[Highlands as a natural neuroprotection laboratory: hypoxia and neurodegenerative processes]

High altitude hypobaric hypoxia presents a unique stressor to the central nervous system, exerting a profound yet contradictory effect on the dopaminergic system. On one hand, uncontrolled hypoxia triggers pathological cascades characterized by a significant neurotoxic release of dopamine, increased oxidative stress, and the initiation of neurodegenerative processes akin to those observed in Parkinson's and Alzheimer's diseases. On the other hand, controlled moderate hypoxia, referred to as hypoxic preconditioning, along with the genetic adaptations found in highland natives, stimulates powerful endogenous neuroprotective mechanisms. This review consolidates data on molecular (e.g., HIF-1α, Wnt, and brain-derived neurotrophic factor) and biochemical (e.g., tyrosine hydroxylase and monoamine oxidase) responses to hypoxia, aiming to resolve this paradox. Special emphasis is placed on evolutionary selection driven by genes associated with the HIF pathway (e.g., EPAS1 and EGLN1), which may «tune» physiological responses to transform chronic hypoxic stress into a state of consistent neuroprotection. Understanding the transition from pathological risk to adaptive resistance opens new avenues for the development of hypoxic therapy in treating dopaminergic neurodegenerative diseases. The highlands, typically defined as altitudes exceeding 2.500 meters above sea level, serve as a natural laboratory for investigating the effects of chronic hypobaric hypoxia and the mechanisms of human adaptation.