Beneficial effects of intermittent hypoxic conditioning on cerebral circulation and prevention of cerebrovascular disorders

Abstract


Disorders of cerebral circulation are a leading cause of neurological morbidity, disability and death. However, there is currently no promising drug therapy or prevention for these disorders. Non-pharmaceutical therapies might provide new opportunities for protection of brain from hypoxia and ischemia induced by tissue hypoperfusion. Intermittent hypoxic conditioning (IHC) has been studied as a potential therapy. Experimental studies showed that IHC was neuroprotective in hemorrhagic stroke induced by epileptiform seizure and reduced the size of infarct, inflammation, and increased blood-brain barrier permeability after transient middle cerebral artery occlusion. In experimental Alzheimer’s disease (AD), which is considered “a cerebrovascular disorder with neurodegenerative consequences”, IHC exerted pronounced beneficial effects on cerebral circulation. In rats with experimental AD, IHC almost completely prevented endothelial dysfunction of both cerebral and extracerebral blood vessels, rarefaction of brain vascular net and the loss of neurons in the brain cortex. Due to these protective effects, IHC eventually prevented the impairment of memory and development of experimental AD. In spontaneously hypertensive rats, IHC also prevented rarefaction of arterioles and capillaries in brain, which is, interestingly, considered a possible mechanism for the antihypertensive effect of IHC. Despite promising preclinical data, the translation of preclinical hypoxic/ischemic conditioning protocols to a clinical application has been difficult, and clinical studies using this non-pharmacological approach are still scarce. In healthy human subjects, repetitive normobaric IHC significantly diminished variations of ce- rebral perfusion in response to hypercapnia and hypocapnia without compromising cerebral tissue oxygena- tion. This mechanism may be protective in sleep apnea. Paradoxically, elderly people with moderate sleep ap- nea have a survival advantage. Perhaps apneas during sleep may activate adaptive pathways in the elderly. IHC was successfully used for treatment of encephalopathy due to improvement of oxidative homeostasis. Several clinical studies have used repetitive bilateral arm ischemic preconditioning, which reduced stroke recurrence in patients with intracranial arterial stenosis. The ability of the brain to produce an endogenous response to a conditioning stimulus that leads to subsequent protection against future injury has been observed in clinical settings. Patients with previous spontaneous, transient ischemic attacks before cerebral infarction had a more favorable outcome than those without such previous attacks. Deleterious effects of hypoxia are strikingly pronounced during prenatal development and asphyxia at birth resulting in anomalous brain development, schi zophrenia, cerebral palsy, and mental retardation. On the other hand, it appears that moderate IHC in early life accelerates brain development, leading to greater learning and memory capacity. IHC-increased learning capacity is associated with increased brain DNA concentrations, increased neurogenesis, and expression of proteins involved in synaptic plasticity. IHC treatment of mothers at risk of eclampsia resulted in more su- ccessful delivery, less frequent occurrence of nephropathy, fetal hypoxia, premature labor, and better physical condition of newborns. More translational research is needed to more completely utilize beneficial effects of IHC on cerebral circulation.

Full Text

Disorders of cerebral circulation are a leading cause of neurological morbidity, disability and death. Howe- ver, there is currently no promising drug therapy or prevention for these disorders. Non-pharmaceutical the- rapies might provide new opportunities for protection of brain from hypoxia and ischemia induced by tissue hypoperfusion. Intermittent hypoxic conditioning (IHC) has been studied as a potential therapy. Experimen- tal studies showed that IHC was neuroprotective in hemorrhagic stroke induced by epileptiform seizure and reduced the size of infarct, inflammation, and increased blood-brain barrier permeability after transient mid- dle cerebral artery occlusion. In experimental Alzheimer’s disease (AD), which is considered “a cerebrovascu- lar disorder with neurodegenerative consequences”, IHC exerted pronounced beneficial effects on cerebral circulation. In rats with experimental AD, IHC almost completely prevented endothelial dysfunction of both cerebral and extracerebral blood vessels, rarefaction of brain vascular net and the loss of neurons in the brain cortex. Due to these protective effects, IHC eventually prevented the impairment of memory and develop- ment of experimental AD. In spontaneously hypertensive rats, IHC also prevented rarefaction of arterioles and capillaries in brain, which is, interestingly, considered a possible mechanism for the antihypertensive effect of IHC. Despite promising preclinical data, the translation of preclinical hypoxic/ischemic conditioning proto- cols to a clinical application has been difficult, and clinical studies using this non-pharmacological approach are still scarce. In healthy human subjects, repetitive normobaric IHC significantly diminished variations of ce- rebral perfusion in response to hypercapnia and hypocapnia without compromising cerebral tissue oxygena- tion. This mechanism may be protective in sleep apnea. Paradoxically, elderly people with moderate sleep ap- nea have a survival advantage. Perhaps apneas during sleep may activate adaptive pathways in the elderly. IHC was successfully used for treatment of encephalopathy due to improvement of oxidative homeostasis. Several clinical studies have used repetitive bilateral arm ischemic preconditioning, which reduced stroke recurrence in patients with intracranial arterial stenosis. The ability of the brain to produce an endogenous response to a conditioning stimulus that leads to subsequent protection against future injury has been observed in clinical settings. Patients with previous spontaneous, transient ischemic attacks before cerebral infarction had a more favorable outcome than those without such previous attacks. Deleterious effects of hypoxia are strikingly pro- nounced during prenatal development and asphyxia at birth resulting in anomalous brain development, schi- X I R U S S I A N C O N F E R E N C E zophrenia, cerebral palsy, and mental retardation. On the other hand, it appears that moderate IHC in early li- fe accelerates brain development, leading to greater learning and memory capacity. IHC-increased learning capacity is associated with increased brain DNA concentrations, increased neurogenesis, and expression of proteins involved in synaptic plasticity. IHC treatment of mothers at risk of eclampsia resulted in more su- ccessful delivery, less frequent occurrence of nephropathy, fetal hypoxia, premature labor, and better physical condition of newborns. More translational research is needed to more completely utilize beneficial effects of IHC on cerebral circulation.

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Copyright (c) 2015 Downey H.F., Shi X., Aleksandrin V.V., Goryacheva A.V., Manukhina E.B.

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