Both techniques can enhance cortical activity, compensating for its reduction related to subcortical dysfunction in PD. However, the use of suboptimal stimulation parameters can lead to therapeutic failure. Clinical studies are warranted to clarify in PD the additional effects of these stimulation techniques on pharmacologic and neurorehabilitation treatments., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Patients with Parkinson disease (PD) may show impairments in the social perception. Whether these deficits have been consistently reported, it remains to be clarified which brain alterations subtend them. To this aim, we conducted a neuroimaging meta-analysis to compare the brain activity during social perception in patients with PD versus healthy controls. Our results show that PD patients exhibit a significantly decreased response in the basal ganglia (putamen and pallidum) and a trend toward decreased activity in the mirror system, particularly in the left parietal cortex (inferior parietal lobule and intraparietal sulcus). This reduced activation may be tied to a disruption of cognitive resonance mechanisms and may thus constitute the basis of impaired others' representations underlying action and emotion perception. We also found increased activation in the posterior cerebellum in PD, although only in a within-group analysis and not in comparison with healthy controls. This cerebellar activation may reflect compensatory mechanisms, an aspect that deserves further investigation. We discuss the clinical implications of our findings for the development of novel social skill training programs for PD patients., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Gastrointestinal (GI) motility disorders include many clinical manifestations associated with various pathologies. They are widespread and can be considered a primary symptom or can be associated to other diseases, such as Parkinson's disease. Understanding the type and site of GI dysmotility is crucial to identify the functional abnormality and to unravel the underlying mechanisms, in order to design adequate therapeutic interventions., Methods: In the present study, we applied radiological analysis, a common tool in clinical practice, to follow up in vivo the progression of GI dysmotility over time and along the entire GI tract in an animal model of central nervous dopaminergic degeneration and compared these results to those obtained with standard techniques commonly used to assess GI motor functions in small rodents., Results: Our radiological data, showing delayed gastric emptying and constipation, agree with and expand previous information obtained with other functional assays in the same model, suggesting that radiological analysis can be an appropriate method to explore GI dysmotility in animal models of human pathologies., Discussion: In this study we have applied for the first time the GI radiological analysis to an animal model of central nervous dopaminergic degeneration providing a non-invasive/animal-preserving approach, ethically more acceptable and useful to follow up the development of GI dysmotility in pathologies evolving over time., (Copyright © 2014 Elsevier Inc. All rights reserved.)

