Novel Nanoparticles Based on N,O-Carboxymethyl Chitosan-Dopamine Amide Conjugate for Nose-to-Brain Delivery

A widely investigated approach to bypass the blood brain barrier is represented by the intranasal delivery of therapeutic agents exploiting the olfactory or trigeminal connections nose-brain. As for Parkinson’s disease (PD), characterized by dopaminergic midbrain neurons degeneration, currently there is no disease modifying therapy. Although several bio-nanomaterials have been evaluated for encapsulation of neurotransmitter dopamine (DA) or dopaminergic drugs in order to restore the DA content in parkinsonian patients, the premature leakage of the therapeutic agent limits this approach. To tackle this drawback, we undertook a study where the active was linked to the polymeric backbone by a covalent bond. Thus, novel nanoparticles (NPs) based on N,O-Carboxymethylchitosan-DA amide conjugate (N,O-CMCS-DA) were prepared by the nanoprecipitation method and characterized from a technological view point, cytotoxicity and uptake by Olfactory Ensheating Cells (OECs). Thermogravimetric analysis showed high chemical stability of N,O-CMCS-DA NPs and X-ray photoelectron spectroscopy evidenced the presence of amide linkages on the NPs surface. MTT test indicated their cytocompatibility with OECs, while cytofluorimetry and fluorescent microscopy revealed the internalization of labelled N,O-CMCS-DA NPs by OECs, that was increased by the presence of mucin. Altogether, these findings seem promising for further development of N,O-CMCS-DA NPs for nose-to-brain delivery application in PD.

Exploring the Mechanisms Underlying Drug-Induced Fractures Using the Japanese Adverse Drug Event Reporting Database

Fractures occur when bones become fragile and are subjected to external forces as occurring during falls. The use of drugs that increase bone fragility or fall risk increases the risk of fracture. This study investigates drug-induced fractures reported in the Japanese Adverse Drug Event Report (JADER) database in patients using 4892 drugs. Atypical femur fracture was the most frequently reported fracture, and 58 other fractures were also reported. Using Volcano plots and multiple logistic regression analysis, we identified the risk factors for drug-induced fractures as being female, of older age, higher body mass index, and using one of 90 drugs. The drug groups significantly associated with drug-induced fractures included bone resorption inhibitors, antiviral drugs, dopaminergic drugs, corticosteroids, and sleep sedatives. Principal component analysis was used to examine the relationship between the use of specific drugs and the site of drug-induced fracture. Bone resorption inhibitors and corticosteroids were associated with atypical femur fractures, jaw fractures, and ulna fractures through an osteoclast-mediated process. Other drugs were found to increase fracture risk via non-osteoclast-mediated mechanisms. These findings suggest that many drugs can result in drug-induced fractures through a variety of mechanisms.

Clustering of Parkinson Subtypes: Strong Influence of D2 Receptor Polymorphism and Gender

Next to motor and non-motor symptoms some more basic features are relevant in idiopathic Parkinson’s disease subtype classification influencing basal ganglia circuitry via dopamine receptor polymorphism and gender dimorphism. By kmeans-clustering algorithm we found an influence of D2 receptor polymorphism and gender on treatment response to dopaminergic drugs -reflected by daily levodopa dosage- opening the door for a more personalized individual therapy in idiopathic Parkinson’s disease.

Subthalamic Nucleus Stimulation Impairs Sequence Processing in Patients with Parkinson’s Disease

Background: Maintaining and manipulating sequences online is essential for language and memory. In Parkinson’s disease (PD), poor performance in sequencing tasks has been associated with basal ganglia dysfunction, especially subthalamic hyperactivity. Objective: This study is aimed to investigate the impact of high-frequency subthalamic nucleus (STN) deep brain stimulation (DBS) on sequence processing in PD. Methods: Twenty-nine patients with PD (17 women) completed a ‘before/after’ sentence task and a digit ordering task with STN DBS ON and OFF. In the sentence task, patients read a sequence of events expressed in the actual order of occurrence (‘after’ sentences) or reversed order (‘before’ sentences) for comprehension. In the digit task, patients recalled a sequence of ordered digits (ordered trials) or reordered and recalled random digits in ascending order (random trials). Volumes of tissue activated (VTAs) were estimated for the motor and associative STN. Results: Patients were slower with STN DBS ON versus OFF in both tasks, although their motor symptoms were significantly improved under DBS. In the sentence task, patients showed higher ordering-related reaction time costs (‘before’ > ‘after’) with DBS ON versus OFF. Moreover, patients with larger left associative VTAs, smaller total motor VTAs, and more daily exposure to dopaminergic drugs tended to show larger reaction time cost increases under DBS. In the digit ordering task, patients with too large or too small right associative VTAs tended to show larger reaction time cost increases under DBS. Conclusion: Stimulating the STN, especially its associative part, might impair sequence processing in language and memory.

