Pathophysiology of motor dysfunction in Parkinson\u2019s Disease as the rationale for drug treatment and rehabilitation

Cardinal motor features of Parkinson\u2019s disease (PD) include bradykinesia, rest tremor, and rigidity, which appear in the early stages of the disease and largely depend on dopaminergic nigrostriatal denervation. Intermediate and advanced PD stages are characterized by motor fluctuations and dyskinesia, which depend on complex mechanisms secondary to severe nigrostriatal loss and to the problems related to oral levodopa absorption, and motor and nonmotor symptoms and signs that are secondary to marked dopaminergic loss and multisystem neurodegeneration with damage to nondopaminergic pathways. Nondopaminergic dysfunction results in motor problems, including posture, balance and gait disturbances, and fatigue, and nonmotor problems, encompassing depression, apathy, cognitive impairment, sleep disturbances, pain, and autonomic dysfunction. There are a number of symptomatic drugs for PD motor signs, but the pharmacological resources for nonmotor signs and symptoms are limited, and rehabilitation may contribute to their treatment. The present review will focus on classical notions and recent insights into the neuropathology, neuropharmacology, and neurophysiology of motor dysfunction of PD. These pieces of information represent the basis for the pharmacological, neurosurgical, and rehabilitative approaches to PD

IDENTIFICATION AND STRUCTURAL CHARACTERIZATION OF BY- PRODUCTS IN THE SYNTHESIS OF 2- AND 3-SULFONYLINDOLES BY EI, ESI-HRMS AND TANDEM MASS SPECTROMETRY

Indole skeleton is a widespread motif in many natural products, pharmaceuticals, and fine chemicals. In particular, considerable attention has been focused on 1- and 3-arylsulfonyl-1H-indoles, some of which demonstrated to be valid HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) In an attempt to prepare more potent heterocyclic derivatives which incorporate the indole nucleus, we synthesised a new series of 2- and 3-sulfonylindoles derivatives by ZnO-mediated regioselective C-arylsulfonylation of indoles using aromatic sulfonyl chlorides under solvent free conditions [1]. However, while developing our methodology, we observed, together with the desired sulfonylindoles, the formation of unexpected by-products when sulfonyl chlorides bearing strong electron withdrawing groups were used. To gain insight into the structure of these unknown compounds and the chemistry of their formation, we decided to undertake first HRMS experiments upon electrospray ionization. Subsequently, in order to achieve more structural information, we performed MSn experiments on the protonated species and on the molecular ion obtained under ESI and EI conditions, respectively. Unexpectedly, we found that the m/z values of the M+. ions observed under EI conditions were shifted, under ESI condition, to m/z 16 higher than expected. These data suggested that these molecules are susceptible to oxidation in positive –ion ESI to form a [M+H+O]+ species. In this work we report the strategy employed for the unequivocal identification of the unknown by-products together with the general fragmentation scheme useful for the identification of similar derivatives

Somatosensory temporal discrimination threshold involves inhibitory mechanisms in the primary somatosensory area

Somatosensory temporal discrimination threshold (STDT) is defined as the shortest time interval necessary for a pair of tactile stimuli to be perceived as separate. Although STDT is altered in several neurological disorders, its neural bases are not entirely clear. We used continuous theta burst stimulation (cTBS) to condition the excitability of the primary somatosensory cortex in healthy humans to examine its possible contribution to STDT. Excitability was assessed using the recovery cycle of the N20 component of somatosensory evoked potentials (SEP) and the area of high-frequency oscillations (HFO). cTBS increased STDT and reduced inhibition in the N20 recovery cycle at an interstimulus interval of 5 ms. It also reduced the amplitude of late HFO. All three effects were correlated. There was no effect of cTBS over the secondary somatosensory cortex on STDT, although it reduced the N120 component of the SEP. STDT is assessed conventionally with a simple ascending method. To increase insight into the effect of cTBS, we measured temporal discrimination with a psychophysical method. cTBS reduced the slope of the discrimination curve, consistent with a reduction of the quality of sensory information caused by an increase in noise. We hypothesize that cTBS reduces the effectiveness of inhibitory interactions normally used to sharpen temporal processing of sensory inputs. This reduction in discriminability of sensory input is equivalent to adding neural noise to the signal

Haloacetophenones as newly potent nematicides against Meloidogyne incognita

Acetophenones are a class of aromatic compounds frequently produced by plants as a response to a stress or as a protection reaction against parasites or herbivors. In the present research, we investigated the role of the carbonyl moiety in a series of commercially available aromatic ketones tested for their nematicidal activity against the root-knot nematode Meloidogyne incognita (Kofoid et White) Chitwood. Interestingly, we found that the presence of electron withdrawing groups onto the aromatic ring were highly efficient in inducing nematode paralysis and death (EC50/24h between 2.5 and 54.8mg/L and EC50/72h between 2.3 and 65.6mg/L, respectively). Moreover, a chlorine atom in α-position to the carbonyl functionality emerged as a key residue in improving acetophenones activity. In this paper, the nematicidal ability of a series of differently substituted acetophenones is reported and the preliminary structure-activity relationship studies are also discussed. We also performed an in vitro GC-MS metabolomics analysis on the potato cyst nematode Globodera pallida, after treatment with 2,4'-dichloroacetophenone (6) at 100mg/L for 24h. The 1-dodecanol and talose were evidenced as the main upregulated metabolites, suggesting a possible V-ATPase dysfunction

