mobic and Brain-Ischemia

Laboratory mice constitute an extensively used model to study the pathologic and functional outcomes of cerebral ischemic stroke. The middle cerebral artery occlusion (MCAO) model requires surgical intervention, which potentially can result in postsurgical pain and stress. In the present study, we investigated whether buprenorphine and meloxicam, at clinically relevant doses provided pain relief without altering infarct volume in male C57BL/6 mice. Common known side-effects of buprenorphine, including decreased food consumption, were noted after surgery in buprenorphine-treated mice, but these effects were brief and seen only during the treatment period. Fecal corticosterone metabolites did not differ significantly between the groups. In the present study, buprenorphine treatment did not alter infarction volume when compared with that of mice that did not receive analgesia. In contrast, meloxicam treatment significantly reduced infarct volume and may be a confounder if used as an analgesic during MCAO surgery. Furthermore, investigation of behavioral profiles by using an automated behavioral scoring system showed that rearing and sniffing behaviors decreased as infarct volume increased. This suggests that studies of exploratory behavior may aid in developing new markers of short-term stroke-related behavioral deficiencies in laboratory mice.

Topics: Analgesics; Animals; Brain Ischemia; Buprenorphine; Corticosterone; Infarction, Middle Cerebral Artery; Male; Meloxicam; Mice; Mice, Inbred C57BL; Pain; Pain Management; Research Design; Thiazines; Thiazoles

Microglia-mediated neuroinflammation plays an important role in ischemic stroke (IS). In this work, a series of novel indole and indazole-piperazine pyrimidine derivatives with anti-neuroinflammatory and neuroprotective activities were designed and synthesized for treatment of IS. Among these compounds, 5j displayed the most attractive cytoprotective effect against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced damage in BV2 cells. Meanwhile, it significantly ameliorated the release of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, nitric oxide (NO) and prostaglandin E2 (PGE2), from lipopolysaccharide (LPS)-induced BV2 cells. Moreover, 5j can decrease the release of TNF-α and IL-1β form LPS-induced mouse brain neuroinflammation model. As a potent inhibitor against both cyclooxygenase-2 (COX-2, IC

Topics: Animals; Anti-Inflammatory Agents; Brain Ischemia; Cyclooxygenase 2; Disease Models, Animal; Indazoles; Indoles; Ischemic Stroke; Lipopolysaccharides; Mice; Microglia; Neuroprotection; Neuroprotective Agents; Piperazine; Pyrimidines; Rats; Stroke; Tumor Necrosis Factor-alpha

This study analyzes how age and inflammation modify the response of the vesicular glutamate transporters (VGLUTs), VGLUT1-3 to global brain ischemia/reperfusion (I/R) in brain areas with different I/R vulnerabilities.. Global ischemia was induced in 3- and 18-month-old male Sprague-Dawley rats and CA1 and CA3 hippocampal areas, dentate gyrus and cerebral cortex of sham-operated and I/R animals were removed 48 h after insult. Real-time PCR analysis revealed that I/R challenge resulted in a significant decrease of the VGLUT mRNA levels in young animals. Western blot assays showed a lessened age-dependent response to the ischemic damage in VGLUT1 and VGLUT3, while VGLUT2 presented an age and structure-dependent response to challenge. The use of the anti-inflammatory agent meloxicam following challenge showed that COX2 inhibition promotes the expression of VGLUTs in both sham and injured animals, which results in a lessened response to I/R injury.. VGLUT1 and VGLUT3 presented an age-dependent response to ischemic damage, while this VGLUT response was age both and structure-dependent. In addition, COX-2 inhibition resulted in an increase of VGLUT1 and VGLUT2 protein amounts both in sham and injured animals together with a lessening of the transporters' response to ischemia.

Topics: Age Factors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Brain; Brain Ischemia; Disease Models, Animal; Male; Meloxicam; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Thiazines; Thiazoles; Vesicular Glutamate Transport Proteins

