There are currently no disease-modifying treatments for Parkinson's disease. Retrospective analysis of routinely collected health data may enable earlier risk detection and identify therapeutic candidates for drug repurposing. We conducted a retrospective case-control study using data from the Clinical Practice Research Datalink. Individuals diagnosed with Parkinson's disease (n = 37,910) were matched by age, sex, and general practice to 113,730 controls. Biometric measures and prescription histories were analysed across two pre-diagnostic windows (5-10 years and 10-20 years before diagnosis). Logistic regression models were used to evaluate associations between biomarkers, medication exposure, and Parkinson's disease incidence. A composite risk score was constructed and assessed using receiver operating characteristic analysis. Individuals who developed Parkinson's disease showed significant deviations in established vascular, metabolic, and inflammatory markers years before diagnosis, including elevated systolic blood pressure, serum urea, and creatinine. The combined risk model demonstrated moderate predictive accuracy (area under the curve = 0.73). Previously reported contrasting associations of salbutamol and propranolol with Parkinson's disease incidence were confirmed. Hormonal therapies and triptan medications were associated with lower disease incidence but were more frequently prescribed to individuals with more favourable biometric risk profiles, suggesting potential confounding. In contrast, glucagon-like peptide-1 receptor agonists were prescribed to individuals with higher underlying risk yet were associated with reduced disease incidence. Integration of biometric and prescription histories improves interpretation of medication-disease associations in population data. These findings support glucagon-like peptide-1 receptor agonists as candidates for further investigation in Parkinson's disease based on observational associations and demonstrate the value of real-world data for early identification of population-level risk patterns and therapeutic discovery in neurodegenerative disease.

The principle endocannabinoids are 2-acylglycerol esters, such as 2-arachidonoylglycerol (2-AG), and N-acylethanolamines, such as anandamide (N-arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re-uptake of endocannabinoids are unclear, although potent and selective inhibitors of facilitated diffusion of endocannabinoids across cell membranes have been developed [32]. FABP5 (Q01469) has been suggested to act as a canonical intracellular endocannabinoid transporter in vivo [19]. For the generation of 2-arachidonoylglycerol, the key enzyme involved is diacylglycerol lipase (DAGL), whilst several routes for anandamide synthesis have been described, the best characterized of which involves N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD, [80]). A transacylation enzyme which forms N-acylphosphatidylethanolamines has been identified as a cytosolic enzyme, PLA2G4E (Q3MJ16) [71]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [6, 26, 82].

Listed in this section are hydrolases not accumulated in other parts of the Concise Guide, such as monoacylglycerol lipase and acetylcholinesterase. Pancreatic lipase is the predominant mechanism of fat digestion in the alimentary system; its inhibition is associated with decreased fat absorption. CES1 is present at lower levels in the gut than CES2 (P23141), but predominates in the liver, where it is responsible for the hydrolysis of many aliphatic, aromatic and steroid esters. Hormone-sensitive lipase is also a relatively non-selective esterase associated with steroid ester hydrolysis and triglyceride metabolism, particularly in adipose tissue. Endothelial lipase is secreted from endothelial cells and regulates circulating cholesterol in high density lipoproteins.

Peptidase family S33 contains mainly exopeptidases that act at the N-terminus of peptides.

