Post-Treatment with Amorfrutin B Evokes PPARγ-Mediated Neuroprotection against Hypoxia and Ischemia.
Agnieszka WnukKarolina PrzepiórskaBernadeta A PietrzakMałgorzata KajtaPublished in: Biomedicines (2021)
In this study, we demonstrate for the first time that amorfrutin B, a selective modulator of peroxisome proliferator-activated receptor gamma-PPARγ, can protect brain neurons from hypoxia- and ischemia-induced degeneration when applied at 6 h post-treatment in primary cultures. The neuroprotective effect of amorfrutin B suggests that it promotes mitochondrial integrity and is capable of inhibiting reactive oxygen species-ROS activity and ROS-mediated DNA damage. PPARγ antagonist and Pparg mRNA silencing abolished the neuroprotective effect of amorfrutin B, which points to agonistic action of the compound on the respective receptor. Interestingly, amorfrutin B stimulated the methylation of the Pparg gene, both during hypoxia and ischemia. Amorfrutin B also increased the protein level of PPARγ during hypoxia but decreased the mRNA and protein levels of PPARγ during ischemia. Under ischemic conditions, amorfrutin B-evoked hypermethylation of the Pparg gene is in line with the decrease in the mRNA and protein expression of PPARγ. However, under hypoxic conditions, amorfrutin B-dependent hypermethylation of the Pparg gene does not explain the amorfrutin B-dependent increase in receptor protein expression, which suggests other regulatory mechanisms. Other epigenetic parameters, such as HAT and/or sirtuins activities, were affected by amorfrutin B under hypoxic and ischemic conditions. These properties position the compound among the most promising anti-stroke and wide-window therapeutics.
Keyphrases
- dna damage
- cerebral ischemia
- reactive oxygen species
- insulin resistance
- binding protein
- genome wide
- endothelial cells
- oxidative stress
- fatty acid
- dna methylation
- copy number
- gene expression
- atrial fibrillation
- genome wide identification
- blood brain barrier
- dna repair
- small molecule
- metabolic syndrome
- adipose tissue
- ischemia reperfusion injury
- subarachnoid hemorrhage
- high glucose
- protein protein
- spinal cord injury
- replacement therapy
- resting state
- smoking cessation
- stress induced