The unfolded protein response (UPR) in the hippocampal regions Cornu Ammonis 1 hippocampal region, Cornu Ammonis 3 hippocampal region, and dentate gyrus, as well as in the cerebral cortex of 3-month-old and 18-month-old rats were studied in a model of 15 min of global cerebral ischemia followed by 48 h of reperfusion. UPR was measured by quantifying the protein disulfide isomerase (PDI), C/EBP-homologous protein (CHOP), GRP78 and GRP94 transcripts using qPCR and the amounts of PDI and GRP78 by western blot. The study shows how the mRNA levels of these genes were similar in 3-month-old and 18-month-old sham-operated animals, but the ischemic insult elicited a noticeable increase in the expression of these genes in young animals that was scarcely appreciable in older animals. The striking increase in the mRNA levels of these genes in 3-month-old animals was abolished or even reverted by treatment with meloxicam, an anti-inflammatory agent. Western blot assays showed that the UPR was still detectable 48 h after ischemia in some of the studied areas, and provided evidence that the UPR is different between young and older animals. Western blot assays carried out in young animals also showed that meloxicam elicited different effects on the levels of PDI and GRP78 in the cerebral cortex and the hippocampus. We conclude that the UPR response to ischemic/reperfusion insult is age- and probably inflammation-dependent and could play an important role in ischemic vulnerability. The UPR appears to be strongly decreased in aged animals, suggesting a reduced ability for cell survival. In this study, we conclude that the unfolded protein response (UPR) to ischemic/reperfusion insult is age- and probably inflammation-dependent and could play an important role in ischemic vulnerability. The UPR strongly decreased in aged rats, suggesting a reduced ability for cell survival. The increase in the mRNA levels of UPR gene transcripts in 3-month-old animals was abolished or even reverted by treatment with meloxicam, an anti-inflammatory agent.

Topics: Age Factors; Animals; Brain Ischemia; Cyclooxygenase Inhibitors; Heat-Shock Proteins; Male; Meloxicam; Membrane Glycoproteins; Protein Disulfide-Isomerases; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger; Thiazines; Thiazoles; Transcription Factor CHOP; Unfolded Protein Response

This study describes the effect of global brain ischemia followed by 48 h reperfusion, when delayed neuronal death can be already observed. We quantified the mRNA levels of the N-methyl-D-aspartate receptor (NMDAR) subunits and those of the astroglia (glial fibrilar acidic protein, GFAP) and microglia (CD11b) markers using real time PCR on the cerebral cortex and hippocampus of 3- and 18-month-old Sprague-Dawley rats. Data show an ischemia/reperfusion-induced decrease in the mRNA levels of the NMDAR NR1, NR2A and NR2B subunits genes, which contrasts with the increase in the CD11b and GFAP mRNA levels. These effects are attenuated in all the genes studied in 18-month-old animals, suggesting that this mechanism of response is less efficient in aged animals. Western blot assays of NR1, NR2A and NR2B show parallels with the real time PCR data, indicating that the down-regulation of these genes is controlled at the transcriptional level. We suggest that a decrease in the efficiency in the control of the NMDAR transcription could account for the higher vulnerability in aged animals, but it cannot explain by itself differences in the vulnerability to ischemia in different areas of the brain. In the assays of ischemia/reperfusion followed by a treatment with the anti-inflammatory agent meloxicam, we observed that ischemic insult was unable to elicit changes in the NMDAR transcription, thus suggesting that inflammation plays a crucial role in the transcriptional control of these genes.

Topics: Aging; Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain Ischemia; Disease Models, Animal; Down-Regulation; Male; Meloxicam; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reperfusion Injury; RNA, Messenger; Thiazines; Thiazoles; Treatment Outcome

Normotensive and hypertensive male Wistar rats were subjected to the 3 h bilateral carotid artery occlusion followed by 72 h of reperfusion. The selective cycloxygenase-2 inhibitor meloxicam was administered intramuscularly after the cerebral reperfusion at a daily dose of 15 mg/kg. Doppler ultrasound was used to evaluate the cerebral blood flow during the reperfusion phase. The level of malondialdehyde (MDA) within the brain tissue homogenate was determined using spectrophotometry. The presence of arterial hypertension caused the altered response of brain tissue to ischemia/reperfusion. The meloxicam treatment significantly decreased the MDA level in normotensive rats subjected to ischemia-reperfusion. The protective effect of meloxicam against cerebral ischemia/reperfusion injury was more pronounced in hypertensive rats as compared to normotensive animals.

Topics: Animals; Blood Pressure; Brain Ischemia; Cerebrovascular Circulation; Disease Models, Animal; Follow-Up Studies; Hypertension; Injections, Intramuscular; Male; Meloxicam; Middle Cerebral Artery; Rats; Rats, Wistar; Reperfusion Injury; Thiazines; Thiazoles; Treatment Outcome; Ultrasonography, Doppler, Transcranial