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Chronopharmacokinetics: Circadian Rhythms and Influence on Drug Response01:15

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Circadian rhythms are cyclic changes that are crucial in plasma drug concentrations. Various standard circadian parameters, including core body temperature, heart rate, and other cardiovascular factors, directly impact disease states and the therapeutic response to drug therapy.
The time of drug administration is an important factor to consider, as it can influence the toxic dose of a drug. For example, a study conducted by Prins et al. in 1997 examined the effects of the timing of...
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Updated: Jan 18, 2026

Remote Limb Ischemic Preconditioning: A Neuroprotective Technique in Rodents
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Timing Matters: How Daily Rhythms Affect Remote Ischemic Postconditioning Therapy for Stroke.

Ester Licastro1,2, Viviana Viscardi2, Ornella Cuomo2

  • 1Departments of Radiology and Neurology, Neuroprotection Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston (E.L., R.M.P., K.H., E.H.L., E.E.).

Stroke
|September 11, 2025
PubMed
Summary

Remote postconditioning shows neuroprotective effects in rodent stroke models, but only during their inactive phase. This circadian timing influences efficacy, potentially via neuronal NO synthase regulation of PER2. Timing is crucial for stroke research translation.

Keywords:
7-nitroindazolebraincircadian rhythmischemic postconditioningstroke

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Area of Science:

  • Neuroscience
  • Circadian Biology
  • Stroke Research

Background:

  • Remote limb ischemic postconditioning shows promise in preclinical stroke models.
  • Translational efficacy in human stroke treatment remains unclear due to mixed clinical trial outcomes.
  • Differences in circadian rhythms between nocturnal rodents and diurnal humans may hinder translation.

Purpose of the Study:

  • To investigate the impact of circadian rhythms on the efficacy of remote limb ischemic postconditioning in a rodent stroke model.
  • To explore the underlying molecular mechanisms, including the role of PER2 and nNOS.

Main Methods:

  • Male C57BL/6J mice underwent transient focal cerebral ischemia and remote postconditioning during active or inactive phases.
  • Infarct volumes and behavioral outcomes were assessed at 24 hours and 3 days.
  • Brain protein levels of PER2 and nNOS were analyzed; nNOS inhibition was used to probe mechanisms.

Main Results:

  • Remote postconditioning reduced infarcts and improved behavior during the rodent inactive phase, but not the active phase.
  • Inactive phase postconditioning decreased PER2 and increased nNOS, effects absent in the active phase.
  • nNOS inhibition abolished PER2 changes during inactive phase postconditioning.

Conclusions:

  • Circadian rhythms significantly influence the neuroprotective effects of remote postconditioning in stroke.
  • Efficacy is greater during the rodent inactive phase, mediated by nNOS-dependent PER2 regulation.
  • Considering circadian timing is essential for improving the translational success of remote postconditioning in stroke therapy.