Faculty Opinions recommendation of Biofilm maturity studies indicate sharp debridement opens a time- dependent therapeutic window.

Baicalein is a natural flavonoid with anti-oxidant activities protecting against ischemia/reperfusion (I/R) injury. Previous studies suggest that oxidative burst early after reperfusion accelerates cell death. We therefore investigated the critical therapeutic window of baicalein by examining the timing of baicalein treatment in relation to its oxidant modulating and cytoprotective effects. Using an established chick cardiomyocyte model of I/R, we administered baicalein at various time points after reperfusion and assessed cell viability and the profiles of reactive oxygen species (ROS), nitric oxide (NO), and Akt phosphorylation. Baicalein administered at the onset of reperfusion resulted in a concentration-dependent reduction of cell death (25 [Formula: see text]M [Formula: see text]%, 50[Formula: see text][Formula: see text]M [Formula: see text]%, 100[Formula: see text][Formula: see text]M [Formula: see text]%, vs. I/R control [Formula: see text]%, all [Formula: see text]). Baicalein (100[Formula: see text][Formula: see text]M) timely and effectively scavenged ROS burst and enhanced NO production in the early reperfusion phase. Cotreatment with NO synthase (NOS) inhibitor l-NAME (200[Formula: see text][Formula: see text]M) partially abrogated the cytoprotective effect. Baicalein (100[Formula: see text][Formula: see text]M) given after reperfusion lost protective effect in a time-dependent manner with cytoprotection completely lost if [Formula: see text][Formula: see text]min. Even with only 15-min delay after reperfusion, the ROS scavenging effect was abolished and the NO enhancing effect markedly reduced. The phosphorylation of Akt, an upstream regulator of eNOS, also diminished as the delay lengthened. In conclusion, baicalein treatment after reperfusion confers cardioprotection in a concentration- and time-dependent manner. The critical therapeutic window lies in the early reperfusion phase, during which ROS scavenging and Akt-eNOS mediated NO signaling are most effective.

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Mesenchymal Stem Cell–Derived Exosomes Improve Functional Recovery in Rats After Traumatic Brain Injury: A Dose-Response and Therapeutic Window Study

Neurorehabilitation and Neural Repair ◽

10.1177/1545968320926164 ◽

2020 ◽

Vol 34 (7) ◽

pp. 616-626 ◽

Cited By ~ 1

Author(s):

Yanlu Zhang ◽

Yi Zhang ◽

Michael Chopp ◽

Zheng Gang Zhang ◽

Asim Mahmood ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Stem Cell ◽

Brain Injury ◽

Mesenchymal Stem Cell ◽

Intravenous Injection ◽

Dose Response ◽

Time Dependent ◽

Male Rats ◽

Therapeutic Window ◽

Single Intravenous Injection

Background. Mesenchymal stem cell (MSC)-derived exosomes play a critical role in regenerative medicine. Objective. To determine the dose- and time-dependent efficacy of exosomes for treatment of traumatic brain injury (TBI). Methods. Male rats were subjected to a unilateral moderate cortical contusion. In the dose-response study, animals received a single intravenous injection of exosomes (50, 100, 200 µg per rat) or vehicle, with treatment initiated at 1 day after injury. In the therapeutic window study, animals received a single intravenous injection of 100 µg exosomes or vehicle starting at 1, 4, or 7 days after injury. Neurological functional tests were performed weekly after TBI for 5 weeks. Spatial learning was measured on days 31 to 35 after TBI using the Morris water maze test. Results. Compared with the vehicle, regardless of the dose and delay in treatment, exosome treatment significantly improved sensorimotor and cognitive function, reduced hippocampal neuronal cell loss, promoted angiogenesis and neurogenesis, and reduced neuroinflammation. Exosome treatment at 100 µg per rat exhibited a significant therapeutic effect compared with the 50- or 200-µg exosome groups. The time-dependent exosome treatment data demonstrated that exosome treatment starting at 1 day post-TBI provided a significantly greater improvement in functional and histological outcomes than exosome treatments at the other 2 delayed treatments. Conclusions. These results indicate that exosomes have a wide range of effective doses for treatment of TBI with a therapeutic window of at least 7 days postinjury. Exosomes may provide a novel therapeutic intervention in TBI.

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