14,15-EET involved in the development of diabetic cardiac hypertrophy mediated by PPARs.

Cardiac hypertrophy is a key structural change in diabetic cardiomyopathy, which mechanism is unknown. 14,15-Epoxyeicosatrienoic acid (14,15-EET) generated from arachidonic acid by CYP2J2 has beneficial effects in metabolic syndrome, which also plays vital roles in inflammatory response. Peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor superfamily and have three subtypes of α, ß (or δ) and γ. Studies have found that 14,15-EET can perform various biological functions by activating PPARs, but its role in diabetic cardiac hypertrophy is unknown. This study aimed to investigate the role of 14,15-EET-PPARs signaling pathway in the development of diabetic cardiac hypertrophy. Diabetic cardiac hypertrophy was developed by high-fat diet feeding combined with streptozotocin (40 mg/kg/d for 5 days, i.p.) in mice and was induced by glucose at 25.5 mmol/L (high glucose, HG) in H9c2 cells. The decreased level of 14,15-EET and the down-regulated expression of PPARα, PPARß and PPARγ were found following diabetic cardiac hypertrophy in mice. Similarly, both the level of 14,15-EET and the PPARs expression were also reduced in HG-induced hypertrophic cardiomyocytes. Supplementation with 14,15-EET improved the cardiomyocyte hypertrophy and up-regulated PPARs expression, which were nullified by 14,15-EEZE, a 14,15-EET antagonist. Taken together, we conclude that the decreased 14,15-EET is involved in the development of diabetic cardiac hypertrophy through the down-regulation of PPARs.

Gastrodin promotes hippocampal neurogenesis via PDE9-cGMP-PKG pathway in mice following cerebral ischemia.

Gastrodin, which is extracted from the Chinese herbal medicine Gastrodia elata Blume, can ameliorate neurogenesis after cerebral ischemia. However, it's possible underlying mechanisms remain still elusive. PDE9-cGMP-PKG signaling pathway is involved in the proliferation of neural stem cells (NSCs) after cerebral ischemia. In this study, we investigated whether the beneficial effect of gastrodin on hippocampal neurogenesis after cerebral ischemia is correlated with the PDE9-cGMP-PKG signaling pathway. Bilateral common carotid artery occlusion (BCCAO) in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) in primary cultured hippocampal NSCs were used to mimic brain ischemic injury. The Morris water maze (MWM) test was executed to detect spatial learning and memory. Proliferation, differentiation, and mature neurons were examined using immunofluorescence. The survival and proliferation of NSCs were assessed by CCK-8 assay and BrdU immunofluorescence staining, respectively. ELISA and western blot were used to detect the level of the PDE9-cGMP-PKG signaling pathway. In BCCAO mice, administering gastrodin (50 and 100 mg/kg) for 14 d restored cognitive behaviors; meanwhile, neurogenesis in hippocampus was stimulated, and PDE9 was inhibited and cGMP-PKG was activated by gastrodin. Consistent with the results, administering gastrodin (from 0.01-1 µmol/L) for 48 h dose-dependently ameliorated the cell viability and promoted greatly the proliferation in primary hippocampal NSCs exposed to OGD/R. Gastrodin further decreased PDE9 activity and up-regulated cGMP-PKG level. KT5823, a PKG inhibitor, markedly abrogated the protective effects of gastrodin on OGD/R-injured NSCs, accompanied by the down-regulation of PKG protein expression, but had no effects on PDE9 activity and cGMP level. Gastrodin could accelerate hippocampal neurogenesis after cerebral ischemia, which is mediated, at least partly, by PDE9-cGMP-PKG signaling pathway.

Decline in nitrogen concentrations of eutrophic Lake Dianchi associated with policy interventions during 2002-2018.

Excessive nutrient discharges have resulted in pervasive water pollution and aquatic eutrophication. China has made massive efforts to improve water quality since 2000. However, how long-term policy interventions govern external and internal fluxes as well as nitrogen (N) concentrations is not well known. Here we examined the historical N concentration change and its key drivers in eutrophic Lake Dianchi (southwest China) over the period 2002-2018, based on monthly observations of water quality and external N fluxes, local surveys of mitigation measures, and process-based model simulations of internal N fluxes. Our data indicated that N concentrations peaked at 3.0 mg L-1 in 2007-2010 but afterwards declined down to 1.2 mg L-1 in 2018. Compared with 2010, the decline in lake N concentrations was attributed to reduced riverine N inflow decreasing by 0.20 g N m-3 month-1 and the water-sediment exchange flux decreasing by 0.07 g N m-3 month-1 from 2010 to 2018. Adoptions of wastewater treatment, pollution interception, and transboundary water transfer dominated the changes in external and internal fluxes of N and thereby the decline of lake N concentrations. These findings underscore the priority of reducing external discharge for historical lake water quality improvement and the need of enhancing internal N removal for future lake ecosystem restoration.