Predicting effects of methylphenidate and sulpiride on brain and cognition: A pharmaco-fMRI, PET study. Design and descriptives.

The large variation observed in the effects of dopaminergic drugs poses a major problem for neuropsychiatry, where therapeutic drugs may be ineffective or detrimental in a proportion of patients, but also for the healthy population. We have conducted a pharmaco-fMRI/PET study in 100 healthy participants to investigate the neural and neurochemical mechanisms of this variability. We studied the cognitive effects of methylphenidate (20mg) and sulpiride (400mg) across various cognitive domains, such as reward learning and motivation, working memory and effort motivation. To establish the baseline dopamine-dependency of the drug effects, all participants underwent an [18F]DOPA positron emission tomography scan on a separate off-drug session to quantify their baseline striatal dopamine synthesis capacity. In addition, multiple putative proxy measures of striatal dopamine activity were acquired, including spontaneous eye blink rate, trait impulsivity, subjective reward sensitivity and working memory capacity. The drug effects on each of the cognitive paradigms and their potential dependency on dopamine synthesis capacity and putative proxy measures are reported in separate papers. In the present paper, we report the design of the full study, as well as drug effects on subjective mood and autonomic arousal. This report aims to serve as a reference for future pharmacological fMRI/PET studies as well as for the specific papers resulting from detailed analyses of the included cognitive paradigms. The study will enable the development of a proxy-model of baseline dopamine, intended to provide a pragmatic handle on predicting the effects of dopaminergic drugs on brain and cognition that maximally generalizes to new participants.

Pramipexole and tolcapone alleviate thermal and mechanical nociception in naive rats.

Introduction: Parkinson&rsquo;s disease (PD) is &#1072; neurodegenerative disorder characterized mainly by its motor symptoms. The non-motor symptoms including pain are increasingly recognized in the last few decades. Existing evidence suggests that the dopaminergic neurotransmission has an essential role in pain control. Aim: The aim of the present study was to investigate the antinociceptive effect of dopaminergic drugs pramipexole and tolcapone against chemical and thermal stimuli in naive rats. Materials and methods: Male Wistar rats divided into 8 groups (n=8): saline; diclofenac 25 mg/kg body weight (bw) (positive control); pramipexole 0.5; 1 and 3 mg/kg bw; tolacapone 5; 15 and 30 mg/kg bw. Paw pressure and plantar tests were performed. Paw withdrawal pressure and latent time were measured. Statistical analysis was done by SPSS 19. Results: In the paw pressure test, pramipexole, in a dose of 1 and 3 mg/kg bw and tolcapone in a dose of 30 mg/kg bw, increased significantly the latency at 1, 2, and 3 hours compared to saline (p<0.05). In the plantar test, only the highest dose of pramipexole reached significance at 3 hours compared to the control rats (p<0.05). In contrast to pramipexole the three experimental groups with tolcapone markedly increased the latent time at 1 and 3 hours compared to saline (p<0.05). Conclusions: Pramipexole and tolcapone reduce mechanical and thermal nociception in na&iuml;ve rats by enhancing dopaminergic neurotransmission at both spinal and supraspinal levels. In addition, tolcapone stimulates noradrenergic mediation which may contribute to its antinociceptive effect.

Role of the Dopaminergic System in the Striatum and Its Association With Functional Recovery or Rehabilitation After Brain Injury

Disabilities are estimated to occur in approximately 2% of survivors of traumatic brain injury (TBI) worldwide, and disability may persist even decades after brain injury. Facilitation or modulation of functional recovery is an important goal of rehabilitation in all patients who survive severe TBI. However, this recovery tends to vary among patients because it is affected by the biological and physical characteristics of the patients; the types, doses, and application regimens of the drugs used; and clinical indications. In clinical practice, diverse dopaminergic drugs with various dosing and application procedures are used for TBI. Previous studies have shown that dopamine (DA) neurotransmission is disrupted following moderate to severe TBI and have reported beneficial effects of drugs that affect the dopaminergic system. However, the mechanisms of action of dopaminergic drugs have not been completely clarified, partly because dopaminergic receptor activation can lead to restoration of the pathway of the corticobasal ganglia after injury in brain structures with high densities of these receptors. This review aims to provide an overview of the functionality of the dopaminergic system in the striatum and its roles in functional recovery or rehabilitation after TBI.

