TABLE 1.

Evidence supporting the neuroprotective properties of diabetes drugs use in the context of treatments for hypoxia-ischemia encephalopathy.

Diabetes drug	Model	Species	Treatment	Effects	References
Biguanide	OGD	bEND.3 cells	Metformin	Inhibition of inflammatory signaling pathways	Liu et al., 2014
Biguanide	OGD	Rat cortical neurons	Metformin	Pre-treatment of neurons alleviated OGD/R-induced injury	Meng et al., 2016
Biguanide	OGD	Primary rat fetal-derived astrocytes	Metformin	Improve cell viability via reduction of apoptosis mechanisms	Gabryel and Liber, 2018
Biguanide	OGD	PC-12 cells	Metformin	Reduce cell death under OGD/R condition and attenuation of ROS generation	Mohammad Alizadeh et al., 2018
Biguanide	OGD	Primary cortical and hippocampal neurons	Metformin	Moderate improvement of cell viability	Mielke et al., 2006
TZD	OGD	Rat hippocampal slices	NP00111 Rosiglitazone	Protection against OGD by a mechanism related to phosphorylation of ERK1/2 via activation of PPARγ	Rosa et al., 2008
TZD	OGD	Primary cultured astrocytes	Pioglitazone	Protective effects with inhibition of pyroptosis mechanism induced by the OGD	Xia et al., 2018
DPP4	OGD	HBMVECs	Alogliptin	Protection against OGD and increasing of permeability in human brain vascular cells	Hao et al., 2019
Incretin GLP1-R agonist	OGD	Rat cortical neurons	Exendin-4	Protects neurons through PKA pathway	Wang M.-D. et al., 2012
Incretin GLP1-R agonist	OGD	Rat cortical neurons	Liraglutide	Neuroprotective action with reduction of apoptosis and ROS via activation of the PI3K/AKT and MAPK pathways	Zhu et al., 2016
Incretin GLP1-R agonist	OGD	Mouse cortical neurons	DMB	Neuroprotection with anti-apoptotic effects, mediated by activation of the GLP-1R through the cAMP-PKA-CREB signaling pathway	Zhang et al., 2016
Sulfonylurea	HI P10	Rat	Glibenclamide	No effects on severe HI model Improvement neurological functions in moderate HI model	Zhou et al., 2009
TZD	HI 8W	Ob/Ob mouse	Darglitazone	Reduction of the infarct size and neuroinflammation response	Kumari et al., 2010
Biguanide	HI P8	Mouse	Metformin	Activation of endogenous NPCs, promoting their migration and differentiation in the injured brain Restoration of sensory-motor function	Dadwal et al., 2015
Biguanide	HI P3	Rat	Metformin	Attenuation of cognitive impairments Induction of OPCs proliferation reducing myelination damage	Qi et al., 2017
Biguanide	HI P7	Rat	Metformin	Attenuation brain infarct and oedema Inhibition of neuronal apoptosis, and neuroinflammation + amelioration of the blood brain barrier breakdown	Fang et al., 2017
Biguanide	HI P8	Mouse	Metformin	Sex-dependent effects on proliferation but increases neurogenesis in both sexes; rescues cognitive deficits in adult females	Ruddy et al., 2019
Incretin GLP1-R agonist	HI P7/P10	Mouse	Exendin-4**	Neuroprotective effect alone or in combination with therapeutic hypothermia	Rocha-Ferreira et al., 2018
Incretin GLP1-R agonist	HI P7	Rat	Liraglutide	Inhibited apoptosis and promoted neuronal survival; PI3K/Akt pathway involved	Zeng et al., 2020

In vitro model with OGD on different cell types and in vivo models with HI at different stage of age. **Only study using combination with hypothermia.