Rutaecarpine Ameliorates Pressure Overload Cardiac Hypertrophy by Suppression of Calcineurin and Angiotensin II.

Cardiac hypertrophy is a major pathological process to result in heart failure and sudden death. Rutaecarpine, a pentacyclic indolopyridoquinazolinone alkaloid extracted from Evodia rutaecarpa with multiple pharmacological activities, yet the underlying protective effects and the mechanisms on cardiac hypertrophy remain unclear. This study aimed to evaluate the potential effects of rutaecarpine on pressure overload cardiac hypertrophy. Cardiac hypertrophy in rat was developed by abdominal aortic constriction (AAC) for 4 weeks, which was improved by rutaecarpine supplementation (20 or 40 mg/kg/day, i.g.) for another 4 weeks. The level of angiotensin II was increased; the mRNA expression and the activity of calcineurin in the left ventricular tissue were augmented following cardiac hypertrophy. Rutaecarpine administration decreased angiotensin II content and reduced calcineurin expression and activity. Noteworthily, in angiotensin II-induced cardiomyocytes, rutaecarpine ameliorated the hypertrophic effects in a dose-dependent manner and downregulated the increased mRNA expression and activity of calcineurin. In conclusion, rutaecarpine can improve cardiac hypertrophy in pressure overload rats, which may be related to the inhibition of angiotensin II-calcineurin signal pathway.

Activation of 20-HETE/PPARs involved in reno-therapeutic effect of naringenin on diabetic nephropathy.

Naringenin is a flavanone compound found in citrus fruits. Recent researches showed that naringenin has many potentially pharmacological effects. However, the therapeutic effect and the potential mechanism of naringenin on diabetic nephropathy (DN) remain to be elucidated. DN model was established by a high-fat diet combined with streptozotocin (STZ), which was confirmed by the levels of fasting blood glucose (FBG, more than 11.1 mmol/L) and urinary albumin (10 times higher than the normal mice). After 5 weeks of STZ injection, the DN was developed in model mice. Then naringenin (25 or 75 mg/kg·d) were supplemented for 4 weeks. At the end of the experiment, the injury of the renal function and structure was deteriorated. Concomitantly, peroxisome proliferators-activated receptors (PPARs) protein expression was down-regulated, and CYP4A expression and 20-hydroxyeicosatetraenoic acid (20-HETE) level were reduced in DN mice. Naringenin administration improved the renal damage of DN mice, and up-regulated PPARs expression, increased CYP4A-20-HETE level. Consistent with the results of in vivo, glucose at 30 mmol/L (high glucose, HG) significantly induced cell proliferation and hypertrophy in NRK-52E cells, following the reductive PPARs protein expression and the downward CYP4A-20-HETE level. Naringenin (0.01, 0.1, 1 µmol/L) reversed these changes induced by HG in a dose-dependent manner. HET0016, a selective inhibitor of 20-HETE synthase, partially blocked the effects of naringenin. In conclusion, naringenin has a therapeutic effect on DN, which may be, at least partly, related to the activation of CYP4A-20-HETE and the up-regulation of PPARs.

[Gastrodin improves hippocampal neurogenesis by NO-cGMP-PKG signaling pathway in cerebral ischemic mice].

