Pathophysiological mechanisms and drug treatment of vascular dementia / 国际脑血管病杂志

Cascade in cerebral ischemic injury may cause cholinergic dysfunction,inflammation and oxidative stress. It plays an important role in the pathological processes of vascular dementia. A large amount of basic research has confirmed that cholinesterase inhibitor and N-methyl-d-aspartate receptor inhibitor may improve cognitive function in patients with vascular dementia. However, the efficacy of these drugs has been confirmed in only a part of the patients, and their safety and efficiency have not achieved the expected results. Thus, it needs further study and exploration.

Effects of MK-801 (dizocilpine) on Brain Cell Membrane Function and Energy Metabolism in Experimental Escherichia coli Meningitis in the Newborn Piglet

We evaluated the efficacy of non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) as an adjuvant therapy in experimental neonal bacterial meningitis. Meningitis was induced by injecting 10(6) colony forming units of Escherichia coli into the cisterna magna. MK-801 3 mg/kg was given as a bolus intravenous injection, 30 min before the induction of meningitis. MK-801 did not down-modulate the inflammatory parameters, such as increased intracranial pressure, cerebrospinal fluid (CSF) leukocytosis, increased lactate and TNF-alpha levels in the CSF, and hypoglycorrhachia observed in the meningitis group. MK-801 did not significantly attenuate the elevated glutamate concentration in the CSF. However, MK-801 showed some neuroprotective effects as evidenced by significant attenuation of cerebral lipid peroxidation products (conjugated dienes) and increase of brain high-energy phosphate compounds (ATP and PCr). Improvement in cerebral cortical cell membrane Na+, K+ -ATPase activity did not reach a statistical significance. These results suggest that MK-801 was effective in ameliorating brain injury in neonatal bacterial meningitis, although it failed to attenuate the inflammatory responses.

Effect of MK801 on the behavior of LID rat model and the possible mechanisms / 中华老年医学杂志

Objective To study the effect of MK801 on behavioral changes and the possible mechanisms. Methods To observe the behavioral changes of levodopa induced dyskinesia (LID) rats during the period of chronic MK801 treatment, immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) were used to measure the changes in expression of FosB, preproenkephalin (PPE) mRNA and prodynorphin (PDyn) mRNA in striatum, respectively. Double labling technique including immunohistochemistry of FosB and retrograde HRP transport tracing was used to observe the cell distribution of FosB. Results Pulsatile treatment with levodopa induced Abnormal involuntary movements (AIM) in PD rats, similar to LID in PD patients. FosB positive neurons and expressions of PPE mRNA and PDyn mRNA in striatum of 6-OHDA-lesioned hemisphere were increased in LID rats, and AIM scores of LID rats were reduced by MK801 treatment(41.9?15.6 vs 7.2?3.0), accompanied by the decrease in expressions of FosB and PDyn mRNA, but not PPE mRNA. Neurons immunoreactive for FosB were mainly located in striatonigral neurons which were labeled by cholera toxin-HRP (CT-HRP) injected in the substantia nigra pars reticulata (SNr). Conclusions MK801 could prevent the occurrence of dyskinesias induced by chronic levodopa treatment. The mechanism might be involved in the high expression of immediate early gene FosB and specific gene PDyn on the direct pathway. It suggests that LID might be related to the abnormal activity of direct pathway.

Antioxidant response element activator protects motor neurons from selected death / 中华神经科杂志

Objective To investigate the effects of antioxidant response element (ARE) activator- 5,6-dihydrocyclopenta[ C ]-1,2-dithiole-3-thione (CPDT) on organotypic spinal cord cultures and to study whether this activation can protect motor neurons from oxidative stress.Methods Organotypic spinal cord cultures were prepared using lumbar spinal cord slices from 8-day-old rat.Threo-hydroxyaspartate (THA) was continuously added into the culture medium for 3 weeks,which caused selective motor neuron death. Thus,the in vitro model of amyotrophic Lateral sclerosis (ALS) was established.15,30 ?mol/L of CPDT were added into the culture medium respectively.Ventral motor neurons survival was evaluated by immunohistochemical staining with monoclonal antibody SMI-32,a nonphosphorylated neurofilament marker. Ultrastructure was observed with electronic microscope.Results The pretreatment of organotypic spinal cord cultures with different concentrations of CPDT significantly increase the total number of ventral motor neurons (15?mol/L:(15.81?6.97) perexplant;30?mol/L:(16.25?6.74) perexplant respectively) compared with THA group ((5.31?5.76) perexplant) and the former had plentiful neurite extensions (n= 15,P

The Effect of NMDA Receptor Antagonist GAPA on the [Ca~(2+)]i of the Bilirubin Precipitated Brain Tissue / 中华围产医学杂志

Objective Study the effect of NMDA receptor antagonist GAPA on the [Ca 2+ ]i of the bilirubin precipitated brain tissue. Methods 10 ug/g of GAPA was administrated peritoneally to Gunn rat with bilirubin induced encephalopathy, brain tissue suspensions was prepared, Fura 2/AM was loaded. the neural cytosolic Ca 2+ was measured by flurescence imaging analysis. Results The concentration of neural cytosolic Ca 2+ in bilirubin precipitated brain tissue was significantly more than that in the control group; NMDA receptor antagonist GAPA could significantly decrease the cytosolic Ca 2+ overload. Conclusion Cytosolic Ca 2+ overload was found in the bilirubin precipitated brain tissue. NMDA receptor antagonist GAPA could prevent the cytosolic Ca 2+ overload in bilirubin induced brain tissue.

Inhibition of morphine tolerance and dependence by LY274614, a competitive NMDA receptor antagonist / 中华麻醉学杂志

Objective To investigate the effect of competitive N-methyl-D-aspartate (NMDA) receptor antagonist LY274614 [(?)-6-phosphonomethyl-decahydroisoquinolin-3-carboxylic acid] on the development of morphine tolerance and dependence.Methods Male Spraque-Dawley rats were rendered tolerant and dependent by subcutaneous injection of morphine(15mg/kg body weight) three times a day for 10 consecutive days. LY274614 (2, 4, 6 mg/kg body weight) was also given subcutaneously by subcutaneous injection. Antinociception was measured by tail-flick (TF) test. Tail was exposed to the heat source(a beam of high intensity light). The time from the beginning of exposure to removal of tail from the path of the heat source was taken as latency. The baseline TF latency without medication was 4-5 seconds. A ten-second maximum exposure to the heat source was used to minimize damage to tissue during the multiple measurements. Morphine prolonged TF latency. With the development of tolerance TF latency gradually returned to baseline value. Physical dependence on morphine was assessed by abstinence syndrome precipitated by subcutaneous injecting naloxone 10 mg/kg on the tenth day. According to method of Blasig, the number of jumping/30min after naloxone injection was recorded as an index pf abstinence syndrome. Rats were randomly divided into 8 groups (n=6-8). Each group received morphine 15 mg/kg or normal saline (NS) 1.5 ml/kg+LY274614 (2.0,4.0,6.0 mg/kg) or NS, group 1: morphine+NS; group 2: NS+NS; group 3:morphine+LY274614 (2mg/kg); group 4: NS+LY274614 (2mg/kg); group 5: morphine+LY274614 (4mg/kg); group 6: NS+LY274614 (4mg/kg); group 7: morphine+LY274614 (6mg/kg); group 4: NS+LY274614 (6mg/kg).Results LY274614 itself did not have analgesic action, but if used with morphine, it did inhibit the development of tolerance. In group 5 and 7 the decrease in TF latency was more gradual than that in morphine+saline group. 4 and 6 mg/kg LY274614 reduced the number of jumping/30min following naloxone injection.Conclusions LY274614 can inhibit morphine tolerance and dependence rendered by consecutive subcutaneous morphine injection.

The effects of isoflurane and 2-amino-5-phosphonovalerate, a NMDA receptor antagonist, on the cerebral cortex glutamate content / 中华麻醉学杂志

Objective To study the changes in cerebral cortex glutamate (G) content induced by isoflurane inhalation alone or combined with 2-amino-5-phosphonovalerate (AP5),a NMDA receptor competitive antagonist.Methods Six adult male SD rats were anesthetized with isoflurane. Dialysis probe (internal diameter=0.05mm) which was connected to a micro-infusion pump filled with artifical cerebrospinal fluid(ACSF) was inserted into cerebral cortex. The dialysate was collected for determination of G concentration. After the baseline MAC for isoflurane was measured, the study was carried out in 4 groups based on the concentration of isoflurane inhalation: group Ⅰ:1%; group Ⅱ:1MAC; group Ⅲ:2% and group Ⅳ: the effect of AP5 on isoflurane MAC value. In group Ⅳ AP5 was continuously infused at a rate of 100 ?g?kg -1?h -1 via the vein in the tail and the MAC for isoflurane was measured again. G concentration of dialysate was measured and EEG and SEP were monitored in every group.Results G concentration of cerebral cortex dialysate was decreasing with increasing concentration of isoflurane from group Ⅰ to group Ⅲ. Concentration of isoflurane was negatively correlated with cerebral G content (r=-0.839,P