Targeting kinases: a promising therapeutic avenue for sensorineural hearing loss
Sensorineural hearing loss is most commonly characterized by damaged outer hair cells, inner hair cells, synapses, and fibers inside the inner ear. Different kinases have been identified in literature as promising targets for sensorineural hearing loss, and several kinase inhibitors have already demonstrated protective effects on hearing against noise trauma and ototoxic drugs.
As seen above, kinase treatment can be locally delivered to reduce systemic side effects, thus making it an advantageous and promising therapeutic approach for sensorineural hearing loss.
INK4 is a family of cyclin-dependent kinase inhibitors, which include CDK2, CDK4, and CDK6. The INK4 is involved in the aging process.
- The deletion of Ink4d in mice results in apoptosis and progressive hearing loss (Chen et al., 2003)
- p19ink4d, which is a cyclin-dependant kinase inhibitor that belongs to the INK4 family, not only regulates the cell cycle but also plays regulatory roles in apoptosis, DNA damage repair, cell differentiation of hematopoietic cells, and cellular senescence. p19INK4d could be promising as a drug target. (Han et al., 2020)
Bruton’s tyrosine kinase, or BTK, is a tyrosine kinase encoded by the BTK gene.
- BTK promotes radiation-induced apoptosis but inhibits Fas-activated apoptosis in B-cells (Uckun, 1998)
- Fas gene expression and hearing thresholds increased in a noise-exposed rat model, and two polymorphisms were associated with noise-induced hearing loss (NIHL) (Zhu, Zhang et al., 2021).
- Polymorphisms of the FAS gene lead to a higher susceptibility to NIHL
Mitogen-activated protein kinases (MAPKs) are a type of protein kinase specific to the amino acids serine and threonine, and c-Jun N-terminal kinases (JNKs) belong to the mitogen-activated protein kinase family.
- Hearing loss can be caused by acoustic trauma and exposure to ototoxins, which affect the viability of hair cells via the MAPK cell death signaling pathway that incorporates JNK. Blocking the MAPK-JNK pathway can prevent hair cell death in ototoxicity and acoustic trauma. D-JNKI-1, a cell permeable peptide, was used to block the MAPK–JNK signal pathway. (Zine et al., 2003)
- Blocking the JNK signaling pathway could be a therapeutic approach for preventing the development of a permanent hearing loss that can be initiated by either neomycin ototoxicity or electrode insertion trauma. Blocking the JNK signaling pathway prevents the increases in hearing thresholds and the loss of auditory hair cells. (Van de Water et al., 2007)
- Targeting the JNK signalling pathway provides a promising therapeutic approach to protect from noise-induced hearing loss (NIHL) and to preserve hearing during cochlear implantation surgery (Eshraghi et al., 2010)
- A peptide inhibitor of JNK kinase-mediated mitochondrial cell death pathway, D-JNKI-1 peptide, has shown promises in protecting the cochlea against noise-induced and aminoglycoside induced HC loss when delivered directly into the scala tympani or locally to the round window membrane (Wong & Ryan, 2015) (Wang et al., 2003b, 2007; Eshraghi et al., 2007)
- BRAF kinase inhibitors could be promising for otoprotection from cisplatin- and noise-induced ototoxicity. (Teitz et al., 2020)
- BRAF kinase inhibitors in the BRAF/MEK/ERK cellular pathway mitigated cisplatin-induced hair cell death in the cell line and mouse cochlear explants. In adult mice, oral delivery of dabrafenib repressed ERK phosphorylation in cochlear cells, and protected from cisplatin- and noise-induced hearing loss. Full protection was achieved in mice with co-treatment with a CDK2 kinase inhibitor. (Teitz et al., 2020)
- Extracellular signal-regulated kinases (ERKs) are members of the MAPK family
The JAK-STAT signaling pathway involves janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors.
- The JAK-STAT pathway is linked to sensorineural hearing loss (SNHL) (Fransen et al., 2015), noise-induced hearing loss (NIHL) (Wilson et al., 2014), age-related hearing loss (ARHL) (Fransen et al., 2015), cisplatin ototoxicity (Chen et al., 2015) and tinnitus.
- JAK2/STAT3 inhibition reduced levels of ROS detected in outer hair cells at two hours post noise exposure. JAK is a key factor for NIHL: a JAK inhibitor could prevent it. (Wilson et al., 2014)
- Therapeutic targets of the JAK/STAT signaling pathway include recombinant cytokines, cytokine antibodies, receptor antibodies designed to target cytokines or receptors, JAK inhibitors designed to target JAKs, peptide inhibitors, small-molecule inhibitors, decoy oligonucleotides (ODNs), antisense oligonucleotides (ASOs), siRNAs target STATs. (Wang et al., 2021)
AMPK & LKB1
5′ adenosine monophosphate-activated protein kinase (AMPK) is an enzyme that plays a role in cellular energy homeostasis. BK channels are large conductance calcium-activated potassium channels.
