Treatment With Liraglutide Exerts Neuroprotection After Hypoxic–Ischemic Brain Injury in Neonatal Rats via the PI3K/AKT/GSK3β Pathway

Abstract

Neonatal hypoxic-ischemic (HI) brain injury is a detrimental disease, which results in high mortality and long-term neurological deficits. Nevertheless, the treatment options for this disease are limited. Thus, the aim of the present study was to assess the role of liraglutide in neonatal HI brain injury in rats and investigate the associated mechanisms. The results showed that treatment with liraglutide significantly reduced infarct volume and ameliorated cerebral edema, decreased inflammatory response, promoted the recovery of tissue structure, and improved prognosis following HI brain injury. Moreover, treatment with liraglutide inhibited apoptosis and promoted neuronal survival both in the rat model and following oxygen-glucose deprivation (OGD) insult. LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), partially reversed these therapeutic effects, suggesting that the PI3K/protein kinase B (Akt) pathway was involved. In conclusion, our data revealed that treatment with liraglutide exerts neuroprotection after neonatal HI brain injury via the PI3K/Akt/glycogen synthase kinase-3β (GSK3β) pathway and may be a promising therapy for this disease.

Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review

“…Conversely, Bax is a pro-apoptotic protein and increases cytochrome C levels. 52 Increased Bcl-2 and reduced Bax levels, contributing to an increased Bcl-2:Bax ratio and representing reduced levels of apoptosis, have been reported in 3 studies of liraglutide 29,33,37 and 1 study for each pro-GLP-1, 45 rhGLP-1, 39 DMB, 22 Ex-4, 50 Lixisenatide, 51 GLP-1/GIP DA 47 and semaglutide. 43 Critically, this reduction of apoptosis was reproduced in normoglycemic models when administered after stroke onset.…”

“…43 Critically, this reduction of apoptosis was reproduced in normoglycemic models when administered after stroke onset. 33,37,43,47 Caspase proteins are also pro-apoptotic and increased levels are associated with higher rates of cell death. 54 Liraglutide, Exendin-4, Lixisenatide, rhGLP-1 and semaglutide have been shown to reduce levels of caspase-3 in pre-clinical models of stroke.…”

“…54 Liraglutide, Exendin-4, Lixisenatide, rhGLP-1 and semaglutide have been shown to reduce levels of caspase-3 in pre-clinical models of stroke. 33,37,39,[41][42][43]46,50,51 Zhu et al have also demonstrated reduced levels of caspase 8 and 9 in models administered liraglutide. 33 Cleavage of PARP by caspases is a signal of apoptosis and has been implicated in cerebral ischemia.…”

“…33,50 TUNEL assays detect DNA degradation during the later stages of apoptosis and have demonstrated reduced apoptotic activity with liraglutide and exendin-4. 37,50,55 GLP-1RA administration following stroke induction has been associated with an anti-inflammatory effect. 26 Tumor necrosis factor alpha (TNF-) is a cytokine synthesised by many cell linesbut particularly by macrophages and microglia.…”

“…20 Reduced levels of other markers of inflammation, such as myeloperoxidase and interleukin, have also been reported. 30,37,51 One study reported a non-statistically significant reduction in pro-inflammatory markers. 25 There is also deterioration in markers of oxidative stress following AIS.…”