Clinical Update: Utilizing Ischemic Preconditioning in Ischemic Stroke

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Ischemic preconditioning has been studied in preclinical trials as a way to preserve brain metabolism.
Ischemic preconditioning has been studied in preclinical trials as a way to preserve brain metabolism.

According to the Centers for Disease Control and Prevention (CDC), more than 800,000 people in the United States experience strokes each year. Of those, an estimated 140,000 people die, and many of the survivors face significant levels of disability.1

While therapeutic advances in clot-busting agents and retrieval techniques have improved stroke survival and outcomes, research has also turned to investigating neuroprotective mechanisms that may limit the neurologic damage that typically follows. One of the most promising avenues of research is the concept of hypoxic conditioning (HC), or ischemic preconditioning (IPC), in which brief periods of oxygen deprivation to the brain have been shown to provide neuroprotective effects that reduce stroke infarct size and improve recovery times.2-4

IPC has been studied in preclinical trials as a way to preserve brain metabolism.5 A 2017 mini-review of the literature by Sébastien Baillieul, MD, MSc, and colleagues at the Grenoble Institute of Neurosciences in France, explored opportunities to use IPC as a “neurotherapeutic model to induce neuroprotection, neuroplasticity, and recovery” in brain and spinal cord injuries.5-7

The Grenoble group defined hypoxic conditioning in the preclinical studies they reviewed as a modality that may consist of a single, sustained, or cyclical/intermittent (interspersed by short periods of normoxia) period of hypoxic stimulation, delivered over several minutes to several hours, and which may be repeated over several days to weeks. They found data from numerous laboratory studies indicating that limited exposure to specific doses of hypoxia can trigger these mechanisms in the central nervous system (CNS).2,5,8-10

The mechanisms of IPC are one of the ongoing challenges to research. Studies have pointed to a reprogramming of the normal transcriptional response to stroke that induces a neuroprotective response, which may then limit the impact of an actual stroke event.2,4,11,12

A 2016 review by McDonough and Weinstein12 in Neurotherapeutics suggested that the preconditioning response appears to occur at a cellular level in a manner similar to expression of hibernation responses in animals. “Different types of priming or preconditioning effects have been shown in a variety of relevant cell types including neurons, astrocytes, microglia/macrophages, oligodendrocytes, and cerebrovascular endothelial cells,” Jonathan Weinstein, MD, PhD, of the department of neurology at the University of Washington in Seattle, told Neurology Advisor. “Basic/translational studies focused on the transcriptomic response to IPC suggest a particularly important role for innate immune signaling and innate immune cells, including microglia and macrophages, in IPC-mediated protection.”  He explained that strong temporal and spatial components to IPC-mediated protective effects have been observed and the literature suggests a trend toward polyphasic response involving multiple cell types in sequence.

Clinical Applications

According to Dr Weinstein, select populations of patients who are at high risk for cerebral ischemic events in the immediate (hours to days) future make the best initial targets for IPC. “This would include patients who are about to undergo major cardiac or carotid artery surgery as well as possibly subarachnoid hemorrhage patients who are at high risk of developing cerebral vasospasm and accompanying delayed cerebral ischemia,” he said, adding that, “It may be possible to improve outcomes in these patients by treating (or pre-treating) them with specific pharmacologic agents that activate molecular signaling pathways thought to be important in preconditioning-mediated protection, such as Toll-like receptor or Type 1 interferon pathways.”

Overcoming Challenges

Design of clinical trials of IPC are especially hampered by the limitations of identifying optimal candidates, particularly in the absence of a strong understanding of the complete underlying mechanisms driving potential neuroprotective benefits. “We know that IPC-mediated pathways require time to activate and are critical for the much longer recovery and regeneration phases following a cerebral ischemic event,” Dr Weinstein pointed out. “In order to fully understand the potential of IPC-based pharmacotherapeutics, we will also need to improve the sensitivity of our clinical scoring scales in a way that better takes into account changes in neurocognitive and neuropsychiatric function following stroke,” he said.

Other factors, such as the duration of priming effects are also unknown. The Grenoble group noted that this needs to be better clarified through further research, and they identified unresolved questions, addressing issues such as the optimal timing of IPC before or after injury onset, and the most appropriate regimen (dose, sustained vs intermittent hypoxia, and number of sessions) which they saw as “limiting applicability and translation from bench to bedside.”5

Dr Weinstein is confident that researchers will overcome the obstacles to investigating IPC in clinical trials, and “will continue to identify and characterize novel and specific cellular and molecular pathways as well as their downstream effector molecules that can be targeted for therapeutic intervention.”

“IPC has proven to be an effective basic/translational experimental strategy for elucidating powerful endogenous neuroprotective mechanisms,” he said. He feels that the implications of IPC research apply to a much wider range of patients with stroke than the specific high-risk groups already identified, and that although IPC is still in very early development, “our ability to therapeutically target specific molecular pathways and cellular sub-types is steadily improving,” he observed. “This should allow us to fully take advantage of the knowledge we are gaining through basic/translational research on preconditioning.” 

References 

  1. Vital signs: preventing stroke deaths. Centers for Disease Control and Prevention (CDC) website. www.cdc.gov/vitalsigns/stroke/index.html. Accessed September 6, 2017.
  2. Dirnagl U, Becker K, Meisel A. Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurol. 2009:8:398-412.
  3. Marsh B, Stevens SL, Packard AE, et al. Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke: a critical role for IRF3. J Neurosci. 2009;29:9839-9849.
  4. Stenzel-Poore MP, Stevens SL, King JS, Simon RP. Preconditioning reprograms the response to ischemic injury and primes the emergence of unique endogenous neuroprotective phenotypes: a speculative synthesis. Stroke. 2007;38:680-685.
  5. Baillieul S, Chacaroun S, Doutreleau S, Detante O, Pépin JL, Verges S. Hypoxic conditioning and the central nervous system: A new therapeutic opportunity for brain and spinal cord injuries? Exp Biol Med. 2017;242:1198-1206.
  6. Dahl NA, Balfour WM. Prolonged anoxic survival due to anoxia pre-exposure: brain atp, lactate, and pyruvate. Am J Physiol. 1964;207:452-456.
  7. Schurr A, Reid KH, Tseng MT, West C, Rigor BM. Adaptation of adult brain tissue to anoxia and hypoxia in vitro. Brain Res. 1986;374:244-248.
  8. Verges S, Chacaroun S, Godin-Ribuot D, Baillieul S. Hypoxic conditioning as a new therapeutic modality. Front Pediatr. 2015;3:58.
  9. Rybnikova E, Samoilov M. Current insights into the molecular mechanisms of hypoxic pre- and postconditioning using hypobaric hypoxia. Front Neurosci. 2015;9:388.
  10. Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 2003;26:248-254.
  11. Stenzel-Poore, MP, Stevens SL, Simon RP. Genomics of preconditioning. Stroke. 2004;35:2683-2686.
  12. McDonough A, Weinstein JR. Neuroimmune response in ischemic preconditioning. Neurotherapeutics. 2016;13:748-761.

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