- The regulation of BK channels contributes to, but does not necessarily fully account for, the protective role of AMPK against noise-induced hearing loss. (Lang et al., 2012)
- Down-regulation of AMPK signaling pathway rescues hearing loss in TFB1 transgenic mice and delays age-related hearing loss. AMPK hyperactivation causes accelerated presbycusisby redox imbalance and dysregulation of the apoptosis pathway. The effects of AMPK downregulation on pro-survival function and reduction of oxidative stress indicate AMPK serves as a target to rescue or relieve mitochondrial hearing loss. (Song et al., 2020)
- Inhibition of AMPK via siRNA attenuated noise-induced loss of outer hair cells (OHCs) and synaptic ribbons, and preserved auditory function. (Sha et al., 2016)
- Regulating the AMPK/FOXO3a signaling pathway may protect from cisplatin-induced hearing loss. (Yang et al., 2021)
LKB1, or liver kinase B1, is a protein kinase encoded by the STK11 gene. AMPKα-1 and AMPKα-2 are substrates of LKB1.
- LKB1 activates the TGF- β1 pathway to allow the proliferation of vascular smooth muscle cells (Makela et al., 2008)
- Noise exposure induces hair cell death and synaptopathy by activating AMPK via LKB1-mediated pathways. Targeting these pathways may provide a novel route to prevent NIHL (Sha et al., 2016).
- The activation of AMPK-α in sensory hair cells is noise intensity dependent and contributes to noise-induced hearing loss by mediating the loss of inner hair cell synaptic ribbons and outer hair cells. Noise induces the phosphorylation of AMPKα1 by LKB1, and the inhibition of AMPK activation by silencing AMPK or LKB1 reduced outer hair cell and synaptic ribbon loss as well as noise-induced hearing loss. (Sha et al., 2016)
- The inhibition of LKB1 by siRNA attenuated the noise-increased phosphorylation of AMPKα in OHCs, reduced the loss of inner hair cell synaptic ribbons and OHCs, and protected against NIHL. (Sha et al., 2016)
TKI & Src
TKI is an acronym for tyrosine kinase inhibitors, and Src is a family of non-receptor tyrosine kinases
- Src-PTK activation plays a role in noise-induced hearing loss (NIHL): Src-PTK inhibitors may offer a novel approach in the treatment of NIHL. Src-protein tyrosine kinase inhibitors could protect against noise trauma (Harris et al., 2005)
- Src inhibitor may provide an effective cotreatment with cisplatin to reduce cisplatin’s ototoxicity, without compromising its antitumor capability (Bielefeld et al., 2012)
- Src inhibitors have successfully prevented noise-induced cochlear damage and hearing loss in animal models (Bielefeld, 2015)
- Activation of Rictor/mTORC2 signaling pathway acts as a pivotal strategy to protect against sensorineural hearing loss (Fu et al., 2022)
A selective adenosine kinase (ADK) inhibitor provided partial protection from ARHL by enhancing adenosine signaling in the cochlea (Vlajkovic et al., 2011).
The tyrosine-protein kinase transmembrane receptor ROR1 is an enzyme encoded by the ROR1 gene.
- ROR1 is an essential gene for the development of the inner ear and hearing in humans and mice. Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions, malformed cochleae, and impaired synapses (Tekin et al., 2016)
- Up-regulating ROR1 decreased cochlear hair cell loss of guinea pigs with NIHL via the Wnt5a-dependent NF-κB signaling pathway (Zhang et al., 2020)
Glycogen synthase kinase-3 (GSK-3) is a proline-directed serine-threonine kinase, and GSK-3β is an isoform of GSK-3.
- Selective GSK-3beta inhibitors prevented cochlear destruction and the production of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and IL-6 in cisplatin-injected mice (Park et al., 2009)
- Enhancing autophagy by down-regulating GSK-3β alleviates cisplatin-induced ototoxicity (Xiao et al., 2019)
Protein kinase C (PKC) is a family of protein kinase enzymes, and PKCγ is an isozyme that requires DAG, Ca2+, and phospholipid for activation.
- An increase in PKCγ expression in the cochlear nucleus is linked to age-related hearing loss in mice. (Kou et al., 2011)