The diacylglycerol lipases, DAGLα and DAGLβ, hydrolyse diacylglycerol (DAG) to produce 2-arachidonoylglycerol (2-AG), a key endocannabinoid (eCB) and CB1/CB2 receptor ligand. While DAGLα is well established as a regulator of CB1-dependent synaptic plasticity, recent studies have identified DAGLB mutations as a cause of autosomal recessive early-onset Parkinson’s disease (PD). Here, we present a comprehensive analysis of DAGLβ mRNA expression, demonstrating its co-expression with DAGLα mRNA predominantly in excitatory neurons throughout the adult nervous system. We see no evidence for enrichment of the DAGLs or CB1 transcripts in the striatum or in dopaminergic neurons. We discuss these findings within a review of recent literature that points to a wider involvement of the eCB system in PD. Notably, DAGLα-dependent 2-AG release at synapses relies on α-synuclein function—a protein central to PD pathophysiology—implicating both DAGLs in PD and pointing to widespread disruption in 2-AG release. Consistent with this, substantial reductions in 2-AG levels have been reported in the cerebrospinal fluid (CSF) of PD patients. Depression, a major non-motor symptom of PD, often precedes the onset of motor deficits by several years. Human and mouse genetic studies suggest that reduced DAGL activity may contribute to depression by impairing 2-AG-mediated CB1 receptor signalling, which is crucial for synaptic plasticity, stress resilience, and mood regulation. These findings point to a potential causal link between DAGL dysfunction and the non-motor symptoms in PD. ### Competing Interest Statement The authors have declared no competing interest.

The principle endocannabinoids are 2-acylglycerol esters, such as 2-arachidonoylglycerol (2-AG), and N-acylethanolamines, such as anandamide (N-arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re-uptake of endocannabinoids are unclear, although potent and selective inhibitors of facilitated diffusion of endocannabinoids across cell membranes have been developed [32]. FABP5 (Q01469) has been suggested to act as a canonical intracellular endocannabinoid transporter in vivo [19]. For the generation of 2-arachidonoylglycerol, the key enzyme involved is diacylglycerol lipase (DAGL), whilst several routes for anandamide synthesis have been described, the best characterized of which involves N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD, [79]). A transacylation enzyme which forms N-acylphosphatidylethanolamines has been identified as a cytosolic enzyme, PLA2G4E (Q3MJ16) [70]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [6, 26, 81].

Listed in this section are hydrolases not accumulated in other parts of the Concise Guide, such as monoacylglycerol lipase and acetylcholinesterase. Pancreatic lipase is the predominant mechanism of fat digestion in the alimentary system; its inhibition is associated with decreased fat absorption. CES1 is present at lower levels in the gut than CES2 (P23141), but predominates in the liver, where it is responsible for the hydrolysis of many aliphatic, aromatic and steroid esters. Hormone-sensitive lipase is also a relatively non-selective esterase associated with steroid ester hydrolysis and triglyceride metabolism, particularly in adipose tissue. Endothelial lipase is secreted from endothelial cells and regulates circulating cholesterol in high density lipoproteins.

Peptidase family S33 contains mainly exopeptidases that act at the N-terminus of peptides.

Listed in this section are hydrolases not accumulated in other parts of the Concise Guide, such as monoacylglycerol lipase and acetylcholinesterase. Pancreatic lipase is the predominant mechanism of fat digestion in the alimentary system; its inhibition is associated with decreased fat absorption. CES1 is present at lower levels in the gut than CES2 (P23141), but predominates in the liver, where it is responsible for the hydrolysis of many aliphatic, aromatic and steroid esters. Hormone-sensitive lipase is also a relatively non-selective esterase associated with steroid ester hydrolysis and triglyceride metabolism, particularly in adipose tissue. Endothelial lipase is secreted from endothelial cells and regulates circulating cholesterol in high density lipoproteins.

The principle endocannabinoids are 2-acylglycerol esters, such as 2-arachidonoylglycerol (2-AG), and N-acylethanolamines, such as anandamide (N-arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re-uptake of endocannabinoids are unclear, although potent and selective inhibitors of facilitated diffusion of endocannabinoids across cell membranes have been developed [29]. FABP5 (Q01469) has been suggested to act as a canonical intracellular endocannabinoid transporter in vivo [17]. For the generation of 2-arachidonoylglycerol, the key enzyme involved is diacylglycerol lipase (DAGL), whilst several routes for anandamide synthesis have been described, the best characterized of which involves N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD, [75]). A transacylation enzyme which forms N-acylphosphatidylethanolamines has been identified as a cytosolic enzyme, PLA2G4E (Q3MJ16) [66]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [5, 24, 77].

