The neuroprotective effect of near infrared light therapy in aged mice with postoperative neurocognitive disorder by upregulating IRF7.

BACKGROUND: Postoperative neurocognitive disorder (PND) is a common central nervous system complication after undergoing surgery and anesthesia especially in elderly patients, while the therapeutic options are very limited. This study was carried out to investigate the beneficial effects of transcranial near infrared light (NIRL) which was employed to the treatment of PND and propose the involved mechanisms. METHODS: The PND mice were established through left carotid artery exposure under isoflurane anesthesia and received transcranial NIRL treatment. Behavioral testing was performed to evaluate the cognitive function of PND mice after transcranial NIRL therapy. Changes in the transcriptomic profiles of prefrontal cortex (PFC) and hippocampus (HP) were identified by next generation sequencing (NGS), and the molecular mechanisms involved were examined by both in vivo mouse model and in vitro cell culture studies. RESULTS: We found that transcranial NIRL therapy effectively ameliorated learning and memory deficit induced by anesthesia and surgery in aged mice. Specifically, we identified down-regulation of interferon regulatory factor 7 (IRF7) in the brains of PND mice that was mechanistically associated with increased pro-inflammatory M1 phenotype of microglia and elevated neuroinflammatory. NIRL treatment produced protective effects through the upregulation of IRF7 expression and reversing microglial phenotypes from pro-inflammatory to neuroprotective, resulting in reduced brain damage and improved cognitive function in PND mice. CONCLUSION: Our results indicate that transcranial NIRL is an effective and safe therapy for PND via alleviating neuroinflammation, and IRF7 plays a key transcription factor in regulating the M1-to-M2 switch of microglia.

Mast cell stabilizer disodium cromoglycate improves long-term cognitive impairment after general anesthesia exposure in neonatal mice.

Background: Prolonged exposure to general anesthesia (GA) results in long-lasting cognitive impairment, especially during critical stages of brain development. An exaggerated neuroinflammation induced by anesthesia is generally considered to be a key cause of cognitive impairment. Materials and methods: Postnatal day 7 (PND 7) mice were exposed to GA by isoflurane inhalation for 6 h or mock anesthesia. Disodium cromoglycate (DSCG) was intraperitoneally injected daily for 2 weeks, beginning from 30 min before anesthesia. The post-anesthesia evaluation included behavioral tests, toluidine blue staining, immunofluorescence and western blot. Results: Our results demonstrated the long-term cognition were impaired after 6 h GA exposure in neonatal mice. DSCG treatment ameliorated early mast cells (MCs) degranulation and mast cell tryptase (MCT) expression, which helps to attenuate subsequent neuroinflammation, activation of microglia and astrocytes, and damage to oligodendrocytes and synapses to improve cognitive impairment. Conclusion: Disodium cromoglycate could effectively improve long-term cognitive impairment after GA exposure in neonatal mice.

Transcranial near-infrared laser improves postoperative neurocognitive disorder in aged mice via SIRT3/AMPK/Nrf2 pathway.

Background: Postoperative neurocognitive disorder (PND) is a common central nervous system (CNS) complication that might increase the morbidity and mortality of elderly patients after anesthesia/surgery. Neuroinflammation, oxidative stress, and synaptic dysfunction are closely related to cognitive dysfunction, an important clinical feature of PND. Transcranial near-infrared laser (TNIL) is regarded as an effective treatment for cognitive-related diseases by improving mitochondrial function and alleviating neuroinflammation and oxidative stress damage. Materials and methods: Aged male C57BL/6 mice underwent a carotid artery exposure procedure under isoflurane anesthesia. We treated PND-aged mice for three consecutive days (4 h post-operation, 1-laser) with 810 nm continuous wave (CW) laser 18 J/cm2 at 120 mW/cm2. The post-treatment evaluation included behavioral tests, RTq-PCR, immunofluorescence, and Western blot. Results: The results demonstrated that TNIL improved PND and the levels of synaptic function-associated proteins such as post-synaptic density protein 95 (PSD95), synaptophysin (SYP), and brain-derived neurotrophic factor (BDNF). Besides, neuroinflammatory cytokine levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß as well as microglia activation and oxidative stress damage were attenuated after TNIL treatment in aged mice with PND. Further investigation suggested that TNIL relieved oxidative stress response by activating the SIRT3/AMPK/Nrf2 pathway. Conclusion: Transcranial near-infrared laser improved cognitive impairment in aged mice with PND, which may be a promising therapeutic for PND.

Clemastine Ameliorates Perioperative Neurocognitive Disorder in Aged Mice Caused by Anesthesia and Surgery.

Perioperative neurocognitive disorder (PND) leads to progressive deterioration of cognitive function, especially in aged patients. Demyelination is closely associated with cognitive dysfunction. However, the relationship between PND and demyelination remains unclear. Here we showed that demyelination was related to the pathogenesis of PND. Clemastine, an antihistamine with potency in remyelination, was predicted to have a potential therapeutic effect on PND by next-generation sequencing and bioinformatics in our previous study. In the present study, it was given at 10 mg/kg per day for 2 weeks to evaluate the effects on PND in aged mice. We found that clemastine ameliorated PND and reduced the expression levels of inflammatory factors such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß). Further investigation suggested clemastine increased the expression of oligodendrocyte transcription factor 2 (OLIG2) and myelin basic protein (MBP) to enhance remyelination by inhibiting the overactivation of the WNT/ß-catenin pathway. At the same time, the expression of post-synaptic density protein 95 (PSD95, or DLG4), brain-derived neurotrophic factor (BDNF), synaptosomal-associated protein 25 (SNAP25) and neuronal nuclei (NEUN) were also improved. Our results suggested that clemastine might be a therapy for PND caused by anesthetic and surgical factors in aged patients.