Parkinson's disease is a neurodegenerative disorder characterized by a combination of severe motor and non-motor symptoms. Over the years, several factors have been discovered to play a role in the ...pathogenesis of this disease, in particular, neuroinflammation and oxidative stress. To date, the pharmacological treatments used in Parkinson's disease are exclusively symptomatic. For this reason, in recent years, the research has been directed towards the discovery and study of new natural molecules to develop potential neuroprotective therapies against Parkinson's disease. In this context, natural polyphenols have raised much attention for their important anti-inflammatory and antioxidant properties, but also for their ability to modulate protein misfolding. In this review, we propose to summarize the relevant in vivo and in vitro studies concerning the potential therapeutic role of natural polyphenols in Parkinson's disease.
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta, leading to classical PD motor symptoms. Current ...therapies are purely symptomatic and do not modify disease progression. Cannabidiol (CBD), one of the main phytocannabinoids identified in Cannabis Sativa, which exhibits a large spectrum of therapeutic properties, including anti-inflammatory and antioxidant effects, suggesting its potential as disease-modifying agent for PD. The aim of this study was to evaluate the effects of chronic treatment with CBD (10 mg/kg, i.p.) on PD-associated neurodegenerative and neuroinflammatory processes, and motor deficits in the 6-hydroxydopamine model. Moreover, we investigated the potential mechanisms by which CBD exerted its effects in this model. CBD-treated animals showed a reduction of nigrostriatal degeneration accompanied by a damping of the neuroinflammatory response and an improvement of motor performance. In particular, CBD exhibits a preferential action on astrocytes and activates the astrocytic transient receptor potential vanilloid 1 (TRPV1), thus, enhancing the endogenous neuroprotective response of ciliary neurotrophic factor (CNTF). These results overall support the potential therapeutic utility of CBD in PD, as both neuroprotective and symptomatic agent.
GBA1 gene encodes for the lysosomal membrane protein glucocerebrosidase (GCase). GBA1 heterozygous mutations profoundly impair GCase activity and are currently recognized as an important risk factor ...for the development of Parkinson's disease (PD). Deficits in lysosomal degradation pathways may contribute to pathological α-synuclein accumulation, thereby favoring dopaminergic neuron degeneration and associated microglial activation. However, the precise mechanisms by which GCase deficiency may influence PD onset and progression remain unclear. In this work we used conduritol-β-epoxide (CBE), a potent inhibitor of GCase, to induce a partial, systemic defect of GCase activity comparable to that associated with heterozygous GBA1 mutations, in mice. Chronic (28 days) administration of CBE (50 mg/kg, i.p.) was combined with administration of a classic PD-like inducing neurotoxin, such as MPTP (30 mg/kg, i.p. for 5 days). The aim was to investigate whether a pre-existing GCase defect may influence the effects of MPTP in terms of nigrostriatal damage, microglia activation and α-synuclein accumulation. Pre-treatment with CBE had tendency to enhance MPTP-induced neurodegeneration in striatum and caused significant increase of total α-synuclein expression in substantia nigra. Microglia was remarkably activated by CBE alone, without further increases when combined with MPTP. Overall, we propose this model as an additional tool to study pathophysiological processes of PD in the presence of GCase defects.
•CBE in dose 50 mg/kg reduced glucocerebrosidase activity by 50%.•Combined treatment with CBE and MPTP caused significant increase in total α-syn in SNc.•Treatment with CBE 50 mg/kg for 28 days was not sufficient to cause α-syn accumulation in SNc.•Significant activation of nigrostriatal microglia was observed with CBE in dose 50 mg/kg.
Aims
Ghrelin is implicated in the control of energy balance and glucose homeostasis. The ghrelin receptor exhibits ligand‐independent constitutive activity, which can be pharmacologically exploited ...to induce inverse ghrelin actions. Because ghrelin receptor inverse agonists (GHSR‐IA) might be effective for the treatment of obesity‐related metabolic disease, we tested 2 novel synthetic compounds GHSR‐IA1 and GHSR‐IA2.
Materials and Methods
In functional cell assays, electrophysiogical and immunohistochemical experiments, we demonstrated inverse agonist activity for GHSR‐IA1 and GHSR‐IA2. We used healthy mice, Zucker diabetic fatty (ZDF) rats and diet‐induced obese (DIO) mice to explore effects on food intake (FI), body weight (BW), conditioned taste aversion (CTA), oral glucose tolerance (OGT), pancreatic islet morphology, hepatic steatosis (HS), and blood lipids.
Results
Both compounds acutely reduced FI in mice without inducing CTA. Chronic GHSR‐IA1 increased metabolic rate in chow‐fed mice, suppressed FI, and improved OGT in ZDF rats. Moreover, the progression of islet hyperplasia to fibrosis in ZDF rats slowed down. GHSR‐IA2 reduced FI and BW in DIO mice, and reduced fasting and stimulated glucose levels compared with pair‐fed and vehicle‐treated mice. GHSR‐IA2‐treated DIO mice showed decreased blood lipids. GHSR‐IA1 treatment markedly decreased HS in DIO mice.
Conclusions
Our study demonstrates therapeutic actions of novel ghrelin receptor inverse agonists, suggesting a potential to treat obesity‐related metabolic disorders including diabetes mellitus.
Mutations in GBA1, the gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson's disease (PD). Here, we ...employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration.
