Neuronal nitric oxide synthase (nNOS) is constitutively expressed in neurons of the central nervous system, where it plays a physiological role in neurotransmission. In this study, we examined the functional role of nNOS in experimental autoimmune encephalomyelitis(EAE). The effects of the specific nNOS inhibitor 7-nitroindazole on normal and EAE rats were studied by immunohistochemistry and Western blot analysis. We found that nNOS is constitutively expressed in the spinal cords of normal rats, whilst in the spinal cords of EAE rats, nNOS expression slightly increased, concomitant with the infiltration of T cells and macrophages. Immunohistochemical studies showed that nNOS expression in macrophages and astrocytes increased at the peak stage of EAE and declined thereafter. Treatment with 7-nitroindazole (30 mg/kg) significantly delayed the onset of EAE paralysis, but had no effect on either the incidence or the severity of the paralysis. These findings suggest that nNOs inhibition has a limited role in the induction of rat EAE, and that constitutive nNOS in the spinal cord functions as a novel neurotransmitter, rather than a pro-inflammatory agent.
Animals ; Astrocytes/*enzymology ; Blotting, Western ; Encephalomyelitis, Autoimmune, Experimental/drug therapy/*enzymology ; Enzyme Inhibitors/therapeutic use ; Immunohistochemistry ; Indazoles/therapeutic use ; Macrophages/*enzymology ; Male ; Nitric Oxide Synthase/antagonists&inhibitors/*metabolism ; Rats ; Rats, Inbred Lew ; Spinal Cord/cytology/*enzymology

OBJECTIVETo evaluate the effect of L-arginine pretreatment on cerebral metabolism for cerebral protection during deep hypothermic circulatory arrest (DHCA).

METHODSFifteen healthy adult canines of either sex weighing 14.7-/+2.4 kg were randomly divided into 3 groups (n=5), namely the normal saline group, L-arginine pretreatment group (pretreated with 100 mg/kg L-arginine 60 min before DHCA), and L-arginine combined with 7- nitroindazole treatment group (pretreated with 100 mg/kg L-arginine and 25 mg/kg7-Ni 60 min before DHCA). For all the canines, extracorporeal circulation was established routinely to allow nasopharyngeal temperature reduction to 18 degrees celsius;, at which point DHCA commenced followed 90 min later by reperfusion. At 30 min before DHCA and 0, 45 and 90 min after DHCA as well as at 60 min after reperfusion initiation, blood samples were collected from the jugular vein and arterial to measure the plasma lactic acid, and the cerebral cortex of the parietal lobe was sampled determine the activity of Na(+)-K(+)ATPase. The cerebral water content was also determined after execution of the canines.

RESULTSIn the two pretreatment groups, the level of lactic acid production (shown by the difference in lactic acid levels between the jugular venous and arterial blood) and the cerebral ATP consumption were similar (P>0.05), but both were significantly lower than those of the control group (P<0.05). The cerebral water content was the lowest in the combined treatment group, followed by exclusive L-arginine group, and the highest in the control group (P<0.05), with significant difference between the 3 groups (P<0.05).

CONCLUSIONL-arginine pretreatment can lower cerebral metabolism during DHCA to offer protective effect on the brain.

Animals ; Arginine ; pharmacology ; therapeutic use ; Brain ; drug effects ; metabolism ; Brain Ischemia ; etiology ; metabolism ; prevention & control ; Circulatory Arrest, Deep Hypothermia Induced ; adverse effects ; methods ; Dogs ; Female ; Indazoles ; pharmacology ; therapeutic use ; Male

OBJECTIVETo study the inhibitory effect and toxicity of axitinib combined with 5-FU in nude mice bearing transplanted tumor of colon cancer LoVo cells.

METHODSNude mouse models bearing LoVo colon cancer xenograft were randomized into vehicle control group, untreated control group, axitinib-treated group, 5-FU-treated group and combined treatment group for corresponding treatments. The tumor dimensions, body weight and tumor weight were recorded, and the efficacy and toxicity were evaluated in terms of complete remission (CR), partial remission (PR), tumor growth delay (TGD), mortality rate and net body weight loss.

