Neuroprotection in Parkinson’s disease : a realistic goal?

The current issue of CNS Neuroscience & Therapeutics contains an interesting review by Kinecses and Vecsei on the progress in our knowledge related to the pathophysiological mechanisms of Parkinson’s disease (PD) and on the development of putative neuroprotective molecules. Since the seminal discovery by Oleh Hornykiewicz that degeneration of DA neurons within the substantia nigra pars compacta (SNc) and the consequential dopamine depletion in the striatum was the cause of neurological symptoms in PD, thousands of reviews have been written on the subject, some of them possibly superfluous. Nevertheless, we found this last work enjoyable in terms of readability and in the way the authors decided to tackle such a difficult enterprise. This brief literature review is obviously far from comprehensive or exhaustive, as it would be impossible to summarize 50 years of fruitful research in the PD field in a few pages. The main contribution of this review is the general overview of the pathomechanism field and a survey of the literature that it provides on the hot topic of neuroprotection. Indeed, molecules able to slow and halt dopaminergic neuronal loss represent the highest ambition of PD research, drug companies and not least, patients. In recent years, research has advanced to the point that halting the progression of PD, restoring lost function, and even preventing the disease might be considered realistic goals. Nevertheless the ultimate goal of preventing PD may take years to achieve, and no strong experimental confirmation hitherto is available for any of the compounds described by Kinecses and Vecsei and others that the authors have not cited.peer-reviewe

Behaviour of consumers of conventional and organic flowers and ornamental plants in Italy

The paper analyses preferences and motivations of Italian consumers of flowers and ornamental plants, both conventional and organic. The results helped to outline their profile. Purchases are still done in the traditional places (flower shops for cut flowers and plant nurseries for potted plants), however positive trend is found for potted plants purchases at large distribution chains. Some differences came out as to purchase motivations: cut flowers are mainly bought in special occasions whereas potted plants purchases are linked to personal use. The results confirm a positive relationship between the purchase of flowers and plants and the age of the interviewees, besides showing that women are interested on purchases. The information we obtained is relevant not only for the sector’s operators in order to define effective managerial strategies, but also for the policy maker to address new market and consumption policies

Impairment of sleep homeostasis in cervical dystonia patients.

Alterations in brain plasticity seem to play a role in the pathophysiology of cervical dystonia (CD). Since evidences indicate that sleep regulates brain plasticity, we hypothesized that an alteration in sleep homeostatic mechanisms may be involved in the pathogenesis of CD. We explored sleep in control subjects (CTL) and CD patients before (Tpre-BoNT) and after (Tpost-BoNT) botulinum toxin (BoNT) treatment. A physiological slow wave activity (SWA) power decrease throughout the night was observed in CTL but not in CD at Tpre-BoNT. BoNT restored the physiological SWA decrease in CD at Tpost-BoNT. Furthermore, in the first part of the night, CD at Tpost-BNT showed a frontal increase and parietal decrease in SWA power compared to CD at Tpre-BoNT, with a SWA distribution comparable to that observed in CTL. Our data highlighted a pathophysiological relationship between SWA during sleep and CD and provided novel insight into the transient central plastic effect of BoNT

High dose of 8-OH-DPAT decreases maximal dentate gyrus activation and facilitates granular cell plasticity in vivo

Although several studies have emphasized a crucial role for the serotonergic system in the control of hippocampal excitability, the role of serotonin (5-HT) and its receptors in normal and pathologic conditions, such as temporal lobe epilepsy (TLE), is still unclear. The present study was therefore designed firstly to investigate the acute effect of 8-OH-DPAT, a mixed 5-HT1A/7 receptor agonist, at a high dose (1 mg/kg, i.p.) known to have antiepileptic properties, in a model of acute partial epilepsy in rats. For this purpose, a maximal dentate activation (MDA) protocol was used to measure electrographic seizure onset and duration. In addition, the effect of 8-OH-DPAT on in vivo dentate gyrus cell reactivity and short- and long-term plasticity was studied. Rats injected with 8-OH-DPAT exhibited a significant reduction in MDA and epileptic discharges, a decrease in paired-pulse facilitation and an increase in long-term potentiation. This study suggests that 8-OH-DPAT or in general 5-HT1A/7 agonists might be useful for the treatment of TLE and also have some beneficial effects on the comorbid cognitive disorders seen in epileptic patients.peer-reviewe

Identification of Human Dihydroorotate Dehydrogenase Inhibitor by a Pharmacophore-Based Virtual Screening Study

Human dihydroorotate dehydrogenase (hDHODH) is an enzyme belonging to a flavin mononucleotide (FMN)-dependent family involved in de novo pyrimidine biosynthesis, a key biological pathway for highly proliferating cancer cells and pathogens. In fact, hDHODH proved to be a promising therapeutic target for the treatment of acute myelogenous leukemia, multiple myeloma, and viral and bacterial infections; therefore, the identification of novel hDHODH ligands represents a hot topic in medicinal chemistry. In this work, we reported a virtual screening study for the identification of new promising hDHODH inhibitors. A pharmacophore-based approach combined with a consensus docking analysis and molecular dynamics simulations was applied to screen a large database of commercial compounds. The whole virtual screening protocol allowed for the identification of a novel compound that is endowed with promising inhibitory activity against hDHODH and is structurally different from known ligands. These results validated the reliability of the in silico workflow and provided a valuable starting point for hit-to-lead and future lead optimization studies aimed at the development of new potent hDHODH inhibitors