CHF5074 is a non-steroidal anti-inflammatory derivative holding disease-modifying potential for the treatment of Alzheimer's disease. The aim of the present study was to characterize the electrophysiological and metabolic profile of CHF5074 in the hippocampus. Electrophysiological recordings show that CHF5074 inhibits in a dose-dependent manner the current-evoked repetitive firing discharge in CA1 pyramidal neurons. This result is paralleled by a dose-dependent reduction of field excitatory post-synaptic potentials with no effect on the paired-pulse ratio. The effects of CHF5074 were not mediated by AMPA or NMDA receptors, since the inward currents induced by local applications of AMPA and NMDA remained constant in the presence of this compound. We also suggest a possible activity of CHF5074 on ASIC1a receptor since ASIC1a-mediated current, evoked by application of a pH 5.5 solution, is reduced by pretreatment with this compound. Moreover, we demonstrate that CHF5074 treatment is able to counteract in hippocampal slices the OGD-induced increase in alanine, lactate and acetate levels. Finally, CHF5074 significantly reduced the apoptosis in hippocampal neurons exposed to OGD, as revealed by cleaved-caspase-3 immunoreactivity and TUNEL staining. Overall, the present work identifies novel mechanisms for CHF5074 in reducing metabolic acidosis, rendering this compound potentially useful also in conditions of brain ischemia., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Bergamot (Citrus bergamia, Risso et Poiteau) essential oil (BEO) is a widely used plant extract showing anxiolytic, analgesic and neuroprotective effects in rodents; also, BEO activates multiple death pathways in cancer cells. Despite detailed knowledge of its chemical composition, the constituent/s responsible for these pharmacological activities remain largely unknown. Aim of the present study was to identify the components of BEO implicated in cell death. To this end, limonene, linalyl acetate, linalool, γ-terpinene, β-pinene and bergapten were individually tested in human SH-SY5Y neuroblastoma cultures at concentrations comparable with those found in cytotoxic dilutions of BEO. None of the tested compounds elicited cell death. However, significant cytotoxicity was observed when cells were cotreated with limonene and linalyl acetate whereas no other associations were effective. Only cotreatment, but not the single exposure to limonene and linalyl acetate, replicated distinctive morphological and biochemical changes induced by BEO, including caspase-3 activation, PARP cleavage, DNA fragmentation, cell shrinkage, cytoskeletal alterations, together with necrotic and apoptotic cell death. Collectively, our findings suggest a major role for a combined action of these monoterpenes in cancer cell death induced by BEO., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Gastrointestinal disorders, constipation in particular, are the most common non-motor dysfunctions affecting Parkinson's disease (PD) patients. We have previously reported that rats bearing unilateral nigrostriatal lesion caused by 6-hydroxydopamine (6-OHDA) stereotaxic injection develop severe constipation together with a region-specific decrease of neuronal nitric oxide synthase (nNOS) in enteric neurons of the lower intestinal tract. Here, we extend these observations on other enteric neuronal subpopulations, investigating also the propulsive activity of isolated colonic specimens. Four weeks post 6-OHDA injection, lesioned rats showed a significant increase of vasoactive intestinal polypeptide (VIP) concomitant with the reduced expression of nNOS in the myenteric plexus of distal ileum and proximal colon; in particular VIP increased in a subpopulation of neurons actively expressing nNOS. On the other hand, choline acetyltransferase (ChAT) was not modified in any of the intestinal segments analyzed. Interestingly, we found a reduced expression of dopamine receptor type 2 (D2R) in proximal (-66.8%) and distal (-54.5%) colon, together with reduced peristalsis efficiency (decrease in intraluminal pressure and frequency of peristaltic events) in the 6-OHDA-lesioned rats. The selective depletion of dopaminergic nigrostriatal neurons is associated with changes in the expression of enteric inhibitory neurotransmitters, as well as of the D2R in intestinal specific regions. Moreover, 6-OHDA-lesioned rats demonstrated altered colon propulsive activity referable to the D2R decrease. Our findings unveil subtle mechanisms underlying the enteric neurochemical plasticity events evoked by disruption of the normal brain-gut cross-talk, giving a peculiar point of view on the pathophysiology of the severe constipation that frequently affects PD patients., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Alteration of key regulatory kinases may cause aberrant protein phosphorylation and aggregation in Alzheimer's disease (AD) and Parkinson's disease (PD). In this study, we investigated expression and phosphorylation status of glycogen synthase kinase 3 (GSK-3), protein kinase B (Akt) and tau protein in peripheral blood lymphocytes of 20 AD, 25 PD patients and 20 healthy controls. GSK-3 was increased in AD and PD patients. In these latter, GSK-3 levels were positively correlated with daily L-Dopa intake. Phosphorylated Akt expression was augmented in both groups; total Akt levels were increased only in AD patients and were positively correlated with disease duration and severity. Total and phosphorylated tau were increased only in AD, with phospho-tau levels being positively correlated with levels of total tau, Akt, and disease duration. No correlations between protein levels and clinical variables were found in PD patients. Investigation of peripheral changes in the expression of specific kinases may, therefore, lead to the development of innovative biomarkers of neurodegeneration, particularly for AD., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Homocysteine, a sulphur-containing amino acid formed by demethylation of methionine, is involved in numerous processes of methyl group transfer, all playing pivotal roles in the biochemistry of the human body. Increased levels of plasma homocysteine (hyperhomocysteinemia) - which may result from a deficiency of folate, vitamin B6 or B12 or mutations in enzymes regulating the catabolism of homocysteine - are associated with a wide range of clinical manifestations, mostly affecting the central nervous system (e.g., mental retardation, cerebral atrophy and epileptic seizures). Recent evidence suggests that changes in the metabolic fate of homocysteine, leading to hyperhomocysteinemia, may also play a role in the pathophysiology of neurodegenerative disorders, particularly Parkinson's disease (PD). The nervous system might be particularly sensitive to homocysteine, due to the excitotoxic-like properties of the amino acid. However, experimental findings have shown that homocysteine does not seem to posses direct, cytotoxic activity, while the amino acid has proven able to synergize with more specific neurotoxic insults. Hyperhomocysteinemia has been repeatedly reported in PD patients; the increase, however, seems mostly related to the methylated catabolism of l-Dopa, the main pharmacological treatment of PD. Therefore, hyperhomocysteinemia may not be specific to movement disorders or other neurological diseases, the condition being, in fact, rather the result of the combinations of different factors, mainly metabolic, but also genetic and pharmacological, intervening in the neurodegenerative process.

