Synergy between L-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: implications for Parkinson's disease treatment and dyskinesia.

International audienceGroup III metabotropic glutamate (mGlu) receptors are localized in presynaptic terminals within basal ganglia (BG) circuitry that become hyperactive due to dopamine depletion in Parkinson's disease (PD). For this reason, group III mGlu receptors, in particular mGlu4, have been considered as key strategic targets for non-dopaminergic pharmacological treatments aimed at modulating these synapses, without producing the well known side-effects of l-DOPA, in particular the highly disabling l-DOPA-induced dyskinesia (LID). Herein we add physiological and functional support to this hypothesis using Lu AF21934, a novel selective and brain-penetrant mGlu4 receptor positive allosteric modulator (PAM) tool compound. By in vitro electrophysiological recordings we demonstrate that Lu AF21934 inhibits corticostriatal synaptic transmission and enhances the effect of the orthosteric mGlu4 receptor-preferred agonist LSP1-2111. In naïve rats, Lu AF21934 dose-dependently (10 and 30 mg/kg) alleviated haloperidol-induced catalepsy. In hemiparkinsonian rats (unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta), Lu AF21934 alone did not affect akinesia at the doses tested (10 and 30 mg/kg). However, when Lu AF21934 was combined with sub-threshold doses of l-DOPA (1 and 5 mg/kg), it acted synergistically in alleviating akinesia in a dose-dependent manner and, notably, also reduced the incidence of LID but not its severity. Interestingly, these effects occurred at Lu AF21934 brain free concentrations that showed functional activity in in vitro screens (calcium flux and electrophysiology assays). These results support the potential for antiparkinsonian clinical use of a combined treatment consisting in l-DOPA and a mGlu4 receptor PAM to reduce efficacious l-DOPA doses (generally known as l-DOPA sparing), while maintaining the same benefit on PD motor troubles, and at the same time minimizing the development of LID. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'

Delayed colorectal cancer care during covid-19 pandemic (decor-19). Global perspective from an international survey

Background The widespread nature of coronavirus disease 2019 (COVID-19) has been unprecedented. We sought to analyze its global impact with a survey on colorectal cancer (CRC) care during the pandemic. Methods The impact of COVID-19 on preoperative assessment, elective surgery, and postoperative management of CRC patients was explored by a 35-item survey, which was distributed worldwide to members of surgical societies with an interest in CRC care. Respondents were divided into two comparator groups: 1) ‘delay’ group: CRC care affected by the pandemic; 2) ‘no delay’ group: unaltered CRC practice. Results A total of 1,051 respondents from 84 countries completed the survey. No substantial differences in demographics were found between the ‘delay’ (745, 70.9%) and ‘no delay’ (306, 29.1%) groups. Suspension of multidisciplinary team meetings, staff members quarantined or relocated to COVID-19 units, units fully dedicated to COVID-19 care, personal protective equipment not readily available were factors significantly associated to delays in endoscopy, radiology, surgery, histopathology and prolonged chemoradiation therapy-to-surgery intervals. In the ‘delay’ group, 48.9% of respondents reported a change in the initial surgical plan and 26.3% reported a shift from elective to urgent operations. Recovery of CRC care was associated with the status of the outbreak. Practicing in COVID-free units, no change in operative slots and staff members not relocated to COVID-19 units were statistically associated with unaltered CRC care in the ‘no delay’ group, while the geographical distribution was not. Conclusions Global changes in diagnostic and therapeutic CRC practices were evident. Changes were associated with differences in health-care delivery systems, hospital’s preparedness, resources availability, and local COVID-19 prevalence rather than geographical factors. Strategic planning is required to optimize CRC care