piperidines and triphenyltetrazolium

The purpose of this study was to investigate the effects of various remifentanil strategies (preconditioning, postconditioning, or continuous infusion) against myocardial ischemia-reperfusion injury.. An in vitro experimental study using the Langendorff system.. A university research laboratory.. Male Sprague-Dawley rats (each n = 9).. Five different remifentanil strategies were performed in isolated rat hearts as follows: remifentanil preconditioning (R-Pre), remifentanil postconditioning (R-Post), ischemic targeting remifentanil (R1), reperfusion targeting remifentanil (R2), or both ischemic and reperfusion targeting remifentanil (R3). Infarct size and cardiodynamics were compared.. The infarct-risk volume ratio in groups R-Pre (13.7% ± 9.9%), R-Post (13.7% ± 12.3%), and R3 (12.6% ± 6.1%) were decreased significantly compared with the untreated control hearts (32.9% ± 11.1%, p < 0.01). There was no significant difference in the left ventricular-developed pressure (LVDP) recovery after reperfusion between the control (43.6% ± 14.5%) and R-Pre (34.8% ± 12.9%, p > 0.05) groups after reperfusion. However, the LVDP recovery in R-Post (21.6% ± 7.7%, p < 0.05), R1 (16.7% ± 19.8%, p < 0.01), R2 (22.2% ± 13.9%, p < 0.05), and R3 (16.2% ± 7.8%, p < 0.01) was decreased significantly compared with control hearts. There was no significant difference in the recovery of dP/dt(max) after reperfusion between the R-Pre (42.0% ± 16.9%) and control groups (39.0% ± 15.4%, p > 0.05), whereas the dP/dt(max) in R3 group (16.9% ± 9.0%) was decreased significantly compared with R-Pre (p < 0.05).. Preconditioning or postconditioning by remifentanil and the continuous infusion of remifentanil effectively reduce myocardial infarction, whereas reperfusion targeting ischemic targeting or reperfusion targeting remifentanil does not. Remifentanil preconditioning better preserves myocardial function, especially LVDP, than other remifentanil strategies.

Topics: Anesthetics, Intravenous; Animals; Body Weight; Cardiotonic Agents; Coloring Agents; Coronary Circulation; Heart; Heart Function Tests; In Vitro Techniques; Ischemic Postconditioning; Ischemic Preconditioning, Myocardial; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Organ Size; Piperidines; Rats; Rats, Sprague-Dawley; Remifentanil; Reperfusion; Tetrazolium Salts; Ventricular Function, Left

Delta(9)-tetrahydrocannabinol (Delta(9)-THC), a primary psychoactive constituent of cannabis, has been reported to act as a neuroprotectant via the cannabinoid CB(1) receptor. In this study, Delta(9)-THC significantly decreased the infarct volume in a 4 h mouse middle cerebral artery occlusion mouse model. The neuroprotective effect of Delta(9)-THC was completely abolished by SR141716, cannabinoid CB(1) receptor antagonist, and by warming the animals to 31 degrees C. Delta(9)-THC significantly decreased the rectal temperature, and the hypothermic effect was also inhibited by SR141716 and by warming to 31 degrees C. At 24 h after cerebral ischemia, Delta(9)-THC significantly increased the expression level of CB(1) receptor in both the striatum and cortex, but not in the hypothalamus. Warming to 31 degrees C during 4 h cerebral ischemia did not increase the expression of CB(1) receptor at the striatum and cortex in MCA-occluded mice. These results show that the neuroprotective effect of Delta(9)-THC is mediated by a temperature-dependent mechanism via the CB(1) receptor. In addition, warming to 31 degrees C might attenuate both the neuroprotective and hypothermic effects of Delta(9)-THC through inhibiting the increase in CB(1) receptor in both the striatum and cortex but not in the hypothalamus, which may suggest a new thermoregulation mechanism of Delta(9)-THC.

Topics: Analysis of Variance; Animals; Blotting, Western; Body Temperature; Body Temperature Regulation; Cerebral Cortex; Cerebral Infarction; Dronabinol; Electrophoresis, Polyacrylamide Gel; Gene Expression Regulation; Hypothermia, Induced; Male; Mice; Piperidines; Pyrazoles; Rimonabant; Tetrazolium Salts

We examined the neuroprotective mechanism of cannabidiol, non-psychoactive component of marijuana, on the infarction in a 4 h mouse middle cerebral artery (MCA) occlusion model in comparison with Delta(9)-tetrahydrocannabinol (Delta(9)-THC). Release of glutamate in the cortex was measured at 2 h after MCA occlusion. Myeloperoxidase (MPO) and cerebral blood flow were measured at 1 h after reperfusion. In addition, infarct size and MPO were determined at 24 and 72 h after MCA occlusion. The neuroprotective effect of cannabidiol was not inhibited by either SR141716 or AM630. Both pre- and post-ischemic treatment with cannabidiol resulted in potent and long-lasting neuroprotection, whereas only pre-ischemic treatment with Delta(9)-THC reduced the infarction. Unlike Delta(9)-THC, cannabidiol did not affect the excess release of glutamate in the cortex after occlusion. Cannabidiol suppressed the decrease in cerebral blood flow by the failure of cerebral microcirculation after reperfusion and inhibited MPO activity in neutrophils. Furthermore, the number of MPO-immunopositive cells was reduced in the ipsilateral hemisphere in cannabidiol-treated group. Cannabidiol provides potent and long-lasting neuroprotection through an anti-inflammatory CB(1) receptor-independent mechanism, suggesting that cannabidiol will have a palliative action and open new therapeutic possibilities for treating cerebrovascular disorders.