The formation of the hydroxyl free radical (HFR) can be quantified indirectly, by measuring two products of the hydroxylation of salicylic acid, 2,3-dihydroxybenzoate (2,3-DHB) and 2,5-dihydroxybenzoate (2,5-DHB). In this study, we used reversed-phase high-performance liquid chromatography with electrochemical (coulometric) detection to measure 2,3-and 2,5-DHB levels in human platelets. The limits of detection of the method were 10 and 5 fmol on column for 2,3-DHB and 2,5-DHB, respectively. We tested the technique by measuring increases in dihydroxybenzoate levels after exposure of platelets to experimentally induced oxidative stress. Then, we measured platelet levels of 2,3- and 2,5-DHB in patients with Parkinson's disease, under therapy with L-DOPA, and in normal subjects. We also measured platelet concentrations of L-DOPA and its major metabolite, 3-O-methyldopa (3-OMD). Parkinsonian patients showed increased levels of both 2,3- and 2,5-DHB. Platelet levels of 2,3-DHB were positively correlated with platelet levels of L-DOPA and 3-OMD. The technique we describe proved simple and extremely sensitive and may represent a useful tool for the study of oxidative stress in humans.

Various high-performance liquid chromatographic (HPLC) methods for the determination of plasma levels of L-dopa and of its metabolite, 3-O-methyldopa (3-OMD), have been previously described. In this study, we report a modification of these methods, that enables the assay of these two compounds in platelets and plasma obtained from the same sample of whole blood. Reversed-phase (RP) HPLC with electrochemical (coulometric) detection was used. The within-run and between-run coefficients of variations, for the two compounds, were less than 10%, in both platelets and plasma; the detection limits for platelet levels of L-dopa and 3-OMD were 2 and 6 ng/10(9) platelets, respectively. In plasma, the detection limits for L-dopa and 3-OMD were 1 and 3 ng/ml, respectively. The method is rapid and simple. When applied to a population of patients with Parkinson's disease under treatment with L-dopa, this method revealed detectable levels of L-dopa and 3-OMD in the platelets of all patients. The application of this technique may provide new insights into the pharmacokinetics of L-dopa in patients with Parkinson's disease.

We have developed an assay for the binding of [3H]-dihydrorotenone ([3H]DHR), an analogue of the pesticide rotenone, to the mitochondrial enzyme, complex I, in intact human platelets. The highly hydrophobic nature of dihydrorotenone, which diffuses easily through biological membranes, rendered the isolation of mitochondrial fractions unnecessary. This allowed us to reduce the amount of blood required and to shorten the processing of samples considerably. [3H]-DHR binding was saturable, specific, and highly reproducible. We also found that MPP+ (1-methyl-4-phenyl-pyridinium species), which is accumulated actively by platelets, inhibited [3H]DHR specific binding in a concentration-dependent manner. This method could provide a simple tool for the study of complex I in those disorders, such as Parkinson's disease (PD), in which a defect of this enzyme has been suggested.

Platelet catecholamines (CAs) do not seem to reflect the acute increases in plasma CAs observed during stress, at least over short periods of time. However, it is well known that stress, via the release of plasma CAs, is capable of affecting platelet function. To better address this issue, we studied platelet and plasma levels of free noradrenaline (NA), adrenaline (A), and dopamine (DA) in 10 healthy subjects undergoing three different stress tests: insulin tolerance test (ITT), cold pressor test (CPT) and handgrip test (HT). We also evaluated platelet count and platelet mean volume (MPV). ITT caused a considerable increase in plasma NA and a massive release of plasma A, while CPT and HT induced discrete increases only in plasma NA. ITT induced a significant decrease in platelet DA and a trend toward a decrease in platelet NA, along with a significant increase in MPV. All these changes occurred in coincidence with the peak levels of plasma CAs. No changes in platelet variables were observed in response to both CPT and HT. The modifications observed during ITT are likely to represent signs of an initial platelet activation in response to the acute plasma CA elevations this test was able to elicit. Our data show that platelet CA content does not represent a mere reflection of the circulating concentrations of plasma CAs, but it is the result of a dynamic balance between these two compartments.

The platelet and plasma levels of catecholamines (CA) were simultaneously studied in a group of normal subjects in order to find possible sex-related changes in the distribution of CA in these two compartments. No significant differences between males and females were observed, but a marked platelet noradrenaline increase was found in the luteal phase as compared to the follicular phase. Furthermore, the platelet and plasma CA levels were strongly correlated in the male group but not in the female group. These results, while confirming the existence of a menstrual-related variability in noradrenergic activity, suggest a sex-related difference in the dynamic balance between platelet and plasma CA levels. The simultaneous assay of platelet and plasma CA enabled this phenomenon to be revealed, whereas the separate evaluation of platelet or plasma CA levels would not have done so.