Inhibition of PGAM5 hyperactivation reduces neuronal apoptosis in PC12 cells and experimental vascular dementia rats

Purpose: The incidence of vascular dementia (VaD), as one of the main types of dementia in old age, has been increasing year by year, and exploring its pathogenesis and seeking practical and effective treatment methods are undoubtedly the key to solving this problem. Phosphoglycerate translocase 5 (PGAM5), as a crossroads of multiple signaling pathways, can lead to mitochondrial fission, which in turn triggers the onset and development of necroptosis, and thus PGAM5 may be a novel target for the prevention and treatment of vascular dementia.

Methods: Animal model of vascular dementia was established by Two-vessel occlusion (2-VO) method, and cellular model of vascular dementia was established by oxygen glucose deprivation (OGD) method. Neuronal damage was detected in vivo and in vitro in different groups using different concentrations of the PGAM5-specific inhibitor LFHP-1c, and necroptosis and mitochondrial dynamics-related factors were determined.

Results: In vivo experiments, 10 mg/kg^-1 and 20 mg/kg^-1 LFHP-1c improved cognitive deficits, reduced neuronal edema and vacuoles, increased the number of nissl bodies, and it could modulate the expression of Caspase family and Bcl-2 family related proteins and mRNAs and ameliorate neuronal damage. Simultaneously, in vitro experiments, 5 μM, 10 μM and 20 μM LFHP-1c increased the activity and migration number of model cells, reduced the number of apoptotic cells, ameliorated the excessive accumulation of intracellular reactive oxygen species, inhibited the over-activation of caspase-family and Bcl-2-family related proteins and mRNAs, and improved the mitochondrial dynamics of the fission and fusion states. Moreover, in vivo and in vitro experiments have shown that LFHP-1c can also upregulate the expression level of BDNF, inhibit the expression content of TNF-α and ROS, regulate the expression of proteins and mRNAs related to the RIPK1/RIPK3/MLKL pathway and mitochondrial dynamics, and reduce neuronal apoptosis.

Conclusions: Inhibition of PGAM5 expression level can reduce neuronal damage caused by chronic cerebral ischemia and hypoxia, which mainly prevents necroptosis by targeting the RIPK1/RIPK3/MLKL signaling pathway and regulates the downstream mitochondrial dynamics homeostasis system to prevent excessive mitochondrial fission, thus improving cognition and exerting cerebroprotective effects.