Elsevier, Peptides, Volume 125, March 2020
Glucose-dependent Insulinotropic polypeptide (GIP) is a peptide hormone of the incretin family. It has growth factor properties and can re-activate energy utilization. In progressive neurodegenerative disorders such as Alzheimer's and Parkinson's disease, energy utilization is much reduced, and GIP has the potential to reverse this. Furthermore, GIP can reduce the inflammation response in the brain and reduce levels of pro-inflammatory cytokines. Tests in animal models of Alzheimer's and Parkinson's disease show good neuroprotective effects. In Parkinson's disease models, motor activity is normalized, dopaminergic neurons are protected, synapse numbers and dopamine levels are maintained. Levels of growth factors that are essential for neuronal and synaptic function are increased and alpha-synuclein levels are reduced. The chronic inflammation response and mitochondrial damage is reduced. In Alzheimer's disease models, memory is rescued, synapse numbers and synaptic plasticity in the hippocampus is normalized, amyloid plaque load and the chronic inflammation is reduced. Similar protective effects have been previously reported with analogues of glucagon-like peptide 1 (GLP-1), the sister incretin hormone. First clinical trials show good protective effects in both diseases. Recently, novel dual GLP-1/GIP receptor agonists have been developed. The ability to cross the blood-brain barrier (BBB) is key to their neuroprotective effects. We have developed two dual GLP-1/GIP receptor agonist that have cell penetrating sequences added for better BBB penetration. In direct comparisons, these dual agonists show improved neuroprotection in a mouse model of Parkinson's disease. Therefore, such novel multiple receptor agonists hold great promise as potential treatments for Alzheimer's and Parkinson's disease.