Listed in this section are hydrolases not accumulated in other parts of the Concise Guide, such as monoacylglycerol lipase and acetylcholinesterase. Pancreatic lipase is the predominant mechanism of fat digestion in the alimentary system; its inhibition is associated with decreased fat absorption. CES1 is present at lower levels in the gut than CES2 (P23141), but predominates in the liver, where it is responsible for the hydrolysis of many aliphatic, aromatic and steroid esters. Hormone-sensitive lipase is also a relatively non-selective esterase associated with steroid ester hydrolysis and triglyceride metabolism, particularly in adipose tissue. Endothelial lipase is secreted from endothelial cells and regulates circulating cholesterol in high density lipoproteins.

Single domain shark antibodies that bind to the transferrin receptor 1 (TfR1) on brain endothelial cells have been used to shuttle antibodies and other cargos across the blood brain barrier (BBB) to the brain. For these studies the TXB4 brain shuttle was fused to a TrkB neurotrophin receptor agonist antibody. The TXB4-TrkB fusion retained potent agonist activity at its cognate receptor and after systemic administration showed a 12-fold increase in brain levels over the unmodified antibody. Only the TXB4-TrkB antibody fusion was detected within the brain and localized to TrkB positive cells in the cortex and tyrosine hydroxylase (TH) positive dopaminergic neurons in the substantia nigra pars compacta (SNc), where it was associated with activated ERK1/2 signaling. When tested in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease (PD), TXB4-TrkB, but not the unmodified antibody, completely prevented the 6-OHDA induced death of TH positive neurons in the SNc. In conclusion, the fusion of the TXB4 brain shuttle allows a TrkB agonist antibody to reach neuroprotective concentrations in the brain parenchyma following systemic administration.

The principle endocannabinoids are 2-acylglycerol esters, such as 2-arachidonoylglycerol (2-AG), and N-acylethanolamines, such as anandamide (N-arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re-uptake of endocannabinoids are unclear, although potent and selective inhibitors of facilitated diffusion of endocannabinoids across cell membranes have been developed [28]. FABP5 (Q01469) has been suggested to act as a canonical intracellular endocannabinoid transporter in vivo [17]. For the generation of 2-arachidonoylglycerol, the key enzyme involved is diacylglycerol lipase (DAGL), whilst several routes for anandamide synthesis have been described, the best characterized of which involves N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD, [70]). A transacylation enzyme which forms N-acylphosphatidylethanolamines has been identified as a cytosolic enzyme, PLA2G4E (Q3MJ16) [62]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [5, 23, 72].

Introduction: In mammals, sn-1-diacylglycerol lipases (DAGL) generate 2-arachidonoylglycerol (2-AG) that, as the major endocannabinoid, modulates synaptic neurotransmission by acting on CB1 cannabinoid receptors (CB1R). Even though the insect genome codes for inaE, which is a DAGL ortholog (dDAGL), its products and their functions remain unknown particularly because insects lack chordate-type cannabinoid receptors. Materials and Methods: Gain-of-function and loss-of-function genetic manipulations were carried out in Drosophila melanogaster, including the generation of both dDAGL-deficient and mammalian CB1R-overexpressing flies. Neuroanatomy, dietary manipulations coupled with targeted mass spectrometry determination of arachidonic acid and 2-linoleoyl glycerol (2-LG) production, behavioral assays, and signal transduction profiling for Akt and Erk kinases were employed. Findings from Drosophilae were validated by a CB1R-binding assay for 2-LG in mammalian cortical homogenates with functionality confirmed in neurons using high-throughput real-time imaging in vitro. Results: In this study, we show that dDAGL is primarily expressed in the brain and nerve cord of Drosophila during larval development and in adult with 2-LG being its chief product as defined by dietary precursor availability. Overexpression of the human CB1R in the ventral nerve cord compromised the mobility of adult Drosophilae. The causality of 2-LG signaling to CB1R-induced behavioral impairments was shown by inaE inactivation normalizing defunct motor coordination. The 2-LG-induced activation of transgenic CB1Rs affected both Akt and Erk kinase cascades by paradoxical signaling. Data from Drosophila models were substantiated by showing 2-LG-mediated displacement of [3H]CP 55,940 in mouse cortical homogenates and reduced neurite extension and growth cone collapsing responses in cultured mouse neurons. Conclusions: Overall, these results suggest that 2-LG is an endocannabinoid-like signal lipid produced by dDAGL in Drosophila.

We have utilised the transcriptional response of lung epithelial cells following infection by the original Severe Acute Respiratory Syndrome coronavirus (SARS) to identify repurposable drugs for COVID-19. Drugs best able to recapitulate the infection profile are highly enriched for antiviral activity. Nine of these have been tested against SARS-2 and found to potently antagonise SARS-2 infection/replication, with a number now being considered for clinical trials. It is hoped that this approach may serve to broaden the spectrum of approved drugs that should be further assessed as potential anti-COVID-19 agents and may help elucidate how this seemingly disparate collection of drugs are able to inhibit SARS-2 infection/replication.

Gene expression data associated with viral infection of human cell lines is harnessed to define a conserved viral response signature. Drugs that tend to drive gene expression in the direction of the cellular viral response are significantly enriched for those with established antiviral activity. Transcription therefore facilitates a simple and effective filtering of candidate drugs to be put forward for bioassay validation.

Peptidase family S33 contains mainly exopeptidases that act at the N-terminus of peptides.

Voltage-gated sodium channel (Nav) expression in non-excitable cells has raised questions regarding their non-canonical roles. Interestingly, a growing body of evidence also points towards the prevalence of aberrant Nav expression in malignant tumors, potentially opening a new therapeutic window. In this study, the transcriptional consequences of channel inhibition were investigated in non-small cell lung carcinoma H460 and neuroblastoma SH-SYSY cell lines, that both express Nav1.7. Channel activity was blocked by the application of both selective, ProTx-II, and non-selective, tetrodotoxin, inhibitors. Global gene expression profiling did not point to any statistically significant inhibition-associated perturbation of the transcriptome. A small subset of genes that showed relatively consistent changes across multiple treatments were further assayed in the context of a multiplex bead expression array which failed to recapitulate the changes seen in the global array. We conclude that there is no robust transcriptional signature associated with the inhibition of two sodium channel expressing cancer cell lines and consequently sodium channel inhibition will not lend itself to therapeutic approaches such as transcription-based drug repurposing.

Endogenous fibroblast growth factor 20 (FGF20) supports maintenance of dopaminergic neurones within the nigrostriatal pathway. Moreover, direct intracerebral infusion of FGF20 protects against nigrostriatal tract loss in the 6-hydroxydopamine lesion rat model of Parkinson’s disease. Increasing endogenous FGF20 production might provide a less-invasive, more translational way of providing such protection. Accordingly, we adopted a targeted repositioning approach to screen for candidate FDA-approved drugs with potential to enhance endogenous FGF20 production in brain. In silico interrogation of the Broad Institute’s Connectivity Map database (CMap), revealed 50 candidate drugs predicted to increase FGF20 transcription, 16 of which had profiles favourable for use in Parkinson’s disease. Of these, 11 drugs were found to significantly elevate FGF20 protein production in MCF-7 cells, between two- and four-fold. Four drugs were selected for examination in vivo . Following oral dosing in rats for 7 days, salbutamol and triflusal, but not dimethadione or trazodone, significantly elevated FGF20 levels in the nigrostriatal tract. Preliminary examination in the unilateral 6-hydroxydopamine-lesioned rat revealed a modest but significant protection against nigral cell loss with both drugs. Our data demonstrate the power of targeted repositioning as a method to identify existing drugs that may combat disease progression in Parkinson’s by boosting FGF20 levels.