Clinical and Genetic Analysis of Psychosis in Parkinson’s Disease

Background: Recent studies explored polymorphisms of multiple genes as contributing to genetic susceptibility to psychosis in Parkinson’s disease (PDP). Objective: We aimed to examine the association of seven selected polymorphisms of genes related to dopamine pathways with PDP development. At the same time, demographic and clinical correlates of PDP were assessed. Methods: PD patients (n = 234), treated with levodopa for at least two years, were genotyped for the rs4680 in COMT, rs6277, rs1076560, and rs2283265 in DRD2, and rs1800497 and rs2734849 polymorphisms in ANKK1 genes. Also, variable number of tandem repeats polymorphism in the DAT gene was examined. Each patient underwent comprehensive neurological examination, assessment of psychosis, as defined by the NINDS/NIMH criteria, as well as screening of depression, anxiety, and cognitive status. Results: Diagnostic criteria for PDP were met by 101 (43.2%) patients. They had longer disease duration, were taking higher doses of dopaminergic agents, and had higher scores of the motor and non-motor scales than the non-PDP group. Multivariate regression analysis revealed LEDD≥900 mg, Unified Parkinson’s Disease Rating Scale III part score, the Hamilton Depression Rating Scale score≥7, the Hamilton Anxiety Rating Scale score > 14,and GG homozygotes of rs2734849 ANKK1 as independent predictors of the onset of PDP. Conclusion: Besides previous exposure to dopaminergic drugs, impairment of motor status, depression and anxiety, as well-established clinical risk factors for the development of PDP, GG rs2734849 ANKK1 could also be a contributing factor, which requires addressing by future longitudinal studies.

Long-term Outcomes (15 Years) After Subthalamic Nucleus Deep Brain Stimulation in Patients With Parkinson Disease

Objective:To evaluate the effects of deep brain stimulation of the subthalamic nucleus (STN-DBS) in Parkinson disease (PD) patients on motor complications beyond 15 years after surgery.Methods:Data about motor complications, quality of life (QoL), activities of daily living, the UPDRS motor scores, dopaminergic treatment, stimulation parameters, and side effects of STN-DBS were retrospectively retrieved and compared between before surgery, at 1 year and beyond 15 years after bilateral STN-DBS.Results:Fifty-one patients with 17.06 ± 2.18 years STN-DBS follow-up were recruited. Compared to baseline, the time spent with dyskinesia and the time spent in the off state were reduced by 75% (p<0.001) and by 58.7% (p<0.001), respectively. Moreover, dopaminergic drugs were reduced by 50.6% (p<0.001). The PDQL total score, and the emotional function and social function domains improved of 13.8% (p=0.005), 13.6% (p=0.01) and 29.9% (p<0.001), respectively. Few and mostly manageable device-related adverse events were observed during the follow-up.Conclusions:STN-DBS is still effective beyond 15 years from the intervention, notably with significant improvement in motor complications and stable reduction of dopaminergic drugs. Furthermore, despite the natural continuous progression of PD with worsening of levodopa-resistant motor and non-motor symptoms over the years, STN-DBS patients could maintain an improvement in QoL.Classification of Evidence:This study provides Class IV evidence that, for patients with PD, STN-DBS remains effective at treating motor complications 15 years after surgery.

Increased risk for developing gambling disorder under the treatment with pramipexole, ropinirole, and aripiprazole: A nationwide register study in Sweden

Gambling Disorder (GD) has recently been reclassified from an impulse-control disorder to a behavioural addiction and, as in other addictive disorders, the dopaminergic reward system is involved. According to neuroimaging studies, alterations within the striatal dopaminergic signalling can occur in GD. However, the findings to date are controversial and there has been no agreement yet on how the reward system is affected on a molecular basis. Within the last 20 years, there has been growing evidence for a higher risk to develop GD in response to certain dopaminergic medication. Especially the dopamine agonists pramipexole and ropinirole, and the dopamine modulator aripiprazole seem to increase the likelihood for GD. The goal of this study was to examine the association between a prescription for either of the three pharmaceuticals and a GD diagnosis in a large cross-sectional study of the Swedish population. Compared to patients with any other dopaminergic drug prescription (38.7% with GD), the diagnosis was more common in patients with a dopamine agonist prescription (69.8% with GD), resulting in an odds ratio of 3.2. A similar association was found between aripiprazole prescriptions and GD diagnoses, which were analysed within the subgroup of all patients with schizophrenia or a schizotypal, delusional, or another non-mood psychotic disorder. An aripiprazole prescription increased the likelihood of GD (88.8%) in comparison to patients without an aripiprazole prescription (71.2%) with an odds ratio of 3.4. This study contributes to the increasingly reliable evidence for an association between several dopaminergic drugs and a higher risk for developing GD. Therefore, one future research goal should be a better understanding of the neurobiology in GD to be able to design more selective dopaminergic medication with less severe side effects. Additionally, this knowledge could enable the development of pharmacotherapy in GD and other addictive disorders.