RESULTSThe combined treatment showed a significantly stronger efficacy than axitinib or 5-FU used alone. TGD of the combined treatment group was 16.73 days, longer than that of axitinib (8.53 days) and 5-FU (9.72 days) used alone. No mouse died during the treatments in the untreated control group, and 1 died in each of the other 4 groups. The mortality rate and weight loss were both less than 20%. One mouse had PR in axitinib-treated group and another in the combination treatment group. Axitinib, alone and in combination with 5-FU, reduced ABCG2 expression in the tumor tissue, and 5-FU has no such effect.

CONCLUSIONCombination of axitinib and 5-FU produces better antitumor effect than either drug used alone and is well tolerated in nude mice bearing colon cancer xenograft.

Animals ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Cell Line, Tumor ; Colonic Neoplasms ; drug therapy ; Female ; Fluorouracil ; administration & dosage ; Humans ; Imidazoles ; administration & dosage ; Indazoles ; administration & dosage ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Xenograft Model Antitumor Assays

A double blind multicenter study of patients suffering from presenile and senile cataracts was performed, bendazac Iysine salt (Bendaline(R))or a placebo was administered orally to the patients and the results were analyzed. Although subjective variability in visual acuity and in the clinical course of cataracts should be taken into consideration together with the short duration of the observation period, the results obtained demonstrate an improvement in the Bendaline(R) treated group with regard to visual acuity and lens opacity, and an aggravation in the group of patients receiving the placebo.
Administration, Oral ; Adult ; Aged ; Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Cataract/*drug therapy ; Clinical Trials as Topic ; Double-Blind Method ; Female ; Humans ; Indazoles/*administration & dosage ; Male ; Middle Aged ; Pyrazoles/*administration & dosage ; Random Allocation ; Tablets ; Visual Acuity/*drug effects

OBJECTIVE: To investigate the effects of blocking the activation of ERK pathway on the expression of matrix metalloproteinase-9 (MMP-9) and the formation of cerebral edema in SD rats after brain injury. METHODS: Ninety SD rats were randomly divided into 3 equal groups, including a sham-operated group, modified Feeney's traumatic brain injury model group, and ERK inhibition group where the ERK inhibitor SCH772984 (500 μg/kg) was injected via the femoral vein 15 min before brain trauma. At 2 h and 2 days after brain trauma, the permeability of blood-brain barrier was assessed by Evans blue method, the water content of the brain tissue was determined, and the phosphorylation level of ERK and the expression level of MMP-9 mRNA and protein were measured by RT-PCR and Western blotting. RESULTS: Compared with the sham-operated group, the rats with brain trauma exhibited significantly increased level of ERK phosphorylation at 2 h and significantly increased expression of MMP-9 mRNA and protein 2 days after the injury ( < 0.01). Treatment with the ERK inhibitor significantly decreased the phosphorylation level of ERK after the injury ( < 0.01), suppressed over-expression of MMP-9 mRNA and protein 2 days after the injury ( < 0.01). The permeability of blood-brain barrier increased significantly 2 h after brain trauma ( < 0.05) and increased further at 2 days ( < 0.01); the water content of the brain did not change significantly at 2 h ( > 0.05) but increased significantly 2 d after the injury ( < 0.01). Treatment with the ERK inhibitor significantly lowered the permeability of blood-brain barrier and brain water content after brain trauma ( < 0.01). CONCLUSIONS Blocking the activation of ERK pathway significantly reduced the over-expression of MMP-9 and alleviates the damage of blood-brain barrier and traumatic brain edema, suggesting that ERK signaling pathway plays an important role in traumatic brain edema by regulating the expression of MMP-9.
Animals ; Brain Edema ; drug therapy ; etiology ; Brain Injuries, Traumatic ; complications ; drug therapy ; Gene Expression Regulation, Enzymologic ; drug effects ; Indazoles ; pharmacology ; therapeutic use ; MAP Kinase Signaling System ; drug effects ; Matrix Metalloproteinase 9 ; genetics ; Piperazines ; pharmacology ; therapeutic use ; Protein Kinase Inhibitors ; pharmacology ; therapeutic use ; Random Allocation ; Rats ; Rats, Sprague-Dawley