TABLE 1.

Overview of publications that tested GLP-1/GIP dual agonists in animal models of AD or PD.

Animal model	Drug tested	Result	References
MPTP mouse model of PD	DA1-JC	Improvement in motor tasks, protection of dopaminergic neurons, enhanced release of BDNF, Pi3k activity was enhanced, pro-apoptotic signaling reduced	Ji et al., 2016
MPTP mouse model of PD	DA1-JC	Improvement in motor tasks, protection of dopaminergic neurons, reduced inflammation in the brain, enhanced synaptic protein levels	Cao et al., 2016
SH-SY5Y cell culture treated with rotenone	DA1-JC	DA1-JC is the most effective drug compared to single GLP-1 or GIP analogs or to oxyntomodulin. Protection of cell viability, reduction of apoptotic signaling, improvement of autophagy, and Pi3k signaling	Jalewa et al., 2016
6-OHDA rat model of PD	DA1-JC	Motor activity was improved, dopaminergic neuronal loss was reduced, levels of GDNF were increased and pAkt/CREB signaling normalized	Jalewa et al., 2017
icv. STZ rat model of AD	DA4-JC	Memory formation was improved, tau phosphorylation reduced, insulin signaling improved, reduced apoptosis and inflammation in the brain	Shi et al., 2017
MPTP mouse model of PD	DA3-CH	DA3-CH is more effective than liraglutide in improving motor activity, protecting dopaminergic neurons, reducing inflammation, and levels of GDNF are increased	Yuan et al., 2017
MPTP mouse model of PD	DA1-JC, DA4-JC, DA5-CH	DA4-JC and DA5-CH are more effective in protecting the brain than liraglutide and DA1-JC. Motor activity was improved, dopaminergic neurons protected, levels of pro-inflammatory cytokines reduced, GDNF levels were increased	Feng et al., 2018
APP/PS1 mouse model of AD	DA5-CH	Memory formation was protected, synaptic plasticity (LTP) preserved and tau phosphorylation reduced, PI3k and Akt activity normalized	Cao et al., 2018
APP/PS1 mouse model of AD	DA3-CH	DA3-CH improved memory formation, normalized autophagy, reduced ER stress and apoptotic signaling, reduced amyloid plaque load in the brain	Panagaki et al., 2018
icv. Amyloid (31-35) AD model	DA1-JC	memory formation was improved, and disturbance of circadian rhythm improved	Wang et al., 2019
APP/PS1 AD mouse model	DA1-JC	DA1-JC was more effective than liraglutide in a slow-release formulation in improving memory formation, reducing inflammation, and reducing oxidative stress	Salles et al., 2020
icv. STZ rat model of AD	DA5-CH	Memory formation is rescued, EEG theta rhythm normalized, tau phosphorylation is reduced, apoptosis signaling is reduced, CREB signaling is normalized, DA5-CH is superior to DA1-JC, liraglutide or exendin-4 in crossing the blood-brain barrier	Li et al., 2020
MPTP mouse model of PD	DA5-CH	Receptor binding study of DA5-CH showing selective binding to GLP-1 and GIP receptors. DA5-CH is superior to DA1-JC, DA2, DA3-CH, liraglutide or exendin-4 in crossing the blood-brain barrier. DA5-CH is superior to exendin-4 in a dose-response study. Motor activity is protected, inflammation is reduced, lipid oxidation is reduced, apoptosis is reduced, DA5-CH is superior to liraglutide	Zhang et al., 2020
APP/PS1/Tau AD mouse model	DA4-JC	DA4-JC receptor binding study shows selective binding. DA4-JC is superior to liraglutide in a dose-response study in reducing amyloid plaques. DA4-JC was more effective than liraglutide in reversing memory loss, enhancing synaptic plasticity (LTP) in the hippocampus, reducing amyloid plaques and lowering pro-inflammatory cytokine levels in the brain.	Cai et al., 2021
6-OHDA rat model of PD	DA5-CH	DA5-CH is more effective than exendin-4 in protecting motor activity, reducing a-synuclein levels and pro-inflammatory cytokine levels in the brain. It was also more effective than exendin-4 in reducing apoptotic signaling. Insulin desensitization was reversed and the levels of autophagy markers were normalized.	Zhang et al., 2021
MPTP mouse model of PD	DA5-CH	DA5-CH is more effective than NLY01, a 40 kDa pegylated form of exendin-4, in protecting motor activity, reducing α-synuclein levels, NF-kB and pro-inflammatory cytokine levels in the brain. DA5-CH can cross the BBB better than the pegylated exendin-4 drug.	Lv et al., 2021