okadaic-acid and capsazepine

The presence of Transient Receptor Potential Vanilloid 1 (TRPV1) channels was detected in many regions of the human and rat brain, including the cortex and hippocampus. TRPV1 channels have functions such as the modulation of synaptic transmission and plasticity and the regulation of cognitive functions. Previous studies conducted with TRPV1 agonists and antagonists show that this channel is associated with the neurodegenerative process. In the present study, the purpose was to investigate the effects of capsaicin, which is a TRPV1 agonist, and capsazepine, a TRPV1 antagonist, in the Alzheimer's Disease (AD) model that was induced by intracerebroventricular (ICV) administration of okadaic acid (OKA).. The AD-like experimental model was created with bilateral ICV OKA injection. Intraperitoneal capsaicin and capsazepine injections were administered to the treatment groups for 13 days and histological and immunohistochemical examinations were performed from the cortex and hippocampal CA3 regions of the brain. The Morris Water Maze Test was used for spatial memory measurement.. ICV OKA administration increased the levels of caspase-3, phosphorylated-tau-(ser396), Aβ, TNF-α, and IL1-β, from the cortex and hippocampal CA3 regions of the brain and decreased the phosphorylated-Glycogen synthase kinase-3 beta-(ser9) levels. In addition, the OKA administration corrupted the spatial memory. The TRPV1 agonist capsaicin reversed the pathological changes induced by ICV OKA administration, but not the TRPV1 antagonist capsazepine.. It was found in the study that the administration of the TRPV1 agonist capsaicin reduced neurodegeneration, neuroinflammation, and deterioration in spatial memory in the AD model induced by OKA.

Topics: Alzheimer Disease; Animals; Antineoplastic Agents; Capsaicin; Humans; Neuroprotective Agents; Okadaic Acid; Rats; TRPV Cation Channels

Using electrophysiological and optical techniques, we studied the mechanisms by which cholesterol depletion stimulates spontaneous transmitter release by exocytosis at the frog neuromuscular junction. We found that methyl-β-cyclodextrin (MCD, 10 mM)-mediated exhaustion of cholesterol resulted in the enhancement of reactive oxygen species (ROS) production, which was prevented by the antioxidant N-acetyl cysteine (NAC) and the NADPH oxidase inhibitor apocynin. An increase in ROS levels occurred both extra- and intracellularly, and it was associated with lipid peroxidation in synaptic regions. Cholesterol depletion provoked a rise in the intracellular Ca(2+) concentration, which was diminished by NAC and transient receptor potential vanilloid (TRPV) channel blockers (ruthenium red and capsazepine). By contrast, the MCD-induced rise in [Ca(2+)]i remained unaffected if Ca(2+) release from endoplasmic stores was blocked by TMB8 (8-(diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride). The effects of cholesterol depletion on spontaneous release and exocytosis were significantly reduced by the antioxidant, intracellular Ca(2+) chelation with BAPTA-AM and blockers of TRPV channels. Bath application of the calcineurin antagonist cyclosporine A blocked MCD-induced enhancement of spontaneous release/exocytosis, whereas okadaic acid, an inhibitor of phosphatases PP1 and PP2A, had no effect. Thus, our findings indicate that enhancement of spontaneous exocytosis induced by cholesterol depletion may depend on ROