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    • br Clinical trials testing GLP mimetics in AD or PD

    2021-10-09


    Clinical trials testing GLP-1 mimetics in AD or PD patients
    GIP analogues show good neuroprotective effects in animal models of AD and PD Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino HBC incretin growth factor which activates pancreatic islets to enhance insulin secretion and to help reduce hyperglycaemia, similar to GLP-1 (Finan et al., 2016, Gault et al., 2003). GIP receptors are also expressed in the brain and are found on larger neurons such as the pyramidal cortical neurons (Nyberg et al., 2005), which is very similar to the pattern of expression of GLP-1 receptors (Hamilton and Holscher, 2009, Nyberg et al., 2007). Stable analogues such as D-ala2-GIP or N-glyc-GIP facilitate synaptic plasticity in the hippocampus, while the antagonist Pro3-GIP impairs LTP (Gault and Holscher, 2008). The GIP analogue D-Ala2-GIP showed neuroprotective effects in the APP/PS1 mouse model of AD. In 12 months old tg mice, synaptic plasticity the hippocampus and spatial memory formation was protected by D-Ala2-GIP. Synapse loss was prevented by the drug. The amyloid plaque load was reduced, as was the chronic inflammation response. Neuronal progenitor cell levels in the dentate gyrus were also increased (Duffy and Holscher, 2013, Faivre and Holscher, 2013b). The drug also had protective effects on synaptic transmission in 19 month old tg mice, increased synaptic numbers and reduced the overall plaque load (Faivre and Holscher, 2013a). GIP injection ip. had protective effects on spatial learning in memory tasks and also reduced plaque formation and amyloid load in a different AD mouse model (Figueiredo et al., 2010). See (Ji et al., 2016a) for a review. When testing GIP in the MPTP mouse model of PD, it was found that the long-lasting protease resistant analogue D-Ala2-GIP-glu-PAL showed good protective effects. Motor activity was partly rescued, and the number of dopaminergic neurons in the substantia nigra was increased. Synapse numbers were increased, and the cAMP/PKA/CREB growth factor second messenger pathway was shown to be activated by the drug (Li et al., 2016). In a chronic model of MPTP lesion, the same drug protected motor activity, dopaminergic neurons, and inhibited the increased levels of expression of alpha-synuclein in the brain induced by MPTP. Furthermore, drug treatment reduced chronic neuroinflammation, oxidative stress and lipid peroxidation, and increased the expression of BDNF (Li et al., 2017). Others found very similar effects with D-Ala2-GIP in the MPTP mouse model (Verma et al., 2017). GIP treatment also protected rat brains in a model of mild traumatic brain injury (Yu et al., 2016).
    Novel dual GLP-1/GIP receptor agonists New dual GLP-1 and GIP receptor agonists have been developed to treat diabetes. Some have already been tested in clinical trials and show superior performance when compared with the single GLP-1 analogue liraglutide (Finan et al., 2013, Frias et al., 2017). There are currently 5 different dual agonists that we have named DA1-DA5 (see Table 1 for details). DA1-DA3 have been developed as treatments for diabetes (Finan et al., 2013). We also have developed two novel dual agonists that have been modified to enhance BBB penetration (DA-JC4 and DA-CH5, see Table 1). When testing DA-JC1 in the MPTP mouse model of PD, we found that it rescued motor activity, synapse numbers, numbers of dopaminergic neurons in the substantia nigra, and reduced chronic inflammation. Interestingly, the expression of BDNF was enhanced, which can explain some of the neuroprotective effects observed (Cao et al., 2016, Ji et al., 2016b). DA-JC1 was furthermore tested in the 6-OHDA lesion rat model of PD. When treating rats for 6 weeks with DA-JC1, motor activity as tested in the Rotarod and in the open field was much improved. In the amphetamine and apomorphine circling behaviour tests, the 6-OHDA induced impairments were much reduced by the DA-JC1 treatment. Dopaminergic neuron numbers in the substantia nigra were decreased by 6-OHDA lesion and normalised by DA-JC1 treatment. Dopamine levels in the basal ganglia were reduced by 6-OHDA lesion and increased by DA-JC1. The levels of the growth factor GDNF and pAkt/CREB growth factor cell signalling was enhanced by DA-JC1. Interestingly, the autophagy marker Beclin1 was also activated by the drug. (Jalewa et al., 2017). We furthermore tested DA1-JC in a mouse model of stroke. The drug protected neuronal survival and prevented secondary neuronal degeneration (Han et al., 2015). The DA-JC1 peptide was also tested in a rat model of mild traumatic brain injury (Tamargo et al., 2017). In a cell culture study testing a range of analogues of GLP-1, GIP, oxyntomodulin and DA-JC1, it was found that DA-JC1 was the most potent drug in the SH-SY5Y rotenone stress model (Jalewa et al., 2016).