Abstract
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.
Highlights
Cerebrovascular accidents are the second leading cause of death and the leading cause of disability worldwide
In the paradigm of post-treatment, i.e., when amorfrutin B was added during the reoxygenation period, the following effects were observed: (i) in the hypoxic model, amorfrutin B (1 μM and 5 μM) post-treatment inhibited Lactate Dehydrogenase (LDH) release to 75% (25% decrease) and 71% (29% decrease) of the hypoxia value, respectively; (ii) in the ischemic model, amorfrutin B (1 μM and 5 μM) post-treatment reduced ischemia-induced LDH activity to 69 and 66% (31 and 34% decrease), respectively (Figure 1c)
Amorfrutin B used at concentrations ranging from 0.1 to 5 μM did not change LDH release, but amorfrutin B at a concentration of 10 μM was cytotoxic to neocortical cells
Summary
Cerebrovascular accidents (commonly known as strokes) are the second leading cause of death and the leading cause of disability worldwide. The only pharmacological treatment approved by the Food and Drug Administration for acute ischemic stroke is recombinant tissue plasminogen activator (rt-PA), which is effective only if administered until 4.5 h after stroke onset. Additional stroke treatment is surgical thrombectomy, which can be used only up to 8 h following the onset of symptoms located in the anterior circulation and is eligible for no more than 2% of patients [4]. Oxygen deprivation is considered the most common cause of death in fetuses and newborns, i.e., 2–4 newborns die per 1000 births. One million children die due to hypoxia and neonatal oxygen deprivation, which leads to permanent brain damage and disability such as hypoxicischemic encephalopathy [5]. Oxygen therapy and moderate hypothermia occurring up to 6 h after the hypoxic episode are the gold standard treatment for neonatal asphyxia [6]
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