Metformin, the magical solution!
Reviewed by Hassan Mohammed

Both noise-induced hearing loss (NIHL) and vestibular schwannomas (VSs) pose a challenge in terms of management. Metformin was suggested as a potential therapeutic drug for NIHL when the drug-target interaction data was investigated. Additionally, there are studies which demonstrate reduction in VS sizes in patients taking metformin. However, this was not supported in other publications. In the NIHL group, mice (males, females, and females with excised ovaries) had baseline ABR, were given metformin, exposed to noise, had another ABR, then had their cochleae dissected. In the schwannoma group, mice were injected with schwannoma tumour cells, had their tumours measured in three dimensions and treated with low or high aspirin or metformin doses intraperitoneally for 21 days. Then they had their tumours studied using immunohistochemistry methods. One week after noise exposure, metformin-treated male mice displayed significantly reduced one-week ABR threshold shifts at 16 and 24 kHz compared with controls. Histology showed significantly reduced outer hair-cell loss in the 32- to 45.2-kHz frequency region but not the 16 and 24 kHz. There was no difference in hearing or cochlear tissue in female mice, including those with removed ovaries. In schwannoma mice, both the low-dose aspirin and the metformin groups showed a significant difference in growth rates on day seven when compared with saline, but this was not seen in the high-dose groups. When treatment with low-dose aspirin and metformin was stopped, there was a significant difference in the treatment and treatment removal growth rates. There was no difference in AMP kinase on immunohistochemistry between groups. The authors commented that metformin might protect against NIHL via its role in activating AMP kinase via phosphorylation, leading to down-stream inhibition of HMG-CoA reductase, which results in decreased mevalonic acid production. However, the exact cellular mechanism is still unknown. The authors of the schwannoma study also mentioned that metformin is theorised to inhibit cell growth through the activation of AMP kinase and the inhibition of oxidative phosphorylation in the mitochondria, creating reactive oxygen species, which in turn induces apoptosis in cells that use oxidative phosphorylation for ATP production. In addition, the activation of AMP kinase inhibits mTOR, which stimulates a starved / calorie-restricted state on the cell promoting autophagy or apoptosis. Metformin appears to have a promising role in both NIHL and schwannomas. The mechanism is not fully clear and further studies in humans are needed.

Metformin Protects Against Noise-Induced Hearing Loss in Male Mice.
Kennedy C, Shuster B, Amanipour R, et al.
OTOL NEUROTOL
2023;44(9):956–63.
And
Metformin Reduces Tumor Growth in a Murine Flank Schwannoma Model.
Manickavel S, Hartman Y, Burns A, et al.
OTOL NEUROTOL
2023;44(9):941–8.