Ambroxol Improves Neuronal Survival and Reduces White Matter Damage through Suppressing Endoplasmic Reticulum Stress in Microglia after Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH) has been becoming a serious public health problem. Pneumonia, occurring in 43% of all ICH patients, is a common complication heavily influencing outcome and accounting for more than 1/3 of the overall mortality in patients with ICH. Ambroxol may be an effective additional treatment for ICH patients with pneumonia. But its effect and potential mechanism on functional recovery post-ICH still remain elusive. In the present study, the results indicated that 35 mg/kg and 70 mg/kg ambroxol facilitated neuronal survival and reduced white matter fiber bundle damage due to mitigating microglial activation and reducing proinflammatory cytokine accumulation in mice with ICH. The possible mechanism might be due to suppressing endoplasmic reticulum stress involving the IRE1α/TRAF2 signaling pathway, which paves a new path for the treatment of ICH and opens a new window for the use of ambroxol in clinical practice.

Ambroxol Upregulates Glucocerebrosidase Expression to Promote Neural Stem Cells Differentiation Into Neurons Through Wnt/β-Catenin Pathway After Ischemic Stroke

“…Next, the crosstalk between astrocyte and microglia promotes the release of Wnt1-like proteins in astrocytes, which results in Wnt/β-catenin activation in microglial cells to hamper GSK-3β activation, resulting in a downregulation of proinflammatory mediators (Marchetti et al, 2013 ; L'Episcopo et al, 2018 ). Most recently, our research has substantiated that ambroxol enhances neuronal survival and diminishes white matter fiber bundle damage through mitigating M1-like microglial activation and reducing pro-inflammatory cytokines accumulation in mice with ICH (Jiang et al, 2020 ).…”

“…Based on our previous investigation that 35 mg/kg and 70 mg/kg ambroxol could facilitate neuronal survival and decrease white matter fiber bundle injury by suppressing microglial activation and decreasing proinflammatory cytokine accumulation in mice with intracerebral hemorrhage (ICH), finally enhance functional recovery (Jiang et al, 2020 ). Here, to explore the effect of administration of ambroxol on functional recovery after ischemic stroke, three concentrations of ambrxol (35, 70, 100 mg/kg) were applied to assess the feasible therapeutic concentration.…”

“…Rotarod test was used to evaluate fore- and hind limb motor coordination and balance as described by our previous work (Yang et al, 2018 ; Jiang et al, 2020 ). The speed was initially set at 5 rpm and gradually increase to 35 rpm, and the latency to fall (or cling to and spin with the rod for 3 full rotations) within 3 min was recorded for further analysis.…”

“…Furthermore, previous researches have revealed that ambroxol therapy is safe and well-tolerated, and might provide a potential novel target for the treatment of Parkinson disease from bench to bedside (Migdalska-Richards et al, 2016 ; Silveira et al, 2019 ; Mullin et al, 2020 ). Most recently, our previous study represents that 35 mg/kg and 70 mg/kg ambroxol promotes neuronal survival and decreases white matter fiber bundle damage via mitigating microglial activation and reducing proinflammatory cytokine accumulation in mice with intracerebral hemorrhage (ICH) (Jiang et al, 2020 ). Above evidence suggests that ambroxol hold neuroprotective ability, except for fighting against post-stroke pneumonia.…”

Revisiting promising preclinical intracerebral hemorrhage studies to highlight repurposable drugs for translation

“… 34 Geranylgeranylacetone, 30 an antiulcer drug, and metformin, 43 prescribed for metabolic syndrome, both protected against neurological deficits in rat models of ICH. Suberoylanilide hydroxamic acid 53 for treatment of cutaneous T-cell lymphoma and ambroxol, 18 an antioxidant mucolytic agent, equally resulted in beneficial outcomes on functional behavior, brain atrophy, apoptosis, and neuroinflammation in mouse models of experimental ICH. Repurposing safe medications for neurological diseases with multiple pathologies such as those seen in ICH is the fastest way to clinical benefit, and these novel therapeutic avenues, usually identified by unbiased drug screens, should be validated by clinical trial.…”