Ozone in Neurodegeneration: An Environmental Toxicant or a Therapeutic Hormetin?

Ozone (also known as triatomic oxygen [O₃]) is an allotropic form of oxygen commonly found in the atmosphere. Growing epidemiological and experimental evidence indicates that chronic exposure to environmental ozone (as a pollutant) may worsen systemic disorders, including neurodegenerative processes. Prolonged exposure to atmospheric uncontrolled ozone increases pulmonary production of reactive oxygen and nitrogen species, triggering oxidative damage and a sustained inflammatory state locally and systemically, and leading to multiple alterations, including blood–brain barrier breakdown and microglial dysfunction, mechanisms strongly implicated in neurodegenerative processes. Interestingly, ozone therapy (controlled and non-inhaled) has been used in medicine for its multiple health benefits, including antimicrobial, anti-inflammatory, and antioxidant effects. Thus, it is plausible to consider ozone as a hormetin with potential neuroprotective effects. Additionally, experimental evidence showing its effects in nerve regeneration, including improved structural and functional recovery following facial or sciatic nerve injury, further strengthens the potential of ozone therapy. However, further studies are required to define optimal dosing strategies and administration protocols. Given these findings, the scope of this review is to critically examine and integrate all available evidence on ozone’s dual role in neurological and neurodegenerative conditions. By combining mechanistic insights, preclinical and clinical data, this review aims to clarify the complex, bidirectional relationship among ozone exposure, redox biology, neuroinflammation, and neurodegeneration. • Ozone shows a dual role: toxicant vs potential hormetin • Chronic uncontrolled ozone exposure promotes oxidative stress and neuroinflammation • Low-dose ozone may activate adaptive antioxidant pathways (Nrf2) • Preclinical data suggest neuroprotective and regenerative effects • Clinical evidence remains limited and requires standardization