Inhibition of Notch 1 signaling in the subacute stage after stroke promotes striatal astrocyte-derived neurogenesis

Well shit this was already confirmed in August 2018. Why didn't you do the followup research that would deliver these results in human testing? Your mentors and senior researchers incompetently didn't know about this earlier research and thus didn't instruct you to actually solve the problem for survivors? How many times do I have to point out stroke incompetence before the offending parties are removed?

Inhibition of Notch1 Signaling at the Subacute Stage of Stroke Promotes Endogenous Neurogenesis and Motor Recovery After Stroke August 2018

The latest here:

Inhibition of Notch 1 signaling in the subacute stage after stroke promotes striatal astrocyte-derived neurogenesis

Xiao-Zhu Hao1, Cheng-Feng Sun1, Lu-Yi Lin1, Chan-Chan Li1, Xian-Jing Zhao1, Min Jiang2, Yan-Mei Yang1, *, Zhen-Wei Yao1, *

AbstractInhibition of Notch1 signaling has been shown to promote astrocyte-derived neurogenesis after stroke. To investigate the regulatory role of Notch1 signaling in this process, in this study, we used a rat model of stroke based on middle cerebral artery occlusion and assessed the behavior of reactive astrocytes post-stroke.We used the γ-secretase inhibitor N-[N-(3,5-diuorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester (DAPT) to block Notch1 signaling at 1, 4, and 7 days after injury. Our results showed that only administration of DAPT at 4 days after stroke promoted astrocyte-derived neurogenesis, as manifested by recovery of white matter fiber bundle integrity on magnetic resonance imaging, which is consistent with recovery of neurologic function. These findings suggest that inhibition ofNotch1 signaling at the subacute stage post-stroke mediates neural repair by promoting astrocyte-derived neurogenesis.Key Words: astrocyte; diffusion kurtosis imaging; magnetic resonance imaging; middle cerebral artery occlusion; N-[N-(3,5-diuorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester; neural repair; neurogenesis; neuron; Notch1 signaling; subacute stagehttps://doi.org/10.4103/1673-5374.363179Date of submission: October 18, 2021Date of decision: February 16, 2022Date of acceptance: October 11, 2022Date of web publication: December 21, 2022IntroductionImpaired neural tissue can be supplemented by endogenous neurogenesisafter stroke. One third of endogenous neurogenesis derives from proliferatedsubventricular neural stem cells, and two thirds from striatal reactiveastrocytes, both of which are negatively regulated by Notch1 signaling(Arvidsson et al., 2002; Li et al., 2010). Notch1 signaling exerts various effectsat different times and locations during neurogenesis, which explains theconflicting results from studies involving interventions at different time points;therefore, timely control of Notch1 signaling is important for promoting theproduction of new neurons (Oya et al., 2009; Wang et al., 2009b; Li et al.,2012; Zhao et al., 2012). In our previous study, we found that the number ofneuroblasts increased in the subacute stage after stroke, and that inhibition ofNotch1 signaling during this period with the γ-secretase inhibitor N-[N-(3,5-diuorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester (DAPT) promotedneuroblast and neuron generation (Hao et al., 2018). However, the temporalprofile of Notch1 signaling activity in astrocytes and whether DAPT treatmentin the subacute stage after stroke can promote transdifferentiation ofastrocytes into the neural linage remained unclear.The Notch1 signaling system comprises the Notch1 receptor and the Notch1ligand (Oya et al., 2009; Wang et al., 2009a, b), which receive and send theNotch1 signal, respectively. Astrocytes can concurrently express both theNotch1 receptor and the Notch1 ligand (Lebkuechner et al., 2015). Notch1signaling has been reported to stimulate proliferation and migration ofresident astrocytes in the subventricular zone (SVZ) and striatum into theperi-infarct area after stroke (Shimada et al., 2011). A recent study indicatedthat striatal astrocytes enter the neurogenic program 3 days after stroke, asNotch1 signaling decreases, and that inhibition of Notch1 signaling at thistime point promotes this process (Magnusson et al., 2014). Two other studiesindicated that striatal astrocytes become neuroblasts 1 week after strokeand transdifferentiate into neurons, and that synapses form 2 weeks later(Arvidsson et al., 2002; Duan et al., 2015). Thus, promoting striatal astrocyte-derived neurogenesis through inhibition of Notch1 signaling in the subacutestage after cerebral ischemia is a promising area for investigation.The central nervous system is a complex neural network. Only newbornneurons have been reported to establish new connections and undergomyelination, which would be beneficial effects for the recovery of damagedbrain tissue (Tanaka et al., 2003; Jiang et al., 2006). In vivo imaging toolsneed to be developed to monitor the functional effects of newborn neuronswithin the existing or newly built neural circuitry and their contribution tobrain function after stroke (Deng et al., 2010). Diffusion kurtosis imaging (DKI)parameters, such as mean kurtosis (MK), axial kurtosis (Ka) and radial kurtosis(Kr), provide detailed information about microstructural deformation andreorganization that indirectly illustrates functional recovery (Hao et al., 2018;Shen et al., 2019; Wei et al., 2019).In this study, we first elucidated the temporal profile of both astrocytictransdifferentiation into neurons and Notch1 activation in astrocytes andthen attempted to analyze the effects of DAPT administered at different timepoints on astrocyte-derived neurons. More importantly, we used magneticresonance imaging (MRI) to evaluate neurogenesis-related microstructuralchanges in the damaged brain in vivo.