Cordycepin confers long-term neuroprotection via inhibiting neutrophil infiltration and neuroinflammation after traumatic brain injury

Abstract

Background The secondary injury caused by traumatic brain injury (TBI), especially white matter injury (WMI), is highly sensitive to neuroinflammation, which further leads to unfavored long-term outcomes. Although the cross-talk between the three active events, immune cell infiltration, BBB breakdown, and proinflammatory microglial/macrophage polarization, plays a role in the vicious cycle, its mechanisms are not fully understood. It has been reported that cordycepin, an extract from Cordyceps militaris, can inhibit TBI-induced neuroinflammation although the long-term effects of cordycepin remain unknown. Here, we report our investigation of cordycepin’s long-term neuroprotective function and its underlying immunological mechanism. Methods TBI mice model was established with a controlled cortical impact (CCI) method. Cordycepin was intraperitoneally administered twice daily for a week. Neurological outcomes were assessed by behavioral tests, including grid walking test, cylinder test, wire hang test, and rotarod test. Immunofluorescence staining, transmission electron microscopy, and electrophysiology recording were employed to assess histological and functional lesions. Quantitative-PCR and flow cytometry were used to detect neuroinflammation. The tracers of Sulfo-NHS-biotin and Evans blue were assessed for the blood-brain barrier (BBB) leakage. Western blot and gelatin zymography were used to analyze protein activity or expression. Neutrophil depletion in vivo was performed via using Ly6G antibody intraperitoneal injection. Results Cordycepin administration ameliorated long-term neurological deficits and reduced neuronal tissue loss in TBI mice. Meanwhile, the long-term integrity of white matter was also preserved, which was revealed in multiple dimensions, such as morphology, histology, ultrastructure, and electrical conductivity. Cordycepin administration inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization after TBI. BBB breach was attenuated by cordycepin administration at 3 days after TBI. Cordycepin suppressed the activities of MMP-2 and MMP-9 and the neutrophil infiltration at 3 days after TBI. Moreover, neutrophil depletion provided a cordycepin-like effect, and cordycepin administration united with neutrophil depletion did not show a benefit of superposition. Conclusions The long-term neuroprotective function of cordycepin via suppressing neutrophil infiltration after TBI, thereby preserving BBB integrity and changing microglia/macrophage polarization. These findings provide significant clinical potentials to improve the quality of life for TBI patients.

Intranasal Salvinorin A Improves Long-term Neurological Function via Immunomodulation in a Mouse Ischemic Stroke Model

“…Circulating neutrophils are the main infiltrating peripheral immune cells within one hour and peaking by 24 h post-injury (Gelderblom et al 2009 ). Previous studies demonstrated that neutrophil depletion reduced BBB leakiness after brain injury (Bodnar et al 2021 ; Wei et al 2021 ). Conversely, the increased permeability of BBB facilitates neutrophil infiltration into the brain after ischemic stroke (Obermeier et al 2013 ).…”

“…Circulating neutrophils are the main infiltrating peripheral immune cells within one hour and peaking by 24 h post-injury (Gelderblom et al 2009). Previous studies demonstrated that neutrophil depletion reduced BBB leakiness after brain injury (Bodnar et al 2021;Wei et al 2021).Conversely, the increased permeability of BBB facilitates neutrophil infiltration into the brain after ischemic stroke (Obermeier et al 2013).In this study, SA treatment significantly decreased the neutrophil/macrophage infiltration into the brain tissue while not altering the peripheral immune cells, suggesting that SA may play an immunomodulatory role though preserving BBB integrity. The cadaverine leakage density and plasma IgG leakage detection further demonstrated the beneficial effect of SA on the BBB.…”

Hu’po Anshen Decoction Accelerated Fracture-Healing in a Rat Model of Traumatic Brain Injury Through Activation of PI3K/AKT Pathway

“…Among these active components, Cordycepin ( Li et al, 2020 ), Chlorogenic acid ( Liu L. et al, 2018 ), Puerarin ( Wong and Rabie, 2007 ), Hyperin ( Saul et al, 2021 ) and Naringenin ( Estai et al, 2011 ) have been proved to promote fracture healing. Meanwhile, these active ingredients can also improve TBI ( Wang et al, 2014 ; Deng et al, 2021 ; Wei et al, 2021 ). These results present a pharmacological basis for HPASD in the treatment of TBI combined with fracture.…”

High-Throughput mRNA Sequencing Reveals Potential Therapeutic Targets of Febuxostat in Secondary Injury After Intracerebral Hemorrhage

“…The behavior tests included the modified neurological severity score, the wire hanging test, the beam walking test, and the forelimb placing test, which were described previously ( Chen et al, 2001 ; Seyfried et al, 2009 ; Luong et al, 2011 ; Matsushita et al, 2011 ; Krafft et al, 2014 ; Xu et al, 2017 ; Wei et al, 2021 ). Before the behavior tests, all animals underwent behavior training for 3 days, and abnormal animals were excluded.…”