Interplay between endocannabinoids and dopamine in the basal ganglia: implications for pain in Parkinson's disease.

Pain is a complex phenomenon, and basal ganglia circuitry integrates many aspects of pain including motor, emotional, autonomic, and cognitive responses. Perturbations in dopamine (DA) signaling are implicated in the pathogenesis of chronic pain due to its involvement in both pain perception and relief. Several lines of evidence support the role of endocannabinoids (eCBs) in the regulation of many electrical and chemical aspects of DAergic neuron function including excitability, synaptic transmission, integration, and plasticity. However, eCBs play an even more intricate and intimate relationship with DA, as indicated by the adaptive changes in the eCB system following DA depletion. Although the precise mechanisms underlying DA control on pain are not fully understood, given the high correlation of eCB and DAergic system, it is conceivable that eCBs may be part of these mechanisms.In this brief survey, we describe the reciprocal regulation of eCB-DA neurotransmission with a particular emphasis on the actions of eCBs on ionic and synaptic signaling in DAergic neurons mediated by CB receptors or independent on them. Furthermore, we analyze the eCB-DA imbalance which characterizes pain condition and report the implications of reduced DA levels for pain in Parkinson's disease. Lastly, we discuss the potential of the eCB-DA system in the development of future therapeutic strategies for the treatment of pain.

Impaired Mitochondrial Respiration in REM-Sleep Behavior Disorder: A Biomarker of Parkinson's Disease?

BACKGROUND: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is associated with prodromal Parkinson's disease (PD), but the mechanisms linking phenoconversion of iRBD to PD have not yet been clarified. Considering the association between mitochondrial dysfunction and sleep disturbances in PD, we explored mitochondrial activity in fibroblasts derived from iRBD patients to identify a biochemical profile that could mark the presence of impending neurodegeneration. METHODS: The study involved 28 participants, divided into three groups: patients diagnosed with iRBD, PD patients converted from iRBD (RBD-PD), and healthy controls. We performed a comprehensive assessment of mitochondrial function, including an examination of mitochondrial morphology, analysis of mitochondrial protein expression levels by western blot, and measurement of mitochondrial respiration using the Seahorse XFe24 analyzer. RESULTS: In basal conditions, mitochondrial respiration did not differ between iRBD and control fibroblasts, but when cells were challenged with a higher energy demand, iRBD fibroblasts exhibited a significant (P = 0.006) drop in maximal and spare respiration compared to controls. Interestingly, RBD-PD patients showed the same alterations with a further significant reduction in oxygen consumption linked to adenosine triphosphate production (P = 0.032). Moreover, RBD-PD patients exhibited a significant decrease in protein levels of complexes III (P = 0.02) and V (P = 0.002) compared to controls, along with fragmentation of the mitochondrial network. iRBD patients showed similar, but milder alterations. CONCLUSIONS: Altogether, these findings suggest that mitochondrial dysfunctions in individuals with iRBD might predispose to worsening of the bioenergetic profile observed in RBD-PD patients, highlighting these alterations as potential predictors of phenoconversion to PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Investigation and Comparison of Active and Passive Encapsulation Methods for Loading Proteins into Liposomes.

In this work, four different active encapsulation methods, microfluidic (MF), sonication (SC), freeze-thawing (FT), and electroporation (EP), were investigated to load a model protein (bovine serum albumin-BSA) into neutral liposomes made from 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC):cholesterol (Chol) and charged liposomes made from DSPC:Chol:Dioleoyl-3-trimethylammonium propane (DOTAP), DSPC:Chol:1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS), and DSPC:Chol:phosphatidylethanolamine (PE). The aim was to increase the protein encapsulation efficiency (EE%) by keeping the liposome size below 200 nm and the PDI value below 0.7, which warrants a nearly monodisperse preparation. Electroporation (100 V) yielded the best results in terms of EE%, with a dramatic increase in liposome size (>600 nm). The FT active-loading method, either applied to neutral or charged liposomes, allowed for obtaining suitable EE%, keeping the liposome size range below 200 nm with a suitable PDI index. Cationic liposomes (DSPC:Chol:DOTAP) loaded with the FT active method showed the best results in terms of EE% (7.2 ± 0.8%) and size (131.2 ± 11.4 nm, 0.140 PDI). In vitro release of BSA from AM neutral and charged liposomes resulted slower compared to PM liposomes and was affected by incubation temperature (37 °C, 4 °C). The empty charged liposomes tested for cell viability on Human Normal Dermal Fibroblast (HNDF) confirmed their cytocompatibility also at high concentrations (1010 particles/mL) and cellular uptake at 4 °C and 37 °C. It can be concluded that even if both microfluidic passive and active methods are more easily transferable to an industrial scale, the FT active-loading method turned out to be the best in terms of BSA encapsulation efficiencies, keeping liposome size below 200 nm.