Treatment duration affects cytoprotective efficacy of positive allosteric modulation of α7 nAChRs after focal ischemia in rats

Nikhil Gaidhani, Victor V. Uteshev-Gaard

Research output: Contribution to journalArticleResearchpeer-review

Abstract

To minimize irreversible brain injury after acute ischemic stroke (AIS), the time to treatment (i.e., treatment delay) should be minimized. However, thus far, all cytoprotective clinical trials have failed. Analysis of literature identified short treatment durations (≤72 h) as a common motif among completed cytoprotective clinical trials. Here, we argue that short cytoprotective regimens even if given early after AIS may only slow down the evolution of ischemic brain injury and fail to deliver sustained long-term solutions leading to relapses that may be misinterpreted for conceptual failure of cytoprotection. In this randomized blinded study, we used young adult male rats subjected to transient 90 min suture middle cerebral artery occlusion (MCAO) and treated with acute vs. sub-chronic regimens of PNU120596, a prototypical positive allosteric modulator of α7 nicotinic acetylcholine receptors with anti-inflammatory cytoprotective properties to test the hypothesis that insufficient treatment durations may reduce therapeutic benefits of otherwise efficacious cytoprotectants after AIS. A single acute treatment 90 min after MCAO significantly reduced brain injury and neurological deficits 24 h later, but these effects vanished 72 h after MCAO. These relapses were avoided by utilizing sub-chronic treatments. Thus, extending treatment duration augments therapeutic efficacy of PNU120596 after MCAO. Furthermore, sub-chronic treatments could offset the negative effects of prolonged treatment delays in cases where the acute treatment window after MCAO was left unexploited. We conclude that a combination of short treatment delays and prolonged treatment durations may be required to maximize therapeutic effects of PNU120596, reduce relapses and ensure sustained therapeutic efficacy after AIS. Similar concepts may hold for other cytoprotectants including those that failed in clinical trials.

Original languageEnglish
Pages (from-to)121-132
Number of pages12
JournalPharmacological Research
Volume136
DOIs
StatePublished - 1 Oct 2018

Fingerprint

Ischemia
Middle Cerebral Artery Infarction
Therapeutics
Stroke
Brain Injuries
Clinical Trials
Recurrence
Cytoprotection
Nicotinic Receptors
Therapeutic Uses
Sutures
Young Adult
Anti-Inflammatory Agents

Keywords

  • Acetylcholine
  • Cholinergic anti-inflammatory pathway
  • Ischemic stroke
  • MCAO
  • PNU-120596
  • PNU120596

Cite this

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title = "Treatment duration affects cytoprotective efficacy of positive allosteric modulation of α7 nAChRs after focal ischemia in rats",
abstract = "To minimize irreversible brain injury after acute ischemic stroke (AIS), the time to treatment (i.e., treatment delay) should be minimized. However, thus far, all cytoprotective clinical trials have failed. Analysis of literature identified short treatment durations (≤72 h) as a common motif among completed cytoprotective clinical trials. Here, we argue that short cytoprotective regimens even if given early after AIS may only slow down the evolution of ischemic brain injury and fail to deliver sustained long-term solutions leading to relapses that may be misinterpreted for conceptual failure of cytoprotection. In this randomized blinded study, we used young adult male rats subjected to transient 90 min suture middle cerebral artery occlusion (MCAO) and treated with acute vs. sub-chronic regimens of PNU120596, a prototypical positive allosteric modulator of α7 nicotinic acetylcholine receptors with anti-inflammatory cytoprotective properties to test the hypothesis that insufficient treatment durations may reduce therapeutic benefits of otherwise efficacious cytoprotectants after AIS. A single acute treatment 90 min after MCAO significantly reduced brain injury and neurological deficits 24 h later, but these effects vanished 72 h after MCAO. These relapses were avoided by utilizing sub-chronic treatments. Thus, extending treatment duration augments therapeutic efficacy of PNU120596 after MCAO. Furthermore, sub-chronic treatments could offset the negative effects of prolonged treatment delays in cases where the acute treatment window after MCAO was left unexploited. We conclude that a combination of short treatment delays and prolonged treatment durations may be required to maximize therapeutic effects of PNU120596, reduce relapses and ensure sustained therapeutic efficacy after AIS. Similar concepts may hold for other cytoprotectants including those that failed in clinical trials.",
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Treatment duration affects cytoprotective efficacy of positive allosteric modulation of α7 nAChRs after focal ischemia in rats. / Gaidhani, Nikhil; Uteshev-Gaard, Victor V.

In: Pharmacological Research, Vol. 136, 01.10.2018, p. 121-132.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Uteshev-Gaard, Victor V.

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