Reduced GABA Content in the Motor Thalamus during Effective Deep Brain Stimulation of the Subthalamic Nucleus

Deep brain stimulation (DBS) of the subthalamic nucleus (STN), in Parkinson's disease (PD) patients, is a well established therapeutic option, but its mechanisms of action are only partially known. In our previous study, the clinical transitions from OFF- to ON-state were not correlated with significant changes of GABA content inside GPi or substantia nigra reticulata. Here, biochemical effects of STN-DBS have been assessed in putamen (PUT), internal pallidus (GPi), and inside the antero-ventral thalamus (VA), the key station receiving pallidothalamic fibers. In 10 advanced PD patients undergoing surgery, microdialysis samples were collected before and during STN-DBS. cGMP, an index of glutamatergic transmission, was measured in GPi and PUT by radioimmunoassay, whereas GABA from VA was measured by HPLC. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in VA (−30%). Simultaneously, cGMP extracellular concentrations were enhanced in PUT (+200%) and GPi (+481%). These findings support a thalamic dis-inhibition, in turn re-establishing a more physiological corticostriatal transmission, as the source of motor improvement. They indirectly confirm the relevance of patterning (instead of mere changes of excitability) and suggest that a rigid interpretation of the standard model, at least when it indicates the hyperactive indirect pathway as key feature of hypokinetic signs, is unlikely to be correct. Finally, given the demonstration of a key role of VA in inducing clinical relief, locally administration of drugs modulating GABA transmission in thalamic nuclei could become an innovative therapeutic strategy

STXBP6 Gene Mutation: A New Form of SNAREopathy Leads to Developmental Epileptic Encephalopathy

Syntaxin-binding protein 6 (STXBP6), also known as amysin, is an essential component of the SNAP receptor (SNARE) complex and plays a crucial role in neuronal vesicle trafficking. Mutations in genes encoding SNARE proteins are often associated with a broad spectrum of neurological conditions defined as "SNAREopathies", including epilepsy, intellectual disability, and neurodevelopmental disorders such as autism spectrum disorders. The present whole exome sequencing (WES) study describes, for the first time, the occurrence of developmental epileptic encephalopathy and autism spectrum disorders as a result of a de novo deletion within the STXBP6 gene. The truncated protein in the STXBP6 gene leading to a premature stop codon could negatively modulate the synaptic vesicles' exocytosis. Our research aimed to elucidate a plausible, robust correlation between STXBP6 gene deletion and the manifestation of developmental epileptic encephalopathy

Cortical slow wave activity correlates with striatal synaptic strength in normal but not in Parkinsonian rats

Urethane-induced cortical slow wave activity (SWA) spreads into the basal ganglia in dopamine (DA)-depleted rat models of Parkinson's disease (PD). During physiological sleep, SWA is powerfully expressed at the beginning of night and progressively reduced during sleep-time reflecting the sleep need. However, its underlying slow oscillations may contribute directly to modulate cortical plasticity. In order to determine the impact of the SWA on synaptic strength and its interplay with DA, we simultaneously recorded the electrocorticogram (ECoG) and the corticocortical- and corticostriatal-evoked potentials (CC-EPs, CS-EPs) during eight hours of robust urethane-induced SWA in both normal and PD animals. A subgroup of PD rats was assessed with repetitive apomorphine (APO) administrations. Normal animals showed a progressive reduction of SWA power during urethane-induced SWA. Compared to normal animals, PD animals showed lower SWA power at the start of anesthesia without a significant reduction over time. Accordingly, synaptic strength measured by CC- and CS-EP amplitudes decreased in normal but not in Parkinsonian rats. The PD animals treated with APO showed a CS-EP amplitude reduction comparable to normal animals. Interestingly, SWA power directly correlated with CS-EP amplitude in normal animals. These data support the hypothesis that cortical SWA is directly associated with the regulation of synaptic efficacy in which DA exerts a crucial role

Persoalan Pewarisan Kuasa Menurut al-Quran: Analisis Politik Dunia Islam Hari Ini

Tulisan ini cuba untuk meninjau keadaan politik dunia Islam hari ini yang dilihat berada dalam keadaan yang lemah berbanding saingan mereka iaitu barat (bukan Islam) dan sekutunya. Untuk itu, tulisan ini akan meneliti nas berkaitan dengan pewarisan kuasa (warathat al-ard) dengan menjadikan ayat 105, surah alAnbiya’ sebagai asas kepada penelitian tersebut. Seterusnya keadaan semasa politik Islam ini akan dianalisis berdasarkan nas di atas beserta beberapa nas yang lain. Di akhir tulisan ini, penulis akan cuba mengemukakan perkara yang diperlukan oleh dunia Islam hari ini sepertimana yang dianjurkan oleh nas berkenaan pewarisan kuasa ini. Akhirnya diharapkan tulisan ini dapat memberikan panduan kepada umat Islam khususnya di Malaysia dalam mendepani cabaran politik dunia hari ini