A new chemotype of ghrelin inverse agonists was discovered through chimeric design based on molecular scaffolds known as growth-hormone secretagogue receptor (GHSR) modulators but with divergent ...pharmacodynamic and pharmacokinetic properties. The structure–activities/properties exploration led to compound 47, which displayed potent human GHSR antagonism and inverse agonism in cellular assays (IC50 = 68 nM, EC50 = 29 nM), moderate oral bioavailability, and notable brain penetration in rat (F = 27%, B/P ratio = 1.9). First in vivo studies demonstrated effective reduction of food intake after oral or parenteral administration to mouse (78% at 1 h and 38% at 8 h, respectively). Further preclinical studies are needed to evaluate the most suited mode of administration with the aim of promoting a first central-acting ghrelin inverse agonist molecule to development, which would represent a significant step toward therapeutic agents to treat metabolic disorders related to obesity, such as type 2 diabetes mellitus.
The gastric hormone ghrelin positively affects energy balance by increasing food intake and reducing energy expenditure. Ghrelin mimetics are a possible treatment against cancer anorexia-cachexia ...syndrome (CACS). This study aimed to characterize the action of the nonpeptidergic ghrelin receptor agonist HM01 on neuronal function, energy homeostasis and muscle mass in healthy rats and to evaluate its possible usefulness for the treatment of CACS in a rat tumor model. Using extracellular single-unit recordings, we tested whether HM01 mimics the effects of ghrelin on neuronal activity in the arcuate nucleus (Arc). Furthermore, we assessed the effect of chronic HM01 treatment on food intake (FI), body weight (BW), lean and fat volumes, and muscle mass in healthy rats. Using a hepatoma model, we investigated the possible beneficial effects of HM01 on tumor-induced anorexia, BW loss, muscle wasting, and metabolic rate. HM01 (10(-7)-10(-6) M) mimicked the effect of ghrelin (10(-8) M) by increasing the firing rate in 76% of Arc neurons. HM01 delivered chronically for 12 days via osmotic minipumps (50 μg/h) increased FI in healthy rats by 24%, paralleled by increased BW, higher fat and lean volumes, and higher muscle mass. Tumor-bearing rats treated with HM01 had 30% higher FI than tumor-bearing controls and were protected against BW loss. HM01 treatment resulted in higher muscle mass and fat mass. Moreover, tumor-bearing rats reduced their metabolic rate following HM01 treatment. Our studies substantiate the possible therapeutic usefulness of ghrelin receptor agonists like HM01 for the treatment of CACS and possibly other forms of disease-related anorexia and cachexia.
Netupitant is a new, selective NK1 receptor antagonist under development for the prevention of chemotherapy‐induced nausea and vomiting. Two studies were conducted to evaluate the brain receptor ...occupancy (RO) and disposition (ADME) of netupitant in humans. Positron emission tomography (PET) imaging with the NK1 receptor‐binding–selective tracer 11C‐GR205171 was used to evaluate the brain penetration of different doses of netupitant (100, 300, and 450 mg) and to determine the NK1‐RO duration. A NK1‐RO of 90% or higher was achieved with all doses in the majority of the tested brain regions at Cmax, with a long duration of RO. The netupitant minimal plasma concentration predicted to achieve a NK1‐RO of 90%, C90%, in the striatum was 225 ng/mL; after administration of netupitant 300 mg, concentrations exceeded the C90%. In the ADME study, a single nominal dose of 14C‐netupitant 300 mg was used to assess its disposition. Absorption was rapid and netupitant was extensively metabolized via Phase I and II hepatic metabolism. Elimination of >90% was predicted at day 29 and was principally via hepatic/biliary route (>85%) with a minor contribution of the renal route (<5%). In conclusion, these studies demonstrate that netupitant is a potent agent targeting NK1 receptors with long lasting RO. In addition, netupitant is extensively metabolized and is mainly eliminated through the hepatic/biliary route and to a lesser extent via the kidneys.
Motivation is a core component of diabetes self-management because it allows adults with diabetes mellitus (DM) to adhere to clinical recommendations. In this context, virtual coaches (VCs) have ...assumed a central role in supporting and treating common barriers related to adherence. However, most of them are mainly focused on medical and physical purposes, such as the monitoring of blood glucose levels or following a healthy diet.
This proof-of-concept study aims to evaluate the preliminary efficacy of a VC intervention for psychosocial support before and after the intervention and at follow-up. The intent of this VC is to motivate adults with type 1 DM and type 2 DM to adopt and cultivate healthy coping strategies to reduce symptoms of depression, anxiety, perceived stress, and diabetes-related emotional distress, while also improving their well-being.
A total of 13 Italian adults with DM (18-51 years) interacted with a VC, called Motibot (motivational bot) using the Telegram messaging app. The interaction covered 12 sessions, each lasting 10 to 20 minutes, during which the user could dialogue with the VC by inputting text or tapping an option on their smartphone screen. Motibot is developed within the transtheoretical model of change to deliver the most appropriate psychoeducational intervention based on the user's motivation to change.
Results showed that over the 12 sessions, there were no significant changes before and after the intervention and at follow-up regarding psychosocial factors. However, most users showed a downward trend over the 3 time periods in depression and anxiety symptoms, thereby presenting good psychological well-being and no diabetes-related emotional distress. In addition, users felt motivated, involved, encouraged, emotionally understood, and stimulated by Motibot during the interaction. Indeed, the analyses of semistructured interviews, using a text mining approach, showed that most users reported a perceived reduction in anxiety, depression, and/or stress symptoms. Moreover, users indicated the usefulness of Motibot in supporting and motivating them to find a mindful moment for themselves and to reflect on their own emotions.
Motibot was well accepted by users, particularly because of the inclusion of mindfulness practices, which motivated them to adopt healthy coping skills. To this extent, Motibot provided psychosocial support for adults with DM, particularly for those with mild and moderate symptoms, whereas those with severe symptoms may benefit more from face-to-face psychotherapy.
PDF