Topics: Animals; Behavior, Animal; Cannabidiol; Cerebrovascular Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Functional Laterality; Glutamic Acid; Infarction, Middle Cerebral Artery; Male; Mice; Motor Activity; Neuroprotective Agents; Perfusion; Peroxidase; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Tetrazolium Salts; Time Factors

The role of endocannabinoid signaling in the response of the brain to injury is tantalizing but not clear. In this study, transient middle cerebral artery occlusion (MCAo) was used to produce ischemia/reperfusion injury. Brain content of N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol were determined during MCAo. Whole brain AEA content was significantly increased after 30, 60 and 120 min MCAo compared with sham-operated brain. The increase in AEA was localized to the ischemic hemisphere after 30 min MCAo, but at 60 and 120 min, was also increased in the contralateral hemisphere. 2-Arachidonoylglycerol content was unaffected by MCAo. In a second set of studies, injury was assessed 24 h after 2 h MCAo. Rats administered a single dose (3 mg/kg) of the cannabinoid receptor type 1 (CB1) receptor antagonist SR141716 prior to MCAo exhibited a 50% reduction in infarct volume and a 40% improvement in neurological function compared with vehicle control. A second CB1 receptor antagonist, LY320135 (6 mg/kg), also significantly improved neurological function. The CB1 receptor agonist, WIN 55212-2 (0.1-1 mg/kg) did not affect either infarct volume or neurological score.

Topics: Animals; Arachidonic Acids; Benzofurans; Benzoxazines; Blood Pressure; Brain Chemistry; Brain Infarction; Chromatography, Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Endocannabinoids; Hemodynamics; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Mass Spectrometry; Morpholines; Naphthalenes; Neurologic Examination; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Reperfusion Injury; Rimonabant; Tetrazolium Salts; Time Factors

Cannabidiol, a non-psychoactive constituent of cannabis, has been reported as a neuroprotectant. Cannabidiol and Delta(9)-tetrahydrocannabinol, the primary psychoactive constituent of cannabis, significantly decreased the infarct volume at 4 h in the mouse middle cerebral artery occlusion model. The neuroprotective effects of Delta(9)-tetrahydrocannabinol but not cannabidiol were inhibited by SR141716, a cannabinoid CB1 receptor antagonist, and were abolished by warming of the animals to the levels observed in the controls. Delta(9)-Tetrahydrocannabinol significantly decreased the rectal temperature, and the hypothermic effect was inhibited by SR141716. These results surely show that the neuroprotective effect of Delta(9)-tetrahydrocannabinol are via a CB1 receptor and temperature-dependent mechanisms whereas the neuroprotective effects of cannabidiol are independent of CB1 blockade and of hypothermia.

Topics: Analysis of Variance; Animals; Body Temperature; Brain Infarction; Cannabidiol; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Drug Interactions; Fever; Infarction, Middle Cerebral Artery; Male; Mice; Neuroprotective Agents; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Tetrazolium Salts; Time Factors

It is of interest whether the acetylcholinesterase inhibitor, 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), can improve cognitive impairment caused by chronic cerebral ischemia in rats. Two weeks after four-vessel occlusion, apparent impairments of spatial retrieval memory were observed in the Morris water maze. Both TAK-147 at doses of 0.1, 0.3 and 1.0 mg/kg and donepezil at doses of 0.3 and 1.0 mg/kg significantly ameliorated ischemia-induced memory deficits dose-dependently, but tacrine had no appreciable effect. Furthermore, we demonstrate that the intensity of staining by 2,3,5-triphenyltetrazolium in the hippocampal and cortical slices was significantly decreased by ischemia (10 min anoxia/aglycemia), and that it was also significantly restored by treatment with TAK-147 and donepezil.

Topics: Animals; Benzazepines; Brain; Brain Ischemia; Cholinesterase Inhibitors; Coloring Agents; Donepezil; Dose-Response Relationship, Drug; Indans; Male; Maze Learning; Neuroprotective Agents; Organ Culture Techniques; Piperidines; Rats; Rats, Sprague-Dawley; Tacrine; Tetrazolium Salts

The purpose of this study was to test the hypothesis that the neuroprotective compound CP101,606 will ameliorate the increase in lactate, retard the development of cytotoxic edema, and decrease the infarct volume after ischemic stroke.. Seventeen adult cats were allocated to control (n = 7) and CP101,606-treated groups (n = 10). Transorbital middle cerebral artery occlusion was performed under anesthesia. Extracellular fluid lactate by microdialysis as well as infarct volume measurement by triphenyltetrazolium chloride (TTC)-stained section, with and without neuroprotective agents, was used to determine the value of these potential "surrogate markers" of ischemic damage.. The control group showed an increased dialysate lactate (15.5% increase) at 30 minutes and a peak (332.0% increase) in dialysate lactate at 1 hour after middle cerebral artery occlusion compared with the drug-treated group. Significant differences between control and drug-treated groups were seen in the rate of fall of the apparent diffusion coefficient at both 1 and 5 hours. A close correlation was seen between the 1- and 5-hour apparent diffusion coefficient maps and the TTC-stained sections. There was a significantly smaller lesion in the CP101,606-treated group (62.9% reduction in infarct size compared with the control group; P < .001).. CP101,606 ranks very highly among the current neuroprotection candidates for clinical trials, and its excellent safety record in both animals and phase II studies in conscious, moderate head injury patients suggests that it will be highly effective in human occlusive stroke.

Topics: Animals; Arterial Occlusive Diseases; Brain; Brain Edema; Brain Ischemia; Cats; Cerebral Arteries; Cerebral Infarction; Dialysis Solutions; Excitatory Amino Acid Antagonists; Female; Lactates; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Piperidines; Receptors, N-Methyl-D-Aspartate; Staining and Labeling; Tetrazolium Salts