The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 11 No. 5 • September 2008

Tinnitus May Be Caused by Peroxynitrite No, Oh No!

A very recent paper1 proposes that tinnitus, as well as diseases such as chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, and posttraumatic stress disorder, may be caused by a “vicious-cycle mechanism known as the NO/ONOO (‘no, oh no!’) cycle mechanism.”1 ONOO (peroxynitrite) is the “oh no!” part of the cycle and is created by the chemical reaction between superoxide radicals and nitric oxide (NO). The authors note that “Tinnitus is also comorbid [i.e., occurs at the same time] with these illnesses, and these are comorbid with one another, suggesting a possible common etiology.”

The authors analyze these medical conditions according to their effects on the NO/ONOO cycle. They note that initiating stressors stimulate the excessive synthesis of nitric oxide or superoxide. Elements of the cycle should be elevated in the chronic phase of the illness, including nitric oxide, peroxynitrite, oxidative stress, intracellular calcium, NF-kappaB [an inflammatory cytokine] activity, other inflammatory cytokines, elevated nitric oxide synthase activity, increased superoxide levels, and activity of two receptor systems, the vanilloid receptor (which responds to capsaicin, among other molecules) and the NMDA receptor, which is excitatory. The authors propose that these illnesses are explained as being consequences of elevation of one or more of these elements and that they may best be treated by using “agents that down-regulate NO/ONOO biochemistry.”

The authors also analyze a number of stressors that initiate tinnitus and relate them to nitric oxide and other cycle elements. The stressors include acoustic overstimulation, bacterial LPS (lipopolysaccharide), carbon monoxide, ischemia, salicylate (salicylic acid or aspirin can cause ringing in the ears when taken in excess), physical trauma, infections (especially in the ear), and others. They note that physical trauma can induce NMDA, salicylate increases NMDA, ischemia increases superoxide and increases glutamate neurotoxicity (via NMDA and non-NMDA activity), bacterial LPS induces iNOS (the induced form of nitric oxide often increased in inflammatory conditions), and so on.

They cite an earlier study in which Takumida et al.2 “provided experimental support for a similar group of [NO/ONOO] agents that lower excitotoxicity (e.g., NMDA activity, nitric oxide synthase activity, superoxide levels, and peroxynitrite levels) and antioxidants to lower oxidative stress.”


  1. Pall and Bedient. The NO/ONOO cycle as the etiological mechanism of tinnitus. Int Tinnitus J 13(2):99-104 (2007).
  2. Takumida et al. Pharmacological models for inner ear therapy with emphasis on nitric oxide. Acta Otolaryngol 121:16-20 (2001).

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