Two 2021 papers, both of which I found by each citing a 2009 Molecular mechanisms underlying cochlear degeneration in the tubby mouse and the therapeutic effect of sulforaphane (not freely available). First was a review:
“Hair cell damage and loss mediated by oxidative stress are important causes of hearing loss. Sensorineural hearing loss is the most common type of hearing loss, including noise induced hearing loss (NIHL), age-related hearing loss (ARHL), and ototoxic hearing loss.
Nrf2 reduces cell damage caused by oxidative stress, and maintains the dynamic balance of systematic redox by inducing and regulating expression of various antioxidant factors. This review summarizes correlation studies of Nrf2 in hearing loss, providing ideas for prevention and treatment of hearing loss with Nrf2 as the target.
There is positive feedback between p62-mediated autophagy and Nrf2. p62 promotes accumulation of Nrf2 and nuclear translocation. Concurrently, increased Nrf2 promotes p62 expression.
How Nrf2 regulates ROS changes in hair cells, and the upstream and downstream regulatory network of Nrf2 in hair cells, are still not fully understood. Studies on early prevention and treatment of hearing loss through the Keap1-Nrf2-ARE [antioxidant response element] signaling axis are still at the exploratory stage.”
https://www.frontiersin.org/articles/10.3389/fphar.2021.620921/full “The Role of Nrf2 in Hearing Loss”
Second paper was a rodent study:
“We examined oxidative stress and antioxidant response of the p62-Keap1-Nrf2 pathway in cochleae during age-related hearing loss (ARHL) and noise-induced hearing loss (NIHL). We elucidated the function of full-length and variant p62/Sqstm1 (referred to here as p62) in regulation of Nrf2 activation.
Cochlear damage was assessed by analyzing auditory brainstem response (ABR) and by counting hair cells (HCs). Malondialdehyde (MDA, a lipid peroxidation product) levels were measured in young and old mice to determine whether oxidative stress contributed to ARHL.
- (A) Audiometric threshold (dB) determined from click and pure tone evoked ABRs. Thresholds were each significantly different (P < 0.001) between young mice and old mice.
- (B) HC loss percentage in basal cochlear turns. Significant differences (P < 0.001) were observed between young and old mice.
- (C) MDA levels in the cochleae of old mice were significantly higher (P = 0.034) than those of young mice.
ROS accumulation is closely related to ARHL and NIHL. The inability of ROS accumulation to activate the Nrf2 antioxidant stress pathway under physiological conditions may be related to alternative splicing of p62 mRNA in cochleae.
However, the agonist of the Nrf2 pathway enhanced Nrf2 nuclear translocation. This suggests a mechanism in which the antioxidant pathway was difficult to be activated in the context of accumulation of ROS.”
https://www.researchsquare.com/article/rs-535219/v1 “New Target of Oxidative Stress Regulation in Cochleae：Alternative Splicing of the p62/Sqstm1 gene”
The study’s two-month-old mice were equivalent to a 20-year-old human. Its 13-to-14-month-old mice were equivalent to humans in their 60s to 70s.
I expected preconditioning to be mentioned in both papers. Maybe these researchers thought it was too obvious and didn’t need to be stated that:
- Repeated use of a Nrf2 activator produces transient mild stress;
- Which elicits a stronger response; and
- Preconditions cells for future stress?
Sulforaphane in the Goldilocks zone and its cited papers exhaustively emphasized preconditioning’s importance. The main thing I’m trying to do with isothiocyanates is to send a weak pro-inflammatory signal to my endogenous ARE system to exercise natural defenses.
Twice-daily drills make me more proficient at responding to actual emergencies. Post-drill, my body recycles material to be ready to respond the next time.
I do the same thing once a day with β-glucan 1,3/1,6 to train my innate immune system. Microphages in my gut are the first responders. Like the very reactive isothiocyanates, I don’t take anything with, or an hour before or after β-glucan 1,3/1,6.
Why tolerate “the antioxidant pathway was difficult to be activated in the context of accumulation of ROS” when a sulforaphane “agonist of the Nrf2 pathway enhanced Nrf2 nuclear translocation”? For all we know, diminished natural defenses and hearing loss may exist to turn old mammals into prey.
Continued in Part 2.