A noteworthy abstract from The Association for Research in Otolaryngology (ARO) 44th Annual MWM held a few months ago:
Attenuation of Age-Related Hearing Loss in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice Treated With Fatty Acid Synthase Inhibitor CMS121
Background
The senescence-accelerated prone strain 8 (SAMP8) mouse model provides opportunities to investigate potential therapies for age-related hearing loss (ARHL), the most common sensory disorder in older humans. In SAMP8 mice, oxidative stress leads to chronic inflammation, apoptosis, and premature senescence. CMS121 is a fatty acid synthase inhibitor previously shown to improve cognitive function in SAMP8 mice through anti-inflammatory and antioxidative effects in the hippocampus. Given the common cellular pathways leading to age-related dysfunction inthe hippocampus and cochlea, the aim of our study is to determine whether CMS121 is protective against ARHL in SAMP8 mice.
Methods
Auditory brainstem responses (ABRs) across six frequencies (4, 8, 12, 16, 24, and 32 kHz) were used to assess baseline hearing in sixteen 4-week-old SAMP8 mice, which were then split into age-matched groups with similar average hearing thresholds. The control group was then fed a vehicle diet, while the experimental group was fed a diet with CMS121. ABR measurements were repeated at seven, ten, and thirteen weeks of age. Cochlear immunohistochemistry was then performed using Ctbp2, GluR2, and Myo7a to analyze the number of paired ribbon-receptor synapses per inner hair cell (IHC). Descriptive statistics are provided with mean ±SEM (Standard Error of the Mean). Two-sample t-tests were performed to compare hearing thresholds and paired synapse count across the two groups, with alpha = 0.05.
Results
Baseline hearing thresholds across the six frequencies in the control group (77.5± 5.9, 59.0 ± 9.5, 44.2 ± 6.1, 47.5 ± 7.8, 36.8 ± 6.0, and 35.0 ± 7.2) were statistically similar to those of the CMS121 group (74.9 ± 2.3, 51.4 ± 3.7, 42.3 ± 3.3, 45.8 ± 5.0, 37.8 ± 4.6, and 33.3 ± 4.7.) While the control group showed progressive ARHL (hearing thresholds at 13 weeks were 84.0 ± 6.4, 63.8 ± 10.0, 56.5 ± 6.1, 64.8 ± 7.4, 37.0 ± 6.4, and 38.3 ± 6.1), the CMS121 group maintained stable hearing thresholds at 13 weeks (73.1 ± 4.0, 50.0 ± 4.5, 39.8 ± 3.8, 43.8 ± 4.4, 31.6 ± 4.3, and 35.8 ± 7.1). At that time, the control group had significantly worse hearing thresholds at 12 kHz (56.5 vs. 39.8, p = 0.044) and 16 kHz (64.8 vs. 43.8, p = 0.040) compared to the CMS121 group. Immunohistochemistry showed a significantly lower synapse count per IHC in the control group (15.7) compared to the CMS121 group (18.4), p = 0.014.
Conclusions
Our study shows a significant reduction in hearing loss and increased preservation of ribbon synapses in the mid-range frequencies among mice treated with CMS121 compared to untreated mice. These findings support expanding the scope of current research on CMS121 to further investigate the promising role of this compound as a protective agent against ARHL.
Further study will be needed to explore whether CMS121 can reverse any pre-existing hearing loss. But considering how nearly all forms of hearing loss are progressive (albeit some are slower than others), a decibel saved is a decibel earned gained.
As far as mechanism is concerned, it seems to show potential in combating the damaging effects of noise-induced lipid peroxidation. But there’s likely a few things going on.
“But human trials must be years away.”
Fortunately this drug candidate has a bit of a head start, as it is being studied in Alzheimer’s disease:
https://www.sciencedirect.com/science/article/pii/S2213231720308533
That’s all for now. More information to follow.
These unfinished notes on CMS121 are for email subscribers. Sign up here.