L-DOPA for Parkinson's disease-a bittersweet pill

3,4‐dihydroxy‐L‐phenylalanine (L‐DOPA) is the gold standard treatment for Parkinson's disease. It has earned that title through its highly effective treatment of some of the motor symptoms in the early stages of the disease but it is a far from perfect drug. The inevitable long‐term treatment that comes with this chronic neurodegenerative condition raises the risk significantly of the development of motor fluctuations including disabling L‐DOPA‐induced dyskinesia. Being unsurpassed as a therapy means that understanding the mechanisms of dyskinesia priming and induction is vital to the search for therapies to treat these side effects and allow optimal use of L‐DOPA. However, L‐DOPA use may also have consequences (positive or negative) for the development of other interventions, such as cell transplantation, which are designed to treat or repair the ailing brain. This review looks at the issues around the use of L‐DOPA with a focus on its potential impact on advanced reparative interventions

A preliminary investigation of adult defence style and physiological reactivity to infant distress signals

Species whose offspring require extended care-giving ought to be predisposed to being biologically responsive to their infant\u27s signalling. This paper examined the interplay between biological and psychological aspects of adult response to an infant\u27s distress. HR (heart rate) and GSR (galvanic skin response) were recorded continuously, while 50 adults listened to white noise and an infant cry audio recording. Participants completed the defence style questionnaire and the state trait anxiety inventory. HR acceleration occurred in response to the control sound, while HR decelerated in response to the infant cry. GSR responsiveness was positively correlated with immature and neurotic defence styles. When controlling for other variables, immature defence was a unique and independent predictor of GSR change in response to infant distress. Defence demonstrated a stronger relationship than self-reported anxiety, than that with physiological responsiveness. Employing defence mechanisms appears to reduce an individual\u27s perceived anxiety, though it has little effect on physiological arousal levels

L-dopa-Dependent Effects of GLP-1R Agonists on the Survival of Dopaminergic Cells Transplanted into a Rat Model of Parkinson Disease

Cell therapy is a promising treatment for Parkinson’s disease (PD), however clinical trials to date have shown relatively low survival and significant patient-to-patient variability. Glucagon Like Peptide-1 receptor (GLP-1R) agonists have potential neuroprotective effects on endogenous dopaminergic neurons. This study explores whether these agents could similarly support the growth and survival of newly transplanted neurons. 6-OHDA lesioned Sprague Dawley rats received intra-striatal grafts of dopaminergic ventral mesencephalic cells from embryonic day 14 Wistar rat embryos. Transplanted rats then received either saline or L-dopa (12 mg/kg) administered every 48 h prior to, and following cell transplantation. Peripheral GLP-1R agonist administration (exendin-4, 0.5 μg/kg twice daily or liraglutide, 100 μg/kg once daily) commenced immediately after cell transplantation and was maintained throughout the study. Graft survival increased under administration of exendin-4, with motor function improving significantly following treatment with both exendin-4 and liraglutide. However, this effect was not observed in rats administered with L-dopa. In contrast, L-dopa treatment with liraglutide increased graft volume, with parallel increases in motor function. However, this improvement was accompanied by an increase in leukocyte infiltration around the graft. The co-administration of L-dopa and exendin-4 also led to indicators of insulin resistance not seen with liraglutide, which may underpin the differential effects observed between the two GLP1-R agonists. Overall, there may be some benefit to the supplementation of grafted patients with GLP-1R agonists but the potential interaction with other pharmacological treatments needs to be considered in more depth

Defining the unknowns for cell therapies in Parkinson's disease

First-in-human clinical trials have commenced to test the safety and efficacy of cell therapies for people with Parkinson's disease (PD). Proof of concept that this neural repair strategy is efficacious is based on decades of preclinical studies and clinical trials using primary foetal cells, as well as a significant literature exploring more novel stem cell-derived products. Although several measures of efficacy have been explored, including the successful in vitro differentiation of stem cells to dopamine neurons and consistent alleviation of motor dysfunction in rodent models, many unknowns still remain regarding the long-term clinical implications of this treatment strategy. Here, we consider some of these outstanding questions, including our understanding of the interaction between anti-Parkinsonian medication and the neural transplant, the impact of the cell therapy on cognitive or neuropsychiatric symptoms of PD, the role of neuroinflammation in the therapeutic process and the development of graft-induced dyskinesias. We identify questions that are currently pertinent to the field that require further exploration, and pave the way for a more holistic understanding of this neural repair strategy for treatment of PD

Potential cellular and regenerative approaches for the treatment of Parkinson’s disease

Parkinson’s disease is most commonly treated with a range of pharmacotherapeutics, with the more recent introduction of surgical techniques including deep-brain stimulation. These have limited capabilities to improve symptoms of the disease in more advanced stages, thus new therapeutic strategies including the use of viral vectors and stem cells are in development. Providing a continuous supply of dopamine to the striatum in an attempt to improve the treatment of motor symptoms using enzymes in the dopamine synthesis and machinery is one approach. Alternatively, there are tools which may serve to both protect and encourage outgrowth of surviving neurons using growth factors or to directly replace lost innervation by transplantation of primary tissue or stem cell-derived dopaminergic neurons. We summarize some of the potential therapeutic approaches and also consider the recent EU directives on practical aspects of handling viral vectors, cells and tissues, and in the running of clinical trials in Europe which impact on their development

