Auckland hearing science discovery and translation in purinergic signaling and inner ear therapeutics

Abstract

The inner ear is a complex sensory organ responsible for hearing and balance. It is deeply embedded in the temporal bone with challenging access for diagnostic and therapeutic purposes. Stress and injury to the peripheral hearing organ (cochlea) lead to temporary or permanent sensorineural hearing loss (SNHL), which is the most common form of hearing loss resulting from cellular and molecular damage to the sensory hair cells and primary auditory neurons in the spiral ganglion. These cells cannot regenerate, and their loss leads to hearing disability. Hearing aids can amplify sound and improve residual hearing ability but cannot restore function; therefore, alternative therapies are urgently needed. The pharmacological approach to treating SNHL has been our mainstream research over the past two decades. This review describes our studies investigating the purinergic signalling system in the cochlea and its implications for inner ear therapies. Using animal models of SNHL, we have established that purinergic P1 (adenosine) and P2 (ATP) receptors can prevent or mitigate cochlear injury by reducing cochlear sensitivity to loud sound and improving the survival of sensorineural tissues. Here, we highlight our research investigating the therapeutic potential of P1 and P2 receptor agonists and antagonists in inner ear disorders.

Keywords: ATP; P2X receptors; P2Y receptors; adenosine; adenosine receptors; cochlea; ectonucleotidases; hearing loss; therapeutic.

Figure 1.

The cochlea is the peripheral organ of hearing. The cochlea comprises three fluid-filled compartments: scala vestibuli and scala tympani containing Na⁺-rich perilymph, and scala media containing K⁺-rich endolymph. The lateral wall of the cochlea comprises the spiral ligament (SL), which is made up of fibrocytes, and the secretory tissues of the stria vascularis (SV). The organ of Corti is the sensory organ of the cochlea sitting on the basilar membrane. It contains two types of sensory cells, inner hair cells (IHC) and outer hair cells (OHC), covered by the tectorial membrane (TM). Sensory cells are surrounded by supporting cells, such as Deiters’ cells (DC), Hensen’s cells (HC) and pillar cells (PC). Created with BioRender.com.

Figure 2.

Purinergic signalling system. Extracellular ATP activates ATP-gated ion channels (P2X receptors) permeable to mono- and divalent cations and G protein-coupled receptors (P2Y receptors) activated by various nucleotides (ATP, UTP, ADP, UDP). ATP is hydrolysed to adenosine by surface-located ectonucleotidases (NTPDases and ecto-5′-nucleotidase). Adenosine activates four types of G protein-coupled adenosine receptors (A₁, A_2A, A_2B, A₃). Created with BioRender.com.

Figure 3.

Adenosine receptors as inner ear therapeutics. The most common forms of sensorineural hearing loss (SNHL) are age-related, drug-induced, and noise-induced hearing loss. The rescue effect of adenosine receptors has been demonstrated in preclinical studies using animal models of SNHL. These studies showed that the balance of A₁ and A_2A receptors is critical for cochlear response to stress and injury. Pharmacological interventions include the intratympanic or systemic administration of A₁ receptor agonists, A_2A receptor antagonists, adenosine kinase (Adk) inhibitors, or RGS4 (Regulator of G protein signalling 4) inhibitors. Local intratympanic injections are the preferred delivery route as they preclude off-target effects associated with systemic administration.