Electron-Deficient Alkynes as Powerful Tools against Root-Knot Nematode Melodogyne incognita: Nematicidal Activity and Investigation on the Mode of Action

The present study reports on the powerful nematicidal activity of a series of electron-deficient alkynes against the root-knot nematode Meloidogyne incognita (Kofoid and White) Chitwood. Interestingly, we found that the conjugation of electron-withdrawing carbonyl groups to an alkyne triple bond was extremely proficient in inducing nematode paralysis and death. In particular, dimethylacetylenedicarboxylate (10), 3-butyn-2-one (1), and methyl propiolate (4), with EC50/48 h of 1.54 ± 0.16, 2.38 ± 0.31, and 2.83 ± 0.28 mg/L, respectively, were shown to be the best tested compounds. Earlier studies reported on the ability of alkynoic esters and alkynones to induce a chemoselective cysteine modification of unprotected peptides. Thus, also following our previous findings on the impairment of vacuolar-type proton translocating ATPase functionality by activated carbonyl derivatives, we speculate that the formation of a vinyl sulfide linkage might be responsible for the nematicidal activity of the presented electron-deficient alkynes

Painful legs and moving toes syndrome: putative underlying pathophysiology as a hint for combined pharmacological treatment?

[no abstract available

Hemichorea-hemiballismus in patients with non-ketotic hyperglycemia

[no abstract available

ZnO-mediated regioselective C-arylsulfonylation of indoles: A facile solvent-free synthesis of 2- and 3-sulfonylindoles and preliminary evaluation of their activity against drug-resistant mutant HIV-1 reverse transcriptases (RTs)

A ZnO-mediated one-pot solvent-free protocol for the regioselective C-arylsulfonylation of indoles is described and some novel derivatives were tested on wild type and non-nucleoside inhibitor resistant K103N and Y181C HIV-1 reverse transcriptases (RTs)

Pain perception in major depressive disorder: A neurophysiological case-control study

BACKGROUND: Depression and pain may sometimes be related conditions. Occasionally, depression may be associated with physical symptoms, such as back pain and headache. Moreover, depression may impair the subjective response to pain and is likely to influence the pain feeling. Conversely, chronic pain may represent an emotional condition as well as physical sensation, and can influence both the mood and behaviour. AIM: To better understand the relationship between pain and depression, we therefore assessed the pain threshold and the tolerance pain threshold in patients with depressive disorders. MATERIALS AND METHODS: We conducted a case-control study and selected patients who had recently received a diagnosis of major depression (DSM-IV), before treatment, and without any significant pain complaints. Age- and sex-matched healthy controls were also included. Tactile and pain thresholds were assessed in all subjects through an electrical stimulation test. All results were compared between the groups. RESULTS: 27 patients and 27 age-matched healthy controls were included in the study. Tactile, pain and tolerance thresholds were evaluated in all subjects. The pain threshold and pain tolerance were lower in patients with major depression than controls. All differences were statistically significant (p<0.05). CONCLUSION: These results suggest the abnormal processing of pain stimuli in depressive disorders

Nematicidal activity of 2-thiophenecarboxaldehyde and methylisothiocyanate from caper (Capparis spinosa) against Meloidogyne incognita

New pesticides based on plant extracts have recently gained interest in the development of nontoxic crop protection chemicals. Numerous research studies are focused on the isolation and identification of new active compounds derived from plants. In this manuscript we report about the use of the Mediterranean species Capparis spinosa as a potent natural nematicidal agent against the root knot nematodes Meloidogyne incognita. Leaves, stems, and caper buds of Capparis spinosa were used to obtain their methanol extracts (LME, SME, BME) that were successively in vitro tested against second stage nematode juveniles (J2). In terms of paralysis induction, the methanol extract of the stem part (SME) was found more effective against M. incognita and then the caper methanol buds and leaves extracts. The chemical composition analysis of the extracts carried out by GC/MS and LC/MS techniques showed that methylisothiocyanate was the main compound of SME. The EC50 for SME after 3 days of immersion was 215 ± 36 mg/L. The constituent components of SME such as 2- thiophenecarboxaldehyde and methylisothiocyanate were successively in vitro tested for their nematicidal activity against J2. Both compounds induced paralysis on root knot nematodes ranking first (EC50 = 7.9 ± 1.6, and 14.1 ± 1.9 mg/L respectively) for M. incognita. Moreover, 2-thiophenecarboxaldehyde showed a strong fumigant activity