Acamprosate effect on neuropathic pain in rats: With emphasis on the role of ERK/MAPK pathway and SCN9A sodium channel.

BACKGROUND: Neuropathic pain is a chronic pain owing to nerve damage or diseases of the central nervous system (CNS). The expression of SCN9A, which encodes the Nav1.7 voltage-gated sodium channel and ERK have been found to change significantly in many cases of neuropathic pain. Here, we investigated effects of acamprosate on neuropathic pain, taking into account the crucial roles of SCN9A, the ERK signaling pathway, and inflammatory markers in a rat model of chronic constriction injury (CCI). METHODS: Acamprosate (300 mg/kg) was injected intraperitoneally (i.p.) for 14 days. The tail-immersion, acetone, and formalin tests were used to determine behavioral tests such as heat allodynia, cold allodynia, and chemical hyperalgesia, respectively. Lumbar spinal cord was extracted and processed for Nissl staining. The amount of spinal SCN9A expression and ERK phosphorylation were examined using ELISA assay. RESULTS: The expression of SCN9A, ERK, inflammatory cytokines (IL-6 and TNF-α), allodynia and hyperalgesia significantly increased on days 7 and 14 following CCI. The treatment not only reduced neuropathic pain but also blocked CCI's effects on SCN9A upregulation and ERK phosphorylation. CONCLUSION: This research demonstrated that acamprosate reduces the neuropathic pain induced by CCI of the sciatic nerve in rats by preventing cell loss, inhibiting spinal SCN9A expression, ERK phosphorylation, and inflammatory cytokines, suggesting potential therapeutic implications of acamprosate administration for the treatment of neuropathic pain.

Intranasal delivery of stem cells labeled by nanoparticles in neurodegenerative disorders: Challenges and opportunities.

Neurodegenerative disorders occur through progressive loss of function or structure of neurons, with loss of sensation and cognition values. The lack of successful therapeutic approaches to solve neurologic disorders causes physical disability and paralysis and has a significant socioeconomic impact on patients. In recent years, nanocarriers and stem cells have attracted tremendous attention as a reliable approach to treating neurodegenerative disorders. In this regard, nanoparticle-based labeling combined with imaging technologies has enabled researchers to survey transplanted stem cells and fully understand their fate by monitoring their survival, migration, and differentiation. For the practical implementation of stem cell therapies in the clinical setting, it is necessary to accurately label and follow stem cells after administration. Several approaches to labeling and tracking stem cells using nanotechnology have been proposed as potential treatment strategies for neurological diseases. Considering the limitations of intravenous or direct stem cell administration, intranasal delivery of nanoparticle-labeled stem cells in neurological disorders is a new method of delivering stem cells to the central nervous system (CNS). This review describes the challenges and limitations of stem cell-based nanotechnology methods for labeling/tracking, intranasal delivery of cells, and cell fate regulation as theragnostic labeling. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease.

Hippocampal chloride transporter KCC2 contributes to excitatory GABA dysregulation in the developmental rat model of schizophrenia.

Recent studies have revealed an altered expression of NKCC1 and KCC2 in prefrontal cortex (PFC) and hippocampus of schizophrenic patients. Despite extensive considerations, the alteration of NKCC1 and KCC2 co-transporters at different stages of development has not been fully studied. Therefore, we evaluated the expression of these transporters in PFC and hippocampus at time points of four, eight, and twelve weeks in post-weaning social isolation rearing rat model. For this purpose, 23-25 days-old rats were classified into social- or isolation-reared groups. The levels of NKCC1 and KCC2 mRNA expression were evaluated at hippocampus or PFC regions at the time-points of four, eight, and twelve weeks following housing. Post-weaning isolation rearing decreased the hippocampal KCC2 mRNA expression level, but does not affect the NKCC1 mRNA expression. However, no significant difference was observed in the PFC mRNA levels of NKCC1 and KCC2 in the isolation-reared group compared to the socially-reared group during the course of modeling. Further, we assessed the therapeutic effect of selective NKCC1 inhibitor bumetanide (10 mg/kg), on improvement of prepulse inhibition (PPI) test on twelve weeks isolation-reared rats. Intraperitoneal administration of bumetanide (10 mg/kg) did not exert beneficial effects on PPI deficit. Our findings show that isolation rearing reduces hippocampal KCC2 expression level and may underlie hippocampal GABA excitatory. In addition, 10 mg/kg bumetanide is not effective in improving the reduced PPI of twelve weeks isolation-reared rats. Collectively, our findings show that hippocampal chloride transporter KCC2 contributes to excitatory GABA dysregulation in the developmental rat model of schizophrenia.

Comparing intravenous dexmedetomidine and clonidine in hemodynamic changes and block following spinal anesthesia with ropivacaine in lower limb orthopedic surgery: a randomized clinical trial.

Dexmedetomidine (DEX) can prolong duration of anesthesia and shorten onset of sensory and motor block relative to clonidine. This study attempted to compare the efficacy of intravenous DEX and clonidine for hemodynamic changes and block after spinal anesthesia with ropivacaine in lower limb orthopedic surgery. In a double-blind randomized clinical trial, 120 patients undergoing spinal anesthesia in lower limb orthopedic surgery were recruited and divided into three groups using balanced block randomization: DEX group (n = 40; intravenous DEX 0.2 µg/kg), clonidine group (n = 40; intravenous clonidine 0.4 µg/kg), and placebo group (n = 40; intravenous normal saline 10 mL) in which pain scores were assessed using visual analogue scales (at recovery, and 2, 4, 6, and 12 hours after surgery) and time to achieve and onset of sensory and motor block. Statistically significant differences were found in mean arterial pressure among the groups at all times except baseline (P = 0.001), with a less mean arterial pressure and a prolonged duration of sensory and motor block (P = 0.001) in the DEX group where pain relieved in patients immediately after surgery and at above mentioned time points (P = 0.001). Simultaneous administration of intravenous DEX with ropivacaine for spinal anesthesia prolongs the duration of sensory and motor block and relieves postoperative pain, and however, can decrease blood pressure. Although intravenous DEX as an adjuvant can be helpful during spinal anesthesia with ropivacaine, it should be taken with caution owing to a lowering of mean arterial pressure in patients especially in the older adults. This study was approved by Ethical Committee of Arak University of Medical Sciences (No. IR.Arakmu.Rec.1395.450) in March, 2017, and the trial was registered and approved by the Iranian Registry of Clinical Trials (IRCT No. IRCT2017092020258N60) in 2017.