Influence of chronic L-DOPA treatment on immune response following allogeneic and xenogeneic graft in a rat model of Parkinson's disease

Although intrastriatal transplantation of fetal cells for the treatment of Parkinson’s disease had shown encouraging results in initial open-label clinical trials, subsequent double-blind studies reported more debatable outcomes. These studies highlighted the need for greater preclinical analysis of the parameters that may influence the success of cell therapy. While much of this has focused on the cells and location of the transplants, few have attempted to replicate potentially critical patient centered factors. Of particular relevance is that patients will be under continued L-DOPA treatment prior to and following transplantation, and that typically the grafts will not be immunologically compatible with the host. The aim of this study was therefore to determine the effect of chronic L-DOPA administered during different phases of the transplantation process on the survival and function of grafts with differing degrees of immunological compatibility. To that end, unilaterally 6-OHDA lesioned rats received sham surgery, allogeneic or xenogeneic transplants, while being treated with L-DOPA before and/or after transplantation. Irrespective of the L-DOPA treatment, dopaminergic grafts improved function and reduced the onset of L-DOPA induced dyskinesia. Importantly, although L-DOPA administered post transplantation was found to have no detrimental effect on graft survival, it did significantly promote the immune response around xenogeneic transplants, despite the administration of immunosuppressive treatment (cyclosporine). This study is the first to systematically examine the effect of L-DOPA on graft tolerance, which is dependent on the donor-host compatibility. These findings emphasize the importance of using animal models that adequately represent the patient paradigm

Hydro-PE: gridded datasets of historical and future Penman-Monteith potential evaporation for the United Kingdom

We present two new potential evaporation datasets for the United Kingdom: a historical dataset, Hydro-PE HadUKGrid, which is derived from the HadUK-Grid gridded observed meteorology (1969&ndash;2021); and a future dataset, Hydro-PE UKCP18 RCM, which is derived from UKCP18 regional climate projections (1980&ndash;2080). Both datasets are suitable for hydrological modelling, and provide Penman-Monteith potential evapotranspiration parameterised for short grass, with and without a correction for interception on days with rainfall. The potential evapotranspiration calculations have been formulated to closely follow the methodology of the existing Meteorological Office Rainfall and Evaporation Calculation System (MORECS) potential evapotranspiration, which has historically been widely used by hydrological modellers in the United Kingdom. The two datasets have been created using the same methodology, to allow seamless modelling from past to future. Hydro-PE HadUK-Grid shows good agreement with MORECS in much of the United Kingdom, although Hydro-PE HadUK Grid is higher in the mountainous regions of Scotland and Wales. This is due to differences in the underlying meteorology, in particular the wind speed, which are themselves due to the different spatial scales of the data. Hydro-PE HadUK-Grid can be downloaded from https://doi.org/10.5285/9275ab7e-6e93-42bc-8e72-59c98d409deb (Brown et al., 2022) and Hydro-PE UKCP18 RCM can be downloaded from https://doi.org/10.5285/eb5d9dc4-13bb-44c7-9bf8-c5980fcf52a4 (Robinson et al., 2021).</p

Factors affecting the choice of first-line therapy in Parkinson's disease patients in Wales: A population-based study

First line treatment for Parkinson’s disease (PD) is typically either L-dopa or a non-ergot dopamine agonist (DA). However, the options for the treatment of motor symptoms in PD patients have increased in the last thirty years, which have seen several new classes of PD medications introduced onto the market. The purpose of this study is to examine the changes in first line therapy of newly diagnosed Parkinson’s patients between 2000 and 2016 in Wales. A population-based study evaluated data from the Secure Anonymised Information Linkage (SAIL) Databank of residents in Wales, aged 40 years or older, newly treated with PD medications between 2000 and 2016. The data was compared across three intervals: 2000–2005, 2006–2011 and 2012–2016. Patients were classified by age at diagnosis into young: 40–60 years; mid, 61–80 years; and older >80 years. Logistic regression was undertaken to determine the predictors of PD medication prescribing. For the whole study period, the profiles of 9142 newly diagnosed PD patients were analysed. L-dopa was the most common first line therapy (80.6%), followed by non-ergot DAs (12.9%) and monoamine oxidase B (MAO-B) inhibitors (7.9%). Odds of L-dopa prescribing were greater in patients >80 years (OR = 20.46 95%CI: 16.25–25.76) and in the period 2012–2016 (OR = 1.98 95% CI: 1.70–2.29). Prescribing of non-ergot DAs significantly declined in 2012–2016 (OR = 0.42 95% CI: 0.35–0.49). Additional factors influencing first line therapy were deprivation, presence of diabetes and prior use of antidepressants. For example, PD patients residing in the least deprived area were less likely to be prescribed L-dopa compared to patients residing in the most deprived area (OR = 0.77 95% CI: 0.65–0.93). First line therapy in PD in Wales has undergone a significant switch towards L-dopa over the last 16 years. The data indicates reasonable compliance with guidelines on efficacy and safety issues related to Parkinson’s medications