This paper was aimed to investigate the effect of gastrodin( GAS) on hippocampal neurogenesis after cerebral was chemic and to explore its mechanism of action related to NO. The cerebral ischemia model of C57 BL/6 mice was established by bilateral common carotid artery occlusion. The pathological changes in hippocampal CA1 region and the cognitive function of mice were assessed by HE staining and Morris water maze test,respectively. The count of Brd U/Neu N positive cells in dentate gyrus was detected by immunofluorescence assay. The NOS activity and the NO content were determined by colorimetric and nitrate reduction methods,respectively.The level of c GMP was measured by ELISA kit,and the PKG protein expression was tested by Western blot. On postoperative day 8,the hippocampal CA1 pyramidal neurons of mice showed irregular structure,with obvious nuclear pyknosis,loose cell arrangement and obvious decrease in the number of neurons. On postoperative day 29,the spatial learning ability and memory were decreased. These results indicated cerebral ischemia in mice. Meanwhile,the Brd U/Neu N positive cells were increased significantly in ischemic mice,indicating that neurogenesis occurred in hippocampus after cerebral ischemia. Treatment with different doses of gastrodin( 50 and 100 mg·kg-1) significantly ameliorated the pathological damages in the CA1 region,improved the ability of learning and memory,and promoted hippocampal neurogenesis. At the same time,both the NOS activity and the NO concentration were decreased in model group,but the c GMP level was increased,and the PKG protein expression was up-regulated. Gastrodin administration activated the NOS activity,promoted NO production,further increased c GMP level and up-regulated PKG protein expression. These results suggested that gastrodin can promote hippocampal neurogenesis after cerebral ischemia and improve cognitive function in mice,which may be related to the activation of NO-cGMP-PKG signaling pathway.

Naringenin exhibits the protective effect on cardiac hypertrophy via EETs-PPARs activation in streptozocin-induced diabetic mice.

Cardiac hypertrophy is one of the key structural changes in diabetic cardiomyopathy. Naringenin, a dihydroflavonoid extracted from citrus plants with multiple pharmacological activities, yet the underlying effects on diabetic cardiac hypertrophy remain unclear. This study aimed to evaluate the potential effects of naringenin on cardiac hypertrophy in diabetic mice. Long-term high-fat feeding combined with streptozotocin resulted in cardiac hypertrophy after a diabetic model has been established for 4 weeks in mice, which were improved by naringenin supplementation (25 or 75 mg/kg/day, i. g.) for another 4 weeks. The protein and mRNA expressions of PPARs were down-regulated, the protein express of CYP2J3 and level of 14, 15-EET were decreased following diabetic cardiac hypertrophy. Naringenin administration up-regulated PPARs expression, elevated CYP2J3 protein and 14,15-EET content. In conclusion, naringenin can improve cardiac hypertrophy in diabetic mice, which may be related to up-regulate the expression of CYP2J3, elevate the level of EETs, and activate the expression of PPARs.

[The principle of treating spirit in clinical acupuncture-moxibustion in terms of three-layer thought].

Treating spirit,which relates to many philosophical theories and techniques,is key to the effect of acupuncture-moxibustion therapy. According to qi monism and the three-layer thought of nature-earth-human,it is believed that the spirit means the ability or possibility to communicate with the nature-earth-human,and response refers to the spirit-interlinking progress between persons and the nature-earth-human. While treating spirit is seen as keeping learning and practicing the progress. The author describes treating spirit by acupuncture-moxibustion in terms of metaphysics and examples. It believes that treating spirit is inevitable as three-layer thought,which stems from traditional Chinese culture,is permeating into acupuncture-moxibustion theory. Treating spirit,a combination between medical ethics and techniques,indicates that doctors understand patients and diseases both generally and detailedly,with mental requirement for the two parts.

Polydatin Restores Endothelium-Dependent Relaxation in Rat Aorta Rings Impaired by High Glucose: A Novel Insight into the PPARß-NO Signaling Pathway.

Polydatin, a natural component from Polygonum Cuspidatum, has important therapeutic effects on metabolic syndrome. A novel therapeutic strategy using polydatin to improve vascular function has recently been proposed to treat diabetes-related cardiovascular complications. However, the biological role and molecular basis of polydatin's action on vascular endothelial cells (VECs)-mediated vasodilatation under diabetes-related hyperglycemia condition remain elusive. The present study aimed to assess the contribution of polydatin in restoring endothelium-dependent relaxation and to determine the details of its underlying mechanism. By measuring endothelium-dependent relaxation, we found that acetylcholine-induced vasodilation was impaired by elevated glucose (55 mmol/L); however, polydatin (1, 3, 10 µmol/L) could restore the relaxation in a dose-dependent manner. Polydatin could also improve the histological damage to endothelial cells in the thoracic aorta. Polydatin's effects were mediated via promoting the expression of endothelial NO synthase (eNOS), enhancing eNOS activity and decreasing the inducible NOS (iNOS) level, finally resulting in a beneficial increase in NO release, which probably, at least in part, through activation of the PPARß signaling pathway. The results provided a novel insight into polydatin action, via PPARß-NO signaling pathways, in restoring endothelial function in high glucose conditions. The results also indicated the potential utility of polydatin to treat diabetes related cardiovascular diseases.

