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    • Recently several dual GLP GIP receptor agonists have

    2022-01-04

    Recently, several dual GLP-1/GIP receptor agonists have been developed as a treatment of type II diabetes. These peptides can activate both the GLP-1 and the GIP receptor. Such dual receptor agonists are superior compared to single GLP-1 analogues such as liraglutide (Finan et al., 2013). Previously, we tested the dual agonist (DA-JC1) in cell culture SH-SY5Y selective serotonin reuptake inhibitor that were stressed with rotenone and demonstrated that DA-JC1 was neuroprotective at much lower doses than GLP-1 receptor agonists (Jalewa et al., 2016). We tested DA-JC1 in the MPTP mouse model of Parkinson as well. The drug reduced the MPTP induced impairment of motor control, increased the number of TH positive neurons in the substantia nigra, and reduced the chronic inflammation response and apoptotic signalling while increasing the levels of the growth factor Brain Derived Neurotrophic Factor (BDNF) (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 increased dopamine levels in the striatum (Jalewa et al., 2017). However, the efficacy of DA-JC1 is not superior to liraglutide at the same drug dose. We therefore tested the novel GLP-1/GIP dual agonists DA-JC4 and DA-CH5 and compared it to the currently most effective GLP-1 analogue liraglutide that is on the market as a T2DM drug (Lovshin and Drucker, 2009) and to DA-JC1in the MPTP mouse model of PD.
    Materials and methods
    Peptides Peptide sequence of the GLP-1/GIP dual agonist DA-JC1 (Finan et al., 2013):
    Reagents
    Determination of glucose levels
    Motor activity tests
    Immunohistochemistry
    Western blotting
    Statistical analysis
    Results
    Discussion The results presented here show that both the GLP-1 analogue liraglutide and the novel GLP-1/GIP dual receptor agonists have neuroprotective properties in the MPTP mouse model of PD. These drugs have been originally developed as treatments for type II diabetes (Finan et al., 2013, Lovshin and Drucker, 2009). GLP-1 and GIP are incretin hormones that play important physiological roles in the control of metabolism. They are expressed in the brain, as are their receptors (Cork et al., 2015, Farr et al., 2016, Heppner et al., 2015, Merchenthaler et al., 1999, Nyberg et al., 2005, Nyberg et al., 2007). The activation of the receptors enhance cAMP levels and activate key secondary cell signalling cascades that increase gene expression for insulin, the insulin receptor, IRS1, Akt, and growth factors such as IGF-1, GDNF and BDNF (Doyle and Egan, 2007, Hölscher, 2016, Perry and Greig, 2002). They also have anti-inflammatory properties (Duffy and Holscher, 2013, Parthsarathy and Holscher, 2013b). Importantly, GLP-1 and GLP-1/GIP analogues do not affect glycaemia levels or body weight in non-diabetic or non-obese animals or humans (Faivre et al., 2012, Gallwitz, 2006, George et al., 2014). Here we show that neither liraglutide nor the dual agonists tested had prominent effects on body weight or blood glucose levels. In the motor tasks, all drugs were able to counteract the detrimental effects of MPTP on motor coordination and muscle strength. DA-CH5 appeared to be the most potent and was significantly more effective than liraglutide. MPTP causes a decrease of protein synthesis of key enzymes such as tyrosine hydroxylase, an enzyme that is required for dopamine synthesis. All drugs were able to protect dopaminergic neurons to some degree, with DA-CH5 being the most effective drug in most assessments. Glial-derived neurotropic factor (GDNF) is a key growth factor that is vital for the differentiation and function of dopaminergic neurons. Its role in neuronal metabolism and its neuroprotective profile has been well established (Airaksinen and Saarma, 2002, Broome et al., 1999) (Drinkut et al., 2012, Kordower and Bjorklund, 2013, Moran and Graeber, 2008). Long-lasting analogues of GDNF and gene therapy strategies are currently under investigation as a potential treatment of PD (see eg. clinical trial NCT01621581), but as GDNF cannot cross the blood-brain barrier (BBB) (Allen et al., 2013), no effective treatment has been developed yet. In our study, levels of GDNF were enhanced by all drugs in the striatum, with DA-JC4 showing the most pronounced effects. GLP-1 and GIP have growth-factor like properties (Hölscher, 2018). We have previously shown that GLP-1 or GIP analogues enhance the expression of BDNF (Ji et al., 2016b, Li et al., 2017), a growth factor that protects synaptic activity from stressors (Nagahara et al., 2009). GLP-1 and GIP can cross the BBB (Dogrukol-Ak et al., 2004, Hunter and Holscher, 2012, Kastin and Akerstrom, 2003, Kastin et al., 2002) and enhance the expression of key growth factors such as BDNF or GDNF. Therefore, the use of GLP-1 and GIP analogues appears to be an effective way of enhancing levels of protective growth factors such as GDNF and BDNF in the brain.