3.5. Amplification of the nrf2 Neuroprotective Pathway via Potentially Low Brain Cocoa Flavanol Levels against Stroke in Young and also Aged Animals
Pharmacological treatment approaches for stroke and other neurodegenerative diseases have been largely unsuccessful. Since ischemic stroke is predominantly a disease of the elderly, issues such as side effects, co-morbidities and contraindications are particularly problematic. Due to such health considerations, natural bioactive compounds are attractive alternatives to standard therapies.
Studies suggest that the flavan-3-ol (–)-epicatechin (EC), which is lipophilic and has essentially no reported toxicity, can protect against cerebrovascular disease and stroke. Although various flavan-3-ols have shown efficacy in young, healthy preclinical animal models, the potential of achieving such benefits in aged mice is understudied. Additionally, the in vivo mechanisms of protection remain elusive.
We hypothesized that EC confers its health benefits by activating the transcriptional factor Nrf2, which exerts pleiotropic effects by upregulating key cytoprotective proteins.
Here, wild type control or Nrf2-/- mice aged four or 12 months were subjected to a permanent stroke model 90 min following oral administration of the minimum effective EC dose established in our previous stroke studies. Similar to previous results with young mice, 12-month-old wild types also showed significant reductions in infarct volume (41.0%) and improved performance in removing adhesive tape relative to vehicle-treated controls; whereas, such a significant beneficial effect was not observed in Nrf2-/-.
However, EC did not reduce immunoreactivity for the microglia/macrophage marker anti-Iba1, suggesting that dampened activation/recruitment did not account for EC brain protection. Furthermore, there were no differences in mouse IgG extravasation or spontaneous hemorrhage between EC-treated groups.
These findings further validate EC building brain resistance to oxidative stress not only in young but also in aging mice and suggest that EC prophylaxis may confer benefits, at least in part, by reducing brain hemorrhage.