Keap1‑Nrf2‑ARE
One of the most essential defense systems against oxidative and/or
electrophilic stressors is the Keap1–Nrf2–ARE Kelch-like
ECH-Associating protein 1 nuclearfactor erythroid 2 related factor
2-antioxidant response element, which is linked to inflammatory
disorders. In response to ROS exposure, it activates a cytoprotective
mechanism. The Nrf2-ARE transcriptional pathway regulates genes that
encode proteins involved in the detoxification and elimination of
reactive oxygen species (ROS) and electrophiles (Nguyen, Nioi &
Pickett, 2009). The Keap1–Nrf2–ARE pathway is important for cell
protection against oxidative and electrophilic stress. The ability of
Nrf2–ARE activators to boost a battery of critical cell-protective
genes involved in reducing oxidative damage and inflammation may be
exploited in the development of antioxidant, anti-inflammatory, and
anticancer medicines (Lu, Ji, Jiang & You, 2016). The study of (Shang
et al., 2013) achieved two goals. It first identified the timing of
Keap1 inhibition and Nrf2 activation in rats during the early stages of
ICH. Nrf2 is an important endogenous regulator of cellular oxidative
stress resistance. Intravenous treatment of a Nrf2 activator (BARD)
significantly raised Nrf2 and HO-1 expression earlier, thereby
protecting neurons from IRI. Taken together, their findings revealed
that Nrf2 activators may be neuroprotective in patients with IRI (Takagi
et al., 2014). In the (Zhao et al., 2007) study, activation of Nrf2 by
SF was related with enhanced expression of many antioxidative enzymes
known to play essential roles in oxidative stress defense, including
catalase, SOD, NAD(P)H dehydrogenase, quinone-1, and glutathione
S-transferase. Nrf2 deficiency contributes to ROS-induced DNA damage and
death largely in neurons in the early stages of ICH, according to (Wang
et al., 2007) Activating Nrf2 prevents leukocytes from entering the
injury site and preventing excessive free radical damage to the brain
tissue. Despite the fact that more research with selective Nrf2 inducers
and inhibitors is needed, the data suggest that Nrf2 could be a
therapeutic target for the treatment of ICH. (Zhang et al., 2019) found
that MitoQ promotes mitophagy and reduces mitochondrial oxidative
stress-related neuronal apoptosis in EBI after SAH via the
Keap1/Nrf2/PHB2 pathway, which is linked to improved short- and
long-term neurological impairment. MitoQ could thus be used as an
antioxidant therapy for EBI as well as a treatment for delayed
neurological impairments following SAH. SalA (10 and 50 mg/kg/day)
administered intraperitoneally was shown to protect EBI following SAH,
at least in part due to its antioxidative, anti-inflammatory, and
antiapoptotic properties. The following is the evidence that led to this
conclusion: At 48 hours following a SAH in a rat model, SalA
dramatically alleviated neurological impairments, reduced brain edema
and BBB permeability, decreased inflammation factors, and repressed
oxidative stress and cortical neuron death. Furthermore, SalA reduced
MDA and ROS production produced by SAH while increasing GSH
concentration and GSH-Px activity. These findings suggested that
treating rats with SalA would be an effective way to protect their
brains from EBI after SAH (Gu et al., 2017). SAH treatment may one day
be based on this promising new discovery, but further studies are needed
to confirm it.