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  • Importantly the levels of the pro

    2021-09-23

    Importantly, the levels of the pro-inflammatory cytokines TNF-α and IL-1β and Nf-κB, a key transcription factor in chronic inflammatory responses that is activated by pro-inflammatory cytokines, were also reduced by the drugs, confirming our previous results that demonstrated anti-inflammatory effects with GLP-1 and GIP analogues (Cao et al., 2016, Jalewa et al., 2017, Li et al., 2017, Parthsarathy and Holscher, 2013a). Chronic inflammation is one of the central pathological processes in chronic neurodegenerative disorders such as PD. The inflammation response leads to enhanced oxidative stress and the release of pro-inflammatory cytokines, which affect neuronal activity and synaptic function (Ferrari and Tarelli, 2011). Importantly, synaptic integrity as shown by levels of synaptophysin was protected by the drugs tested in our study. We have tested GLP-1 or GIP receptor agonists in the MPTP mouse model of PD and showed that the second generation GLP-1 mimetics liraglutide and lixisenatide were more effective than the older drug exendin-4 (Liu et al., 2015a). The GLP-1 analogue (Val8)GLP-1-Glu-PAL also showed neuroprotective effects (Zhang et al., 2015). We furthermore tested an analogue of GIP, D-Ala2 GIP-glu-PAL, in the acute MPTP mouse model of PD. This protease resistant GIP analogue protected the mice from the effects of MPTP on motor activity and coordination, and dopamine levels in the substantia nigra and striatum were enhanced, too. The MPTP treatment reduced synapse numbers in the striatum, and the GIP analogue reversed this. Importantly, the cAMP/PKA/CREB growth factor second messenger signalling pathway was activated by this drug (Li et al., 2016). In a chronic MPTP treatment design study, we found that MPTP treatment increased the levels of alpha-synuclein in the brain, and D-Ala2-GIP-glu-PAL reduced these levels back to near control values (Li et al., 2017). D-Ala2-GIP-glu-PAL furthermore reduced the chronic inflammation response in the brain, reduced lipid peroxidation and apoptotic signalling, and increased the expression of the growth factor BDNF in the PF-04691502 receptor (Li et al., 2017). We now show in this study that a combined GLP-1/GIP receptor agonist is superior to liraglutide, and thereby demonstrate that novel dual GLP-1/GIP receptor agonists are a promising strategy to treat PD. Such novel dual agonists have already shown superior effects in preclinical and clinical trials in diabetes when compared to liraglutide (Finan et al., 2013). We found in a previous study that DA-JC1 reduced the MPTP-induced impairment of motor control, increased the level of TH positive neurons in the substantia nigra, reduced the activation of microglia and astrocytes, enhanced growth factor cell signalling such as Pi3k activity and Bcl-2 and BDNF levels, while reducing pro-apoptotic BAX signalling (Cao et al., 2016, Ji et al., 2016b). We also tested DA-JC1 in the 6-OHDA rat model of PD where it displayed good neuroprotective effects and enhanced dopamine levels in the striatum. GDNF levels were also enhanced, and the inflammation response reduced (Jalewa et al., 2017). However, the effects were not superior to liraglutide, and higher doses were required to see the effects previously demonstrated with single GLP-1 analogues. We therefore tested the novel DA-JC4 and DA-CH5 GLP-1/GIP dual agonist in direct comparison with DA-JC1 and liraglutide, and we show here for the first time that these novel dual agonists not only show good neuroprotective effects in the MPTP mouse model of PD, but that they are superior to DA-JC1 and liraglutide when compared at equal concentrations. Because of the positive preclinical data, first clinical trials have started to investigate the neuroprotective effects of exendin-4 and liraglutide, drugs that are already on the market as type II diabetes treatments, in PD patients. A pilot study of the effects of exendin-4 (Byetta®) in PD patients has already shown good effects. In the MDS-UPDRS motor tests, the progressive degradation was halted by the drug, and cognition had improved in the Mattis scoring system. In comparison, the control group worsened in cognition and motor control assessments (Aviles-Olmos et al., 2013a). Patients were re-tested 12 months later, and the improvement in motor performance and cognitive scores was still visible in the drug group, while the control group deteriorated further (Aviles-Olmos et al., 2014). The encouraging results of this pilot trial were followed by a phase II double-blind, placebo controlled clinical trial that tested the once-weekly formulation of exendin-4, Bydureon®. The trial showed a clear protective effect in the MDS-UPDRS test battery. After 48 weeks, the drug group was 4.3 points superior to the placebo group. After a wash-out period of 12 weeks when no drug was given, the difference between groups was still 3.5 points, demonstrating that the drug treatment has disease-modifying properties (as defined as improvements still present even when the drug is no longer present in the body). CSF analysis confirmed that exendin-4 had crossed the BBB, and that there was no drug present after wash-out (Athauda et al., 2017). A phase II trial testing liraglutide in PD patients has started in 2017, the duration of drug/placebo treatment is one year (NCT02953665). A third clinical trial testing the GLP-1 receptor agonist Lixisenatide in PD patients is in preparation (Hölscher, 2016).