Curcumin attenuates cardiomyocyte hypertrophy induced by high glucose and insulin via the PPARγ/Akt/NO signaling pathway.

AIM: To investigate the potential effect of curcumin on cardiomyocyte hypertrophy and a possible mechanism involving the PPARγ/Akt/NO signaling pathway in diabetes. METHODS: The cardiomyocyte hypertrophy induced by high glucose (25.5mmol/L) and insulin (0.1µmol/L) (HGI) and the antihypertrophic effect of curcumin were evaluated in primary culture by measuring the cell surface area, protein content and atrial natriuretic factor (ANF) mRNA expression. The mRNA and protein expressions were assayed by reverse transcription PCR and Western blotting, whereas the NO concentration and endothelial NO synthase (eNOS) activity were determined using nitrate reduction and ELISA methods, respectively. RESULTS: The cardiomyocyte hypertrophy induced by HGI was characterized by increasing ANF mRNA expression, total protein content, and cell surface area, with downregulated mRNA and protein expressions of both PPARγ and Akt, which paralleled the declining eNOS mRNA expression, eNOS content, and NO concentration. The effects of HGI were inhibited by curcumin (1, 3, 10µmol/L) in a concentration-dependent manner. GW9662 (10µmol/L), a selective PPARγ antagonist, could abolish the effects of curcumin. LY294002 (20µmol/L), an Akt blocker, and N(G)-nitro-l-arginine-methyl ester (100µmol/L), a NOS inhibitor, could also diminish the effects of curcumin. CONCLUSIONS: The results suggested that curcumin supplementation can improve HGI-induced cardiomyocytes hypertrophy in vitro through the activation of PPARγ/Akt/NO signaling pathway.

[Effect and mechanism of polydatin on diabetic myocardial hypertrophy in mice].

To observe the preventive effect of polydatin on diabetic myocardial hypertrophy in mice and discuss its and mechanism. The diabetic model was induced with low dose STZ (40 mg x kg(-1) x d(-1) x 5 d, ip) for five days in mice. The myocardial hypertrophy was determined by hypertrophy indexes (LVHI, left ventricular/right ventricle and septum), left ventricular/body weight (LV/BW), the histological examination and the mRNA expression of atrial natriuretic factor(ANF). The fast blood glucose(FBG), serum insulin and plasma hemoglobin A1c ( HbA1c) levels were detected, and then HOMA insulin resistance index ( HOMA. IR) was calculated. The mRNA and protein expressions were measured by qRT-PCR and western blotting, respectively. According to the results, the FBG of the model group exceeded 11.1 mmol x L(-1), with notable decrease in BW and significant increase in insulin, HbA1c and HOME. IR, suggesting the successful establishment and stability of the diabetic model. The increases in LVHI, LV/BW, cell surface and ANF mRNA indicated a myocardial hypertrophy in diabetic mice. Meanwhile, the model group showed decrease in mRNA and protein expressions of PPARß and significant increase in NF-κB p65, COX-2 and iNOS expressions. After the preventation with PD (50, 100 mg x kg(-1) x d(-1)), diabetic mice showed increase in BW, reduction in the levels of FBG, insulin and HbA1 c, relief in insulin resistance and significant recovery in hypertrophy indexes, indicating PD has the protective effect in diabetic myocardial hypertrophy. Meanwhile, PD up-regulated the expression of PPARß, inhibited the expressions of NF-κB p65, COX-2 and iNOS, demonstrating that PD's protective effect may be related to the activation of PPARß and the inhibition of NF-κB, COX-2 and iNOS signaling pathways.

[A brief talk on the embodiment of Three-Layer thought in the science of acupuncture and moxibustion].

Three-Layer thought is an important proposition in Chinese traditional philosophy. This thought embodies the Chinese people's cosmology and methodology and exerts a far-reaching influence on various aspects of Chinese culture. The embodiment of Three-Layer thought in the theory and practice of acupuncture and moxibustion from naming of acupoints, principles of treatment, needling instruments, prescription of acupoints as well as needling techniques is elaborated and briefly analyzed. Thus it illustrates the comprehensive application of Three-Layer thought in acupuncture and moxibustion through the history and the significance of Chinese traditional philosophy in the science of acupuncture and moxibustion.

Effect of Berberine on PPAR α /NO Activation in High Glucose- and Insulin-Induced Cardiomyocyte Hypertrophy.

Rhizoma coptidis, the root of Coptis chinensis Franch, has been used in China as a folk medicine in the treatment of diabetes for thousands of years. Berberine, one of the active ingredients of Rhizoma coptidis, has been reported to improve symptoms of diabetes and to treat experimental cardiac hypertrophy, respectively. The objective of this study was to evaluate the potential effect of berberine on cardiomyocyte hypertrophy in diabetes and its possible influence on peroxisome proliferator-activated receptor- α (PPAR α )/nitric oxide (NO) signaling pathway. The cardiomyocyte hypertrophy induced by high glucose (25.5 mmol/L) and insulin (0.1 µ mol/L) (HGI) was characterized in rat primary cardiomyocyte by measuring the cell surface area, protein content, and atrial natriuretic factor mRNA expression level. Protein and mRNA expression were measured by western blot and real-time RT-PCR, respectively. The enzymatic activity of NO synthase (NOS) was measured using a spectrophotometric assay, and NO concentration was measured using the Griess assay. HGI significantly induced cardiomyocyte hypertrophy and decreased the expression of PPAR α and endothelial NOS at the mRNA and protein levels, which occurred in parallel with declining NOS activity and NO concentration. The effect of HGI was inhibited by berberine (0.1 to 100 µ mol/L), fenofibrate (0.3 µ mol/L), or L-arginine (100 µ mol/L). MK886 (0.3 µ mol/L), a selective PPAR α antagonist, could abolish the effects of berberine and fenofibrate. N (G) -nitro-L-arginine-methyl ester (100 µ mol/L), a NOS inhibitor, could block the effects of L-arginine, but only partially blocked the effects of berberine. These results suggest that berberine can blunt HGI-induced cardiomyocyte hypertrophy in vitro, through the activation of the PPAR α /NO signaling pathway.

[Baicalin suppresses beta-amyloid protein induced hippocampal cyclooxygenase-2 expression].

OBJECTIVE: To study the brain protection of baicalin on rats with Alzheimer's disease (AD) and its probable mechanism of action. METHODS: Thirty-six male healthy Wistar rats were randomly divided into the sham-operative group, the AD group, and the baicalin group, twelve in each. beta-amyloid protein 1-40 was injected to the bilateral hippocampus of rats in the AD group and the baicalin group to establish the AD rat model. The sham operation was performed to rats of the sham-operative group in the same way. Equal volume of 0.9% sodium chloride solution was injected to the bilateral hippocampus of rats in the sham-operative group. Baicalin was intraperitoneally injected at the daily dose of 40 mg/kg to rats in the baicalin group before and after operation, once daily for 7 successive days. Equal volume of buffer solution was intraperitoneally injected to rats in the sham-operative group and the AD group in the same procedures at the same time points. The expression of hippocampal cyclooxygenase-2 (COX-2) was determined by Western blot. The spatial learning memory capacities was observed using T-morris test. Histological changes were observed using hematoxylin-eosin (HE) staining. RESULTS: Results of the T-morris test showed the spontaneous alternation selective ratio decreased in the AD group (28.33% +/- 7.50%) and the baicalin group (38.33% +/- 7.50%) (both P < 0.05) when compared with the sham-operative group (61.67% +/- 7.50%). There was significant difference between the AD group and the baicalin group (P < 0.05). Results of HE staining showed degeneration and necrosis of cortical and hippocampal neurons in the AD group and the baicalin group. Changes in the AD group were more obvious. Results of Western blot showed the expression of hippocampal cyclooxygenase (COX-2) obviously increased in the AD group, while it obviously decreased in the baicalin group (P < 0.05). CONCLUSION: Baicalin could alleviate beta-amyloid protein induced brain injury, which might be associated with its inhibition on the COX-2 expression.

Inhibitory effect of ginsenoside Rb1 on cardiac hypertrophy induced by monocrotaline in rat.

Ginseng, the root of Panax ginseng, has been used as folk medicine in the treatment of various diseases for thousands of years in China. Ginsenoside Rb1 (Rb1), one of the effective components of ginseng, has been reported to release nitric oxide and decrease intracellular free Ca2+ in cardiac myocytes, both of which play important roles in antihypertrophic effect. This study was to investigate the potential effect of Rb1 on right ventricular hypertrophy (RVH) induced by monocrotaline (MCT) and its possible influence on calcineurin (CaN) signal trasnsduction pathway. MCT-treated animals were administered with Rb1 (10 and 40 mg /kg) from day 1 to day 14 (preventive administration) or from day 15 to day 28 (therapeutic administration), or with vehicle as corresponding controls. After 2 weeks, significantly hypertrophic reactions, including RVH index and the expressions of atrial natriuretic peptide mRNA, appeared in right ventricle of all MCT-treated animals (p < 0.05), which were significantly decreased with some improvements of myocardial pathomorphology in both Rb1 prevention- and therapy-groups (p < 0.05). Similarly, MCT-treatment caused the high expressions of mRNA and/or proteins of CaN, NFAT3 and GATA4 from cardiocytes (p < 0.05) and Rb1 could alleviate the expressions of these factors above (p < 0.05). These results suggest that Rb1 treatment can inhibit the RVH induced by MCT, which may be involved in its inhibitory effects on CaN signal transduction pathway.

[Brief discusion on importance of accurate location in acupuncture treatment for periarthritis of shoulder].

Briefly discuss some recognation problems about acupuncture treatment of periarthritis of shoulder at present and put forward the methods for diagnosis and acupuncture treatment based on accurate location.

[Protective effects of total alkaloids from rhizoma Coptis chinensis on alcohol-induced gastric lesion in rats].

OBJECTIVE: To study the effects of total alkaloids(TA) from rhizoma Coptis chinensis on alcohol-induced gastric lesion in rats and the possible mechanisms. METHOD: The experimental gastric damges were established by intragastric(ig) absolute ethanol, and possible protective effects of TA given orally previously were evaluated by following parameters: gastric damage indexes, gastric juice volume, acidity, and mucus quantity. The contents of NO, MDA, *OH, and SOD activity were also measured in gastric mucosa. RESULT: TA showed significantly inhibitive effects on gastric damages induced by ig ethanol in a dose dependent manner. The effects of TA (120 mg x kg(-1)) were stronger than that of both cimitidine(70 mg x kg(-1)) and berberine(100 mg x kg(-1)), the quantity of later was equal to TA as calculated with berberine. TA significantly suppressed secretion of gastric acid caused by ethanol without clear influences on gastric juice volume and mucus secretion. TA obviously blunted ethanol-induced elevation of MDA and *OH, as well as decrease of NO level and SOD activity from gastric mucosa. CONCLUSION: It is suggested that the TA is a potent protective agent against ethanol-induced gastric damages. The mechanism of actions may be related with inhibiting the secretion of gastric acid and blunting the increase of MDA and *OH, as well as the decrease of NO level and SOD activity from gastric mucus.

Effects of nimodipine and fructose-1,6-diphosphate on cerebral damage in carbon monoxide poisoning mice.

OBJECTIVE: To study the dose- and time-dependent protective effects and the synergistic effects of nimodipine (NMDP) and fructose-1,6-diphosphate (FDP) against cerebral damage induced by acute carbon monoxide (CO) poisoning in mice. METHODS: Male mice were exposed to CO 170 mL/kg, i.p. After CO intraperitonealy exposure, mortality of mice, change in memory function estimated by passive avoidance test, the pathomorphologic observation of brain tissue slices, as well as changes of activities of monoamine oxidase (MAO)-B and Ca(2+)-Mg(2+)-ATPase in cerebral tissue were studied. In dose-dependent protective effect study, NMDP (10.6, 5.3, 2.7 mg/kg) and FDP (2.6, 1.3, 0.67 g/kg) was injected ip, respectively 15 min after CO exposure. To study the time-effect relationship of drugs, NMDP (5.3 mg/kg) and FDP (1.3 g/kg) were administered ip respectively 15 minutes, 45 minutes and 120 minutes after CO exposure. The combination of NMDP (2.7 mg/kg) and FDP (0.67 g/kg) was administered ip15 minutes, 45 min and 120 minutes after CO exposure to study the synergism of the two drugs. RESULTS: Either NMDP (10.6, 5.3 mg/kg) or FDP (2.6, 1.3 g/kg) administered ip within 15 minutes after CO exposure significantly decreased the impairment of memory function and mortality rate induced by CO, inhibited the decrease of Ca(2+)-Mg(2+)-ATPase activity, blunted the rising of MAO-B activity and prevented the delayed hippocampal neuronal death in poisoning mice. To our surprise, the combined use of NMDP (2.7 mg/kg) and FDP (0.67 g/kg) within 15 minutes after CO exposure had similar effects to that in NMDP (10.6, 5.3 mg/kg) and FDP (2.6, 1.3 g/kg). CONCLUSIONS: These results suggest that the impairment of CO on brain can be attenuated if NMDP or FDP are administered sufficiently and quickly as soon as possible after CO exposure and there exists a synergism of FDP and NMDP against CO poisoning damage.