Ischemic Preconditioning: Exploring the Potential to Reduce the Impact of Stroke

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While current therapies have helped reduce stroke mortality, researchers are hoping to identify a way to reduce neurologic damage and disability.
While current therapies have helped reduce stroke mortality, researchers are hoping to identify a way to reduce neurologic damage and disability.

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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