Pentoxifylline alleviates ischemic white matter injury through up-regulating Mertk-mediated myelin clearance

Abstract

Background Vascular dementia (VAD) is the second most common type of dementia lacking effective treatments. Pentoxifylline (PTX), a nonselective phosphodiesterase inhibitor, displays protective effects in multiple cerebral diseases. In this study, we aimed to investigate the therapeutic effects and potential mechanisms of PTX in VAD. Methods Bilateral common carotid artery stenosis (BCAS) mouse model was established to mimic VAD. Mouse behavior was tested by open field test, novel object recognition test, Y-maze and Morris water maze (MWM) tests. Histological staining, magnetic resonance imaging (MRI) and electron microscopy were used to define white matter integrity. The impact of PTX on microglia phagocytosis, peroxisome proliferator-activated receptors-γ (PPAR-γ) activation and Mer receptor tyrosine kinase (Mertk) expression was assessed by immunofluorescence, western blotting and flow cytometry with the application of microglia-specific Mertk knockout mice, Mertk inhibitor and PPAR-γ inhibitor. Results Here, we found that PTX treatment alleviated cognitive impairment in novel object recognition test, Y-maze and Morris water maze tests. Furthermore, PTX alleviated white matter injury in corpus callosum (CC) and internal capsule (IC) areas as shown by histological staining and MRI analysis. PTX-treatment group presented thicker myelin sheath than vehicle group by electron microscopy. Mechanistically, PTX facilitated microglial phagocytosis of myelin debris by up-regulating the expression of Mertk in BCAS model and primary cultured microglia. Importantly, microglia-specific Mertk knockout blocked the therapeutic effects of PTX in BCAS model. Moreover, Mertk expression was regulated by the nuclear translocation of PPAR-γ. Through modulating PPAR-γ, PTX enhanced Mertk expression. Conclusions Collectively, our results demonstrated that PTX showed therapeutic potentials in VAD and alleviated ischemic white matter injury via modulating Mertk-mediated myelin clearance in microglia.

Maternal repetitive hypoxia prior to mating confers epigenetic resilience to memory impairment in male progeny.

“…Results of our second study, showing that adult female mice exhibit no significant loss of recognition memory after 3 months of CCH—as commonly reported for males (Ben-Ari et al, 2019; Bhatia et al, 2022; Cao et al, 2022; Dominguez et al, 2018; Inaba et al, 2019; Khan et al, 2015; Ohtomo et al, 2020; Patel et al, 2017; Toyama et al, 2018; Tsai et al, 2015; Zheng et al, 2022)—reveal a previously undescribed sexual dimorphism in this VCID model. This dimorphism is consistent with the finding that 4-month-old male mice treated with 1 month of oral estradiol post-BCAS are protected against BCAS-induced memory impairment in the NOR test (Dominguez et al, 2018).…”

“…The aforementioned mouse model of VCID we employed herein and previously to document epigenetically mediated protection against CCH-induced dementia is well-established, but has relied almost exclusively on the use of male mice to characterize the underlying pathology and to assess the efficacy of potential therapeutics (Ben-Ari et al, 2019; Bhatia et al, 2022; Cao et al, 2022; Dominguez et al, 2018; Inaba et al, 2019; Khan et al, 2015; Ohtomo et al, 2020; Patel et al, 2017; Toyama et al, 2018; Tsai et al, 2015; Zheng et al, 2022). Thus, a secondary aim was to determine if impairments in recognition memory secondary to CCH, independent of treatment, exhibited a sexual dimorphism.…”

Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia

“…For example, Zheng et al reported that A1 astrocytes inhibited microglial phagocytosis of myelin debris via an astrocytic C3-microglial C3aR axis, aggravating WMI after intracerebral hemorrhage [ 7 ]. Our previous study reported that pentoxifylline (PTX) alleviated ischemic WMI in BCAS model via facilitating microglial phagocytosis of myelin debris [ 8 ]. Thus, key molecules modulating glial cell function may be primary therapeutic targets for WHI in CSVD.…”

Metformin attenuates white matter injury and cognitive impairment induced by chronic cerebral hypoperfusion

“…36 Indeed, in the BCAS model which is considered to highly mimic the clinical carotid stenosis-induced cerebral hypoperfusion, white matter lesions are demonstrated to be closely related to cognitive impairments. [37][38][39] In this study, we found that working memory significantly declined in mice 60 days after BCAS as examined by the Y-maze test. Meanwhile, the recognition ability of the mice was greatly decreased as detected by the novel object recognition test.…”