Our earlier studies have shown that cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients causes death of motor neurons, both in in-vitro as well as in-vivo. There was an aberrant phosphorylation of neurofilaments in cultured spinal cord neurons of chick and rats following exposure to CSF of ALS patients (ALS-CSF). Other features of neurodegeneration, such as swollen neuronal soma and beading of neurites were also observed. In neonatal rat pups exposed to ALS-CSF, we observed phosphorylated neurofilaments in the soma of spinal motor neurons in addition to the increased lactate dehydrogenase activity and reactive astrogliosis. The present study examines the effect of ALS-CSF on the expression of glial glutamate transporter (GLT-1) in embryonic rat spinal cord cultures as well as in spinal astrocytes of neonatal rats. Immunostaining suggested a decrease in the expression of GLT-1 by astrocytes both in culture and in-vivo following exposure to ALS-CSF. Quantification of Western blots confirmed the decreased expression of GLT-1. Our results provide evidence that toxic factor(s) present in ALS-CSF depletes GLT-1 expression. This could lead to an increased level of glutamate in the synaptic pool causing excitotoxicity to motor neurons, possibly by triggering the 'glutamate-mediated toxicity-pathway'. 相似文献
Accumulating evidence supports neuroprotective role of trophic factors in amyotrophic lateral sclerosis (ALS). Previous studies
from our laboratory report that the CSF of patients with sporadic ALS (ALS-CSF) induces degenerative changes in the rat spinal
motor neurons and reactive astrogliosis in the surrounding gray matter. The present study was aimed to investigate if the
ALS-CSF affected the expression of trophic factors namely, brain-derived neurotrophic factor (BDNF), fibroblast growth factor
2 (FGF2) and insulin-like growth factor 1 (IGF1) in the newborn rat spinal cords. ALS-CSF was intrathecally injected into
the neonatal rats and the mRNA levels of the trophic factors were determined by quantitative real-time polymerase chain reaction.
Here, we report significant down regulation in the gene expression of trophic factors for BDNF, FGF2 and IGF1. BDNF mRNA levels
were found to be reduced by 6.8-fold in the ALS-CSF injected group compared to control groups. The levels of IGF1 and FGF2
mRNA were also decreased by 3.91- and 2.13-fold, respectively, in the ALS group. We further found that exogenous supplementation
of BDNF considerably reduced the aberrant phosphorylation of neurofilaments, complementing our earlier findings of restored
expression of voltage gated sodium channel. Reduced expression of trophic factors indicates an altered microenvironment of
the motor neurons and could possibly be one of the contributing factors in the degeneration process. 相似文献
We have earlier shown that cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients’ produces selective degeneration of motor neurons, both in vitro as well as in vivo. The present study further evaluates the effect of ALS–CSF on the astrocytes in embryonic rat spinal cord cultures. We quantified the number of flat and process-bearing astrocytes in spinal cord cultures exposed to ALS–CSF and compared them against controls. In addition, GFAP and S100β expression were quantified by Western blot and measurement of immunofluorescence intensity respectively. We found higher number of process-bearing astrocytes in the cultures exposed to ALS–CSF. Both these proteins increased significantly in cultures exposed to ALS–CSF. Our results provide evidence that astroglia respond to toxic factor(s) present in ALS–CSF by undergoing morphological transformation from flat to process bearing which is further confirmed by elevated expression of GFAP and S100β. The above changes could possibly alter the microenvironment hastening the motor neuron degeneration. 相似文献
Opioids are the primary analgesics used in patients undergoing spine surgery. Postoperative pain is common despite their liberal use and so are opioid-associated side effects. Non-opioid analgesics are gaining popularity as alternative to opioids in spine surgery.
Methods
This systematic review evaluated current evidence regarding opioid and non-opioid intraoperative analgesia and their influence on immediate postoperative pain and adverse events in spine surgery.
Results
A total of 10,459 records were obtained by searching Medline, EMBASE and Web of Science databases and six randomized controlled trials were included. Differences in postoperative pain scores between opioid and non-opioid groups were not significant at 1 h: 4 studies, mean difference (MD) = 0.65 units, 95% confidence intervals (CI) [−0.12 to 1.41], p = 0.10, but favored non-opioid at 24 h after surgery: 3 studies, MD = 0.75 units, 95%CI [0.03 to 1.46], p = 0.04. The time for first postoperative analgesic requirement was shorter (MD = −45.06 min, 95%CI [−72.50 to −17.62], p = 0.001), and morphine consumption during first 24 h after surgery was higher in opioid compared to non-opioid group (MD = 4.54 mg, 95%CI [3.26 to 5.82], p < 0.00001). Adverse effects of postoperative nausea and vomiting (Relative risk (RR) = 2.15, 95%CI [1.37 to 3.38], p = 0.0009) and shivering (RR = 2.52, 95%CI [1.08 to 5.89], p = 0.03) were higher and bradycardia was lower (RR = 0.35, 95%CI [0.17 to 0.71], p = 0.004) with opioid analgesia.
Conclusion
The certainty of evidence on GRADE assessment is low for studied outcomes. Available evidence supports intraoperative non-opioid analgesia for overall postoperative pain outcomes in spine surgery. More research is needed to find the best drug combination and dosing regimen.
Microglial cell-associated neuroinflammation is considered as a potential contributor to the pathophysiology of sporadic amyotrophic lateral sclerosis. However, the specific role of microglia in the disease pathogenesis remains to be elucidated.
Methods
We studied the activation profiles of the microglial cultures exposed to the cerebrospinal fluid from these patients which recapitulates the neurodegeneration seen in sporadic amyotrophic lateral sclerosis. This was done by investigating the morphological and functional changes including the expression levels of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), TNF-α, IL-6, IFN-γ, IL-10, inducible nitric oxide synthase (iNOS), arginase, and trophic factors. We also studied the effect of chitotriosidase, the inflammatory protein found upregulated in the cerebrospinal fluid from amyotrophic lateral sclerosis patients, on these cultures.
Results
We report that the cerebrospinal fluid from amyotrophic lateral sclerosis patients could induce an early and potent response in the form of microglial activation, skewed primarily towards a pro-inflammatory profile. It was seen in the form of upregulation of the pro-inflammatory cytokines and factors including IL-6, TNF-α, iNOS, COX-2, and PGE2. Concomitantly, a downregulation of beneficial trophic factors and anti-inflammatory markers including VEGF, glial cell line-derived neurotrophic factor, and IFN-γ was seen. In addition, chitotriosidase-1 appeared to act specifically via the microglial cells.
Conclusion
Our findings demonstrate that the cerebrospinal fluid from amyotrophic lateral sclerosis patients holds enough cues to induce microglial inflammatory processes as an early event, which may contribute to the neurodegeneration seen in the sporadic amyotrophic lateral sclerosis. These findings highlight the dynamic role of microglial cells in the pathogenesis of the disease, thus suggesting the need for a multidimensional and temporally guarded therapeutic approach targeting the inflammatory pathways for its treatment.
Objective – To detect cardiac autonomic dysfunction, using analysis of heart rate variability in genetically defined spinocerebellar ataxias (SCA). Materials and methods – Consecutive RR intervals were analyzed for time- and frequency- domain parameters in 22 genotypically proven SCA patients (SCA1 = 11, SCA2 = 6 and SCA3 = 5) and compared with that of age- and gender- matched controls. Results – Reduction in the standard deviation of RR interval (RR_SD) was seen in 72.7% of SCA patients. There was a reduction in both the parasympathetic and sympathetic parameters in SCA without any change in the ratio of low- to high- frequency power. In SCA1, there was a significant negative correlation between RR_SD and duration of illness but not with the CAG repeat lengths of the abnormal allele. Small sample size of SCA2 and SCA3 precluded similar comparison. Conclusions – Cardiac autonomic dysfunction, predominantly parasympathetic, was seen in SCA, and the severity correlated with the duration of illness in SCA1. 相似文献