Photobiomodulation therapy promotes neurogenesis by improving post-stroke local microenvironment and stimulating neuroprogenitor cells

Abstract

Recent work has indicated that photobiomodulation (PBM) may beneficially alter the pathological status of several neurological disorders, although the mechanism currently remains unclear. The current study was designed to investigate the beneficial effect of PBM on behavioral deficits and neurogenesis in a photothrombotic (PT) model of ischemic stroke in rats. From day 1 to day 7 after the establishment of PT model, 2-minute daily PBM (CW, 808nm, 350mW/cm, total 294J at scalp level) was applied on the infarct injury area (1.8mm anterior to the bregma and 2.5mm lateral from the midline). Rats received intraperitoneal injections of 5-bromodeoxyuridine (BrdU) twice daily (50mg/kg) from day 2 to 8 post-stoke, and samples were collected at day 14. We demonstrated that PBM significantly attenuated behavioral deficits and infarct volume induced by PT stroke. Further investigation displayed that PBM remarkably enhanced neurogenesis and synaptogenesis, as evidenced by immunostaining of BrdU, Ki67, DCX, MAP2, spinophilin, and synaptophysin. Mechanistic studies suggested beneficial effects of PBM were accompanied by robust suppression of reactive gliosis and the production of pro-inflammatory cytokines. On the contrary, the release of anti-inflammatory cytokines, cytochrome c oxidase activity and ATP production in peri-infarct regions were elevated following PBM treatment. Intriguingly, PBM could effectively switch an M1 microglial phenotype to an anti-inflammatory M2 phenotype. Our novel findings indicated that PBM is capable of promoting neurogenesis after ischemic stroke. The underlying mechanisms may rely on: 1) promotion of proliferation and differentiation of internal neuroprogenitor cells in the peri-infarct zone; 2) improvement of the neuronal microenvironment by altering inflammatory status and promoting mitochondrial function. These findings provide strong support for the promising therapeutic effect of PBM on neuronal repair following ischemic stroke.

WITHDRAWN: Angelica Sinensis Extract Protects Against Memory Deficits by Promoting P38 MAPK–mediated Hippocampal Neurogenesis and Neuronal Survival in the Chronic Phase of Transient Global Cerebral Ischemia in Rats

“…MAP-2, a marker of neuronal dendrites, stabilizes the microtubule cytoskeleton of dendrites and is a sensitive and early indicator for evaluating dendritic integrity, neuronal damage, and neuron maturity in post-ischemia neurogenesis [2,23,43]. In the process of neurogenesis, BrdU/MAP-2 double-labeled cells are generated in the SGZ and migrate to the GCL, where they become mature neurons, whereas reduced MAP-2 expression in the hippocampal CA1 region indicates neuronal damage or death [43,44].…”

“…Microtubule-associated protein 2 (MAP-2), located in the neuronal perikarya and dendrites, is crucial in plasticity and in stabilizing the dendrite shape during neuronal development [22]. MAP-2, a neuronal dendritic marker, can be used as an early indicator for measuring the development of mature neurons in neurogenesis after cerebral ischemia [23].…”

Microglia Polarization, Gene-Environment Interactions and Wnt/β-Catenin Signaling: Emerging Roles of Glia-Neuron and Glia-Stem/Neuroprogenitor Crosstalk for Dopaminergic Neurorestoration in Aged Parkinsonian Brain

“…Interestingly, glia-NSC interactions are in part regulated by crosstalk between inflammatory and Wnt/β-catenin signaling cascades. While further studies are clearly needed to address the causal relationship between the reversal of SVZ impairment and nigrostriatal neurorepair in aged-MPTP mice, such inflammatory modulation of SVZ neurogenesis herein described appears of special interest in light of accumulating evidence documenting that mitigating the inflammatory status, improving the neuronal microenvironment, and promoting mitochondrial function all together may represent a window of opportunity for therapeutic strategies aimed at upregulating endogenous neurogenesis, to favor the integration or survival of new neurons, to incite neurorepair, and/or to ameliorate some cognitive functions (Ehninger et al, 2011 ; L'Episcopo et al, 2012 , 2014b ; Rueger et al, 2012 ; Sakata et al, 2012 ; Vukovic et al, 2012 ; Wallenquist et al, 2012 ; Marchetti and Pluchino, 2013 ; Radad et al, 2017 ; Wadhwa et al, 2017 ; Yang et al, 2017 ).…”

The Combination of Human Urinary Kallidinogenase and Mild Hypothermia Protects Adult Rats Against Hypoxic-Ischemic Encephalopathy-Induced Injury by Promoting Angiogenesis and Regeneration

“…Cyclin D1 is a member of the cyclin protein family, plays essential roles in regulating cell cycle progression and proliferation and is usually recognized as a biomarker of regeneration of cells (Bouchard-Cannon et al, 2013 ; Cheyuo et al, 2015 ). Ki67 labels the G and S phase cells and highly expresses in proliferative cells (Yang et al, 2018 ). In the current study, our observation that cyclin D1 and Ki67 decreased with adult HIE insult implies that hypoxic-ischemic cells undergo death and regeneration is markedly reduced.…”