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Parkinson´s Disease (PD) is the second most common neurodegenerative disorder, affecting ~2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy Bodies (LBs). Recently, Genome-Wide Association Studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Psychological stress may be a risk factor for dementia, but the association between exposure to stressful life events and the development of cognitive dysfunction has not been conclusively demonstrated. We hypothesize that if a stressful event has an impact on the subjects, its effects would be different in the three diseases., Objective: This study aims to assess the effects of stressful events in senior patients who later developed ischemic stroke, Alzheimer's, or Parkinson's disease., Material and Methods: Together with demographic variables (age, sex, race, socioeconomic and cultural levels), five types of past stressful events, such as death or serious illness of close relatives, job dismissal, change of financial status, retirement, and change of residence, were recorded in 1024 patients with Alzheimer's disease, Parkinson's disease, and ischemic stroke. Time-todiagnosis (months from the event to the first symptoms: retrospective study) and evolution time (years of follow-up of each patient: prospective study) were recorded. The variance and nonparametric methods were analyzed to the variables time-to-diagnosis and evolution time to analyze differences between these diseases., Results: The demographic variables, such as age, sex, race, economic and cultural levels, were found to be statistically non-significant; differences in the economic level were significant (P<0.05). Significant differences (P<0.001) were found in the mean time-to-diagnosis between diseases (Alzheimer's disease>Parkinson's disease >Stroke), and minor differences (P<0.05) in evolution time., Conclusion: Differences in time-to-diagnosis between the diseases indicate that the stressful effect of having experienced the death or serious illness of a close relative has an impact on their emergence. The measurement of time-to-diagnosis and evolution time proves useful in detecting differences between diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Robust evidence has described that Parkinson´s disease (PD) is associated with an increased risk for developing epileptic seizures. In fact, an interplay between PD and epilepsy has been of interest for many years. An emerging hypothesis is that inflammation could link both diseases., Objective: Bearing in mind the experience of our group in the field of Ca 2+ /cAMP signalling pathways, this article discussed, beyond inflammation, the role of these signalling pathways in this link between PD and epilepsy., Methods: Publications involving Ca 2+ /cAMP signalling pathways, PD, and epilepsy (alone or combined) were collected by searching PubMed and EMBASE., Results: The comprehension of the interplay between PD and epilepsy could improve the drug therapy. In addition, a Ca 2+ signalling dyshomeostasis due to Coronavirus disease 2019 (COVID-19), an emerging and rapidly evolving situation, has been reported., Conclusion: Thus, this article also debated recent findings about therapeutics involving Ca2+ channel blockers for preventing Ca 2+ signalling dyshomeostasis due to COVID-19, including the correlation among COVID-19, epilepsy, and PD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: A link between diabetes and Parkinson´s disease (PD) has been established by several reports. Consistent data report that people diagnosed with diabetes have demonstrated an enhanced risk of manifesting PD in their lifetime. The working principles involved in this link have been extensively discussed. Over the last decade, diabetes has been reported to be correlated with an increased risk of dementia, suggesting a potential role of diabetes, or insulin signalling dysregulations, in neurodegeneration. In addition, it is nowadays highly debated that dysregulations related to Ca2+ signalling may be an upstream issue which could also link diabetes and PD. Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling) control both the neurotransmitters/hormones release and neuronal death., Conclusion: Considering our previous reports about Ca2+/cAMP signalling, the putative contribution of Ca2+/cAMP signalling in this link (between diabetes and PD) is discussed in this paper., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Parkinson´s disease (PD) and depression have an interplay at multiple cellular levels, a phenomenon which is translated into clinical data showing that depressive patients presented an enhanced risk for developing PD. The pathogenesis of both diseases is under intensive debate as correlated to dysregulations related to Ca2+ signaling., Objective: Then, revealing this interplay between these diseases may provide novel insights into the pathogenesis of them., Methods: Publications involving Ca2+ signaling, PD and depression (alone or combined) were collected by searching PubMed and EMBASE., Results: Not surprisingly, calcium (Ca2+) channel blockers (CCBs), classical antihypertensive medicines, have been demonstrated off-label effects, such as alleviating both PD and depression symptoms., Discussion: A mechanism under debate for the antiparkinsonism and antidepressant effects associated to CCBs is focused on the restoration of Ca2+ signaling dysregulations. In addition, previous studies have observed that CCBs can affect Ca2+/cAMP signaling., Conclusion: Thus, this article discussed the role of Ca2+/cAMP signaling in the interplay between depression and PD, including the implications for the pharmacotherapy involving CCBs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Neurodegenerative diseases, like Alzheimer´s and Parkinson´s disease, are a group of disorders that have in common their increasingly high prevalence along with the shortage of effective treatments. In addition, the scientific community faces the challenge of getting the drugs used in these treatments to cross the blood-brain barrier (BBB) and reach the brain in sufficient concentration to be able to exert its effect. Hence, researchers across multiple disciplines are working together in order to improve the ability of therapeutics to penetrate the BBB. In this sense, the use of nanomedicine, nanoscale structures for drug delivery, exhibits a really high therapeutic potential in the field of neurodegenerative diseases therapy. Since there is new evidence that neuroinflammation produced by reactive microglia contributes to the activation and pathogenesis of neurological disorders, many investigations focus on the identification of new targets whose inhibition can reduce, totally or partially, microglial activation. This review analyzes a wide variety of compounds as possible candidates to achieve this target, from compounds with a natural origin to anti-diabetics, antidepressants, antibiotics and hormones. We also discuss the different strategies to enhance the capacity of these compounds to cross the BBB. Although this review focuses on PLGA nanoparticles as one of the most versatile drug delivery nanosystems, we also describe other strategies, such as direct intranasal administration (nose-tobrain), novel viral vectors and novel implanted catheters., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Parkinson´s Disease (PD) is a chronic, progressive condition, being the second most common neurodegenerative disorder worldwide. The classical features include: bradykinesia, resting tremor, rigidity and festination. These neurological alterations are probably due to the death of dopaminergic neurons in the Substantia Nigra pars compacta and consequent reduction of dopamine input into the striatum. The decrease of dopamine levels may also be involved in the emergence of non-motor symptoms, including cognitive impairment, anxiety and depression symptoms. Neurotrophic Factors (NF) are proteins that modulate neuronal function, development, and survival. It has been reported that NF might exert a protective role in PD., Objective: We aim to discuss the emerging evidence from pre-clinical and clinical studies regarding the role of NF in PD as well as their potential as promising therapeutic strategies., Methods: We carried out an extensive literature search in PubMed central., Results: Pre-clinical studies using NF to treat PD are divergent probably due to several methodological differences, thus precluding any conclusion. Clinical studies findings obtained with the administration of NF in patients with PD were even more disappointed. On the other hand, pre-clinical and clinical studies generally support that physical activity is a low-cost, non-pharmacologic strategy with good results to treat PD., Conclusion: The use of NF as a treatment for PD is still a promise not incorporated in clinical practice. Methods to deliver NFs, doses and compounds administered, side effects, population characteristics and duration of disease may probably contribute to the unsuccessful results., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

A new controlled delivery system has been developed for ropinirole (RP) for the treatment of Parkinson´s Disease (PD) consisting in PLGA microparticles (MPs) which exhibited in vitro constant release of RP (78.23 µg/day/10 mg MPs) for 19 days. The neuroprotective effects of RP released from MPs were evaluated in SKN-AS cells after exposure to rotenone (20 µM). Cell apoptosis was significantly reduced by RP (100-120 µM). Daily doses of rotenone (2 mg/kg) given i.p. to rats induced neuronal and behavioral changes similar to those of PD. After 15 days, animals received RP in saline (1 mg/kg/day for 45 days) or as MPs at two dose levels (amount of MPs equivalent to 7.5 mg/kg or 15 mg/kg RP given on days 15 and 30). Brain immunochemistry (Nisslstaining, GFAP and TH immunohistochemistry) and behavioral testing (catalepsy, akinesia, rotarod and swim test) showed that animals receiving RP either in solution or encapsulated within the MPs reverted the PD symptoms with the best results obtained in animals receiving RP microspheres at the highest dose assayed, thereby confirming the potential therapeutic interest of the new RP delivery system., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Alzheimer's and Parkinson's disease represent the two most common neurodegenerative disorders, affecting an increasing number of patients worldwide. Population ageing and lack of effective therapies and biomarkers strongly contribute to the socio-economical impact of these conditions. Message and Conclusion: The aim of the review is to present a summary of the discoveries made on the epigenetics of Alzheimer's and Parkinson's disease, with a special focus on the recent advances towards the identification of new targeted therapies and biomarkers. Data supporting broad spectrum and selective small-molecule inhibition of enzymes controlling DNA methylation and histone modifications are discussed in the context of Alzheimer's and Parkinson's disease. The results obtained from studies performed on patients samples are also mentioned, to provide a picture of the efforts made toward identification of epigenetic-based biomarkers. Finally, given the importance of non-coding RNAs in neurodegeneration, their contribution to Alzheimer's and Parkinson's disease will be examined, together with a brief summary of the available miRNA-based biomarker signatures for these two conditions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

NADPH oxidase (Nox) is a unique, multi-protein, electron transport system that produces large amounts of superoxide via the reduction of molecular oxygen. Nox-derived reactive oxygen species (ROS) are known to be involved in a variety of physiological processes, including host defense and signal transduction. However, over the past decade, the involvement of (Nox)-dependent oxidative stress in the pathophysiology of several neurodegenerative diseases has been increasingly recognized. ROS produced by Nox proteins contribute to neurodegenerative diseases through distinct mechanisms, such as oxidation of DNA, proteins, lipids, amino acids and metals, in addition to activation of redox-sensitive signaling pathways. In this review, we discuss the recent literature on Nox involvement in neurodegeneration, focusing on Parkinson and Alzheimer diseases.

Neuroprotection refers to the protection of neurons from excitotoxicity, oxidative stress and apoptosis as principal mechanisms of cell loss in a variety of diseases of the central nervous system. Our interest in Parkinson's disease (PD) treatment is focused on drugs with neuroprotective properties in preclinical experiments and evidence-based efficacy in human subjects. To this date, neuroprotection has never been solidly proven in clinical trials but recent adequate markers and/or strategies to study and promote this important goal are described. A myriad of compounds with protective properties in cell cultures and animal models yield to few treatments in clinical practice. At present, markers of neuronal vitality, disease modifying effects and long term clinical stability are the elements searched for in clinical trials. This review highlights new strategies to monitor patients with PD. Currently, neuroprotection in subjects has not been solidly achieved for selegiline and pramipexole; however, a recent rasagiline trial design is showing new indications of disease course modifying effects. In neurological practice, it is of utmost importance to take into account the potential neuroprotection exerted by a treatment in conjunction with its symptomatic efficacy.