Inflammatory depression is closely related to neuroinflammation. However, current anti-inflammatory drugs have low permeability to cross blood-brain barrier with difficulties reaching the central ...nervous system to provide therapeutic effectiveness. To overcome this limitation, the nano-based drug delivery technology was used to synthesize melanin-like polydopamine nanoparticles (PDA NPs) (~ 250 nm) which can cross the blood-brain barrier. Importantly, PDA NPs with abundant phenolic hydroxyl groups function as excellent free radical scavengers to attenuate cell damage caused by reactive oxygen species or acute inflammation. In vitro experiments revealed that PDA NPs exhibited excellent antioxidative properties. Next, we aimed to investigate the therapeutic effect of PDA NPs on inflammatory depression through intraperitoneal injection to the lipopolysaccharide-induced inflammatory depression model in mice. PDA NPs significantly reversed the depression-like behavior. PDA NPs was also found to reduce the peripheral and central inflammation induced by LPS, showing that alleviated splenomegaly, reduced serum inflammatory cytokines, inhibited microglial activation and restored synaptic loss. Various experiments also showed that PDA NPs had good biocompatibility both in vivo and in vitro. Our work suggested that PDA NPs may be biocompatible nano-drugs in treating inflammatory depression but their clinical application requires further study.
Patients with chronic pain often experience memory impairment, but the underlying mechanisms remain elusive. The myelin sheath is crucial for rapid and accurate action potential conduction, playing a ...pivotal role in the development of cognitive abilities in the central nervous system. The study reveals that myelin degradation occurs in the hippocampus of chronic constriction injury (CCI) mice, which display both chronic pain and memory impairment. Using fiber photometry, we observed diminished task-related neuronal activity in the hippocampus of CCI mice. Interestingly, the repeated administration with clemastine, which promotes myelination, counteracts the CCI-induced myelin loss and reduced neuronal activity. Notably, clemastine specifically ameliorates the impaired memory without affecting chronic pain in CCI mice. Overall, our findings highlight the significant role of myelin abnormalities in CCI-induced memory impairment, suggesting a potential therapeutic approach for treating memory impairments associated with neuropathic pain.
Neuropathic pain, a severe clinical symptom, significantly affects the quality of life in the patients. The molecular mechanisms underlying neuropathic pain have been the focus of research in recent ...decades; however, the neuronal circuit-mediated mechanisms associated with this disorder remain poorly understood. Here, we report that a projection from the lateral hypothalamus (LH) glutamatergic neurons to the lateral habenula (LHb), an excitatory LH-LHb neuronal circuit, participates in nerve injury-induced nociceptive hypersensitivity. LH glutamatergic neurons are activated and display enhanced responses to normally non-noxious stimuli following chronic constriction injury. Chemogenetic inhibition of LH glutamatergic neurons or excitatory LH-LHb circuit blocked CCI-induced nociceptive hypersensitivity. Activation of the LH-LHb circuit led to augmented responses to mechanical and thermal stimuli in mice without nerve injury. These findings suggest that LH neurons and their triggered LH-LHb circuit participate in central mechanisms underlying neuropathic pain and may be targets for the treatment of this disorder.
•LH glutamatergic neurons are involved in neuropathic pain.•The activity of the LH-LHb circuit is enhanced in neuropathic pain.•Inhibition of the LH-LHb circuit relieves neuropathic pain.•Activation of the LH-LHb circuit induces nociceptive hypersensitivity in mice without nerve injury.
Aims
Sevoflurane is widely used for general anesthesia in children. Previous studies reported that multiple neonatal exposures to sevoflurane can induce long‐term cognitive impairment in adolescent ...rats, but the underlying mechanisms were not defined.
Methods
Postnatal day 6 (P6) to P8 rat pups were exposed to 30% oxygen with or without 3% sevoflurane balanced with air. The Y maze test (YMT) and Morris water maze (MWM) tests were performed in some cohorts from age P35 to assess cognitive functions, and their brain samples were harvested at age P14, 21, 28, 35, and 42 for measurements of various molecular entities and in vivo electrophysiology experiments at age P35.
Results
Sevoflurane exposure resulted in cognitive impairment that was associated with decreased synCAM1 expression in parvalbumin (PV) interneurons, a reduction of PV phenotype, disturbed gamma oscillations, and dendritic spine loss in the hippocampal CA3 region. Enriched environment (EE) increased synCAM1 expression in the PV interneurons and attenuated sevoflurane‐induced cognitive impairment. The synCAM1 overexpression by the adeno‐associated virus vector in the hippocampal CA3 region restored sevoflurane‐induced cognitive impairment, PV phenotype loss, gamma oscillations decrease, and dendritic spine loss.
Conclusion
Our data suggested that neonatal sevoflurane exposure results in cognitive impairment through decreased synCAM1 expression in PV interneurons in the hippocampus.
Neonatal exposure to repeated sevoflurane anesthesia resulted in cognitive impairment associated with decreased synCAM1 expression in the hippocampal PV interneurons, reduced PV interneurons phenotype, and disturbed gamma oscillations. Moreover, overexpression of synCAM1 in the hippocampal PV interneurons improved cognitive function by restoring PV expression and gamma oscillations after repeated sevoflurane exposure.
•Intraplantar CFA caused upregulation of MZF1 in the DRG.•MZF1 inhibition attenuated CFA-induced inflammatory pain.•CFA-induced increased MMP-9/2 in the DRG was reversed by MZF1 inhibition.•MZF1 ...knock down prevented the reduction of Kv1.2 in the DRG.
Myeloid zinc finger 1 (MZF1) belongs to the Kruppel family of zinc-finger transcription factors. Recent studies have demonstrated that in dorsal root ganglion (DRG) neurons, MZF1 is involved in the development and maintenance of neuropathic pain. However, the role of MZF1 in inflammatory pain still remains unknown. In the present study, the mechanism of MZF1 in chronic inflammatory pain was investigated in rats received an intraplantar injection of complete Freund’s adjuvant (CFA). Subsequently, a series of assays including Western blotting, qRT-PCR, immunohistochemistry, and chromatin immunoprecipitation (ChIP) were performed. We found that CFA led to MZF1 upregulation in ipsilateral L4/5 DRGs. Pre- and post-microinjection of MZF1 siRNA into the ipsi-L5 DRG blocked the development of CFA-induced chronic inflammatory pain and alleviated the mechanical allodynia and thermal hyperalgesia in the maintenance phase. CFA also increased MMP-2/9 and Nav1.8 expression but reduced voltage-gated potassium 1.2 (Kv1.2) and Cav1.2 expression in L4/L5 DRGs. Microinjection of MZF1 siRNA into DRG diminished the CFA-induced changes in MMP-2/9 and Kv1.2 expression. However, the expressions of Nav1.8 and Cav1.2 were not changed by the treatment. Double immunofluorescence staining showed that MMP-2/9 and Kv1.2 were co-localized with MZF1 in DRGs. The ChIP-PCR results revealed that MZF1 binds directly to the promoter region of MMP-2/9 gene. Together, the above results imply that upregulation of MZF1 in DRGs might contribute to the development and maintenance of CFA-induced chronic inflammatory pain by regulating MMP-2/9 and Kv1.2 expression. Targeting DRG-localized MZF1 might be a promising therapeutic strategy for the treatment of chronic inflammatory pain in the clinic.
N6-methyladenosine (m
A) is the most abundant methylation modification on mRNA in mammals. Fat mass and obesity-related protein (FTO) is the main RNA m
A demethylase. FTO is involved in the ...occurrence and maintenance of neuropathic pain (NP). NP often induces mental disorders. We found that NP downregulated the expression of FTO in the anterior cingulate cortex (ACC), inhibited the expression of matrix metalloproteinase-9 (MMP-9) in the ACC, maladjusted the brain-derived neurotrophic factor precursor (proBDNF) and mature brain-derived neurotrophic factor (mBDNF) levels in the ACC, and induced anxiety- and depression-like behaviors in mice. Blocking the downregulation of FTO in the ACC induced by peripheral nerve injury could reverse the anxiety- and depression-like behaviors of mice. Contrarily, downregulation of simulated FTO induced anxiety- and depression-like behaviors in mice. After peripheral nerve injury, the binding of FTO to MMP-9 mRNA decreased and the enrichment of m
A on MMP-9 mRNA increased. In conclusion, downregulation of FTO in ACC by regulating MMP-9 mRNA methylation level contributes to the occurrence of anxiety- and depression-like behaviors in NP mice.
Regional anesthesia has been used to reduce acute postsurgical pain and to prevent chronic pain. The best technique, however, remains controversial.
The aim of this study was to assess the short- ...and long-term postoperative analgesic efficacy of ultrasound-guided quadratus lumborum block (QLB) in open gastrointestinal surgery.
A randomized, double-blinded, controlled trial.
Operating room; postoperative recovery room and ward.
One hundred eighteen patients underwent elective gastrointestinal surgery randomly assigned into 2 groups (QLB group or control group). Before anesthetic induction, QLB was performed bilaterally under ultrasound guidance using 20 mL of 0.375% ropivacaine or saline solution at each abdominal wall. The primary outcome was cumulative oxycodone consumption within 24 h after surgery. The secondary outcomes were acute pain intensity, incidence of chronic pain, and incidence of postoperative nausea or vomiting (PONV), dizziness, and pruritus.
The cumulative oxycodone consumption was significantly lower in the QLB group during the first 6, 6-24, 24, and 48 h postoperatively when compared to the control group. At rest or during coughing, the numeric rating scale scores were significantly lower at 1, 3, 6, and 12 h postoperatively in the QLB group compared to the control group. There were no significant differences between the 2 groups regarding the incidence of chronic postoperative pain at 3 or 6 months after surgery. Significant differences were found in the incidence of PONV between the two groups, but other complications, such as dizziness and pruritus, did not differ significantly.
We did not confirm the QLB effectiveness with sensory level testing after local anesthetic injection. Cumulative oxycodone consumption could have been affected by the patients' use of oxycodone for nonsurgical pain.
Ultrasound-guided QLB provided superior short-term analgesia and reduced oxycodone consumption and the incidence of PONV after gastrointestinal surgery. However, the incidence of chronic pain was not significantly affected by this anesthetic technique.
In this paper, a distribute feedback laser diode (DFB LD) composed microwave photonic bandpass filter is proposed and experimentally demonstrated for subcarrier multiplexing (SCM)-based radio over ...fiber (RoF) transport systems. To realize the photonic filter, a multiwavelength laser, composed by directly modulating single-tone RF signal with a DFB LD, is developed to simultaneously generate six identical optical carriers. When these optical carriers are phase-modulated with SCM signals and communicated through optical fiber to optical network units (ONUs), a bandpass filter function is accomplished automatically due to the interaction of the accumulated chromatic dispersion and the optical interference among those transmitted optical carriers. Experimental results proof that the central frequency of the passband window of the photonic filter is not fixed, instead, it can be shifted accurately by alerting the optical channel spacing of the generated six optical carriers. By applying the proposed photonic filter for SCM-based RoF transport systems, each connected ONU will receive dedicated SCM signals only and the other SCM signals will be rejected, so no more electrical microwave filter is required to be deployed in the ONU. With the proposed scheme, the SCM-based RoF transport systems can be greatly simplified and the system transmission efficiency can be promoted and controlled centrally.
Chronic neuropathic pain is frequently accompanied by memory impairment, yet the underlying mechanisms remain unclear. Here, we showed that mice displayed memory impairment starting at 14 days and ...lasting for at least 21 days after chronic constriction injury (CCI) of unilateral sciatic nerve in mice. Systemic administration of the pan histone deacetylase (HDAC) inhibitor sodium butyrate attenuated this memory impairment. More specifically, we found that hippocampus HDAC3 was involved in this process because the levels of its mRNA and protein increased significantly in the hippocampus at 14 and 21 days after CCI, but not sham surgery. Systemic administration of the selective HDAC3 antagonist RGFP966 attenuated CCI-induced memory impairment, improved hippocampal long-term potentiation impairment, and rescued reductions of dendritic spine density and synaptic plasticity-associated protein in the hippocampus. In addition, HDAC3 overexpression in the hippocampus led to memory impairment without affecting basal nociceptive responses in naive mice. Our findings suggest that HDAC3 contributes to memory impairment after CCI by impairing synaptic plasticity in hippocampus. Histone deacetylase 3 might serve as a potential molecular target for therapeutic treatment of memory impairment under neuropathic pain conditions.
