Cerebral ischemia-reperfusion (CIR) is a common feature of
ischemic stroke and is a major cause of disability and death among
stroke patients worldwide.
Phyllanthin, a
lignin polyphenol, is known for its varied biological properties, although its protective effects against CIR have not been reported. We evaluated the neuroprotective property of
phyllanthin against CIR as well as the involvement of the
AMP-activated protein kinase/nuclear factor erythroid 2-related factor 2 (AMPK/Nrf2) and
nuclear factor kappa B (NF-κB) signaling pathways. Experimental animals were divided into five groups: controls (
sham-operated), CIR-induced by
middle cerebral artery occlusion (MCAO), and CIR-induced and administered
phyllanthin at 2.5, 5, and 10 mg/kg, respectively. We investigated neurological functions, various signaling genes, and inflammatory clues. The results of in vitro assays demonstrated that
phyllanthin assertively improved cellular functions through abrogation of the Nrf2 pathway. In vivo, CIR rats demonstrated neurological function deficits, while ischemic severity was evidenced by the activation of neuroinflammatory
cytokines and tissue oxidative stress. Moreover, the expression of apoptosis markers such as Bax,
B-cell lymphoma (Bcl-2),
caspase-3, COX-2,
PGE2, and LOX-1 abruptly increased.
Phyllanthin prevented brain dysfunction and
cerebral edema, and protected brain integrity. Conversely, it improved antioxidative
enzyme activity, abrogated inflammatory
cytokines, and increased
IL-10 in
chemokines. Also,
phyllanthin significantly reduced Nrf2 and AMPK levels, with reduced expression of NF-κB indicating that cross-talk between the
NF-kB and Nrf2 pathways is activated in CIR.
Phyllanthin rescues the ischemic brain by regulating cellular signaling, which supports its use for complications like CIR and associated injury.