Chronotherapy to reinforce circadian rhythms improves poststroke outcomes and glymphatic function in mice
Emma Waight, Yuxi Zhu, Ashley Caudell, Velia S. Vizcarra, Evan Newbold, Michael J. Giannetto, Evalien Duyvestyn, Estephanie Balbuena, Wei Song, Tanzil M. Arefin, Yuki Mori, Maiken Nedergaard, Lauren M. Hablitz
Emma Waight, Yuxi Zhu, Ashley Caudell, Velia S. Vizcarra, Evan Newbold, Michael J. Giannetto, Evalien Duyvestyn, Estephanie Balbuena, Wei Song, Tanzil M. Arefin, Yuki Mori, Maiken Nedergaard, Lauren M. Hablitz
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Research Article Cell biology Neuroscience

Chronotherapy to reinforce circadian rhythms improves poststroke outcomes and glymphatic function in mice

Abstract

Stroke remains a leading cause of morbidity and mortality worldwide, with few effective interventions to promote recovery. Targeting circadian timing and glymphatic function may represent viable therapeutic strategies. Here, we show that the small-molecule clock modulator, KL001; high-dose melatonin; acute light pulses; and active-phase time-restricted feeding were each sufficient to enhance glymphatic function in mice. Moreover, initiating treatment with either KL001 or active-phase time-restricted feeding 3 days after preclinical models of stroke improved motor outcomes, reduced lesion volume, increased glymphatic flow, and lowered poststroke brain cytokine burden. These findings suggest that reinforcing normal daily rhythmicity after stroke can markedly enhance neurological recovery, even when interventions are initiated several days after stroke onset.

Authors

Emma Waight, Yuxi Zhu, Ashley Caudell, Velia S. Vizcarra, Evan Newbold, Michael J. Giannetto, Evalien Duyvestyn, Estephanie Balbuena, Wei Song, Tanzil M. Arefin, Yuki Mori, Maiken Nedergaard, Lauren M. Hablitz

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Figure 4

Chronotherapy improves stroke outcome in longitudinal MRI.

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Chronotherapy improves stroke outcome in longitudinal MRI. (A) Experimen...
(A) Experimental design. (B) Representative coronal images of T2-weighted MRI before and after chronotherapy with KL001 (green), control (Ctrl, gray), or active-phase restricted feeding (TRF, blue) that began on day 3 after stroke. The image of the first section anterior to where corpus callosum was continuous was selected. (C) (left) Paired scatterplot of stroke volume for mice day 3 before chronotherapy and day 11 after chronotherapy with KL001. (right) Box plot of total volume reduction in lesion size before minus after chronotherapy. (D) Same as in C, but with active-phase restricted feeding (blue). (E) (left) Box plot of stroke volume on day 3, before chronotherapy. (right) Box plot of total brain volume change (day 11 minus day 3) for control- (gray), KL001- (green), and TRF-treated (blue) groups. For all box plots, vehicle (gray), KL001 (green), active feeding (light blue) mice. Median and quartiles are shown by box-and-whisker plots, with individual mice shown as colored dots. *P < 0.05. C, left, and D, left: 2-way ANOVA tests with repeated measures. C, right: Mann-Whitney test. D, right: unpaired 2-tailed t test. E, left: 1-way ANOVA test. E, right: Welch’s ANOVA. All statistics are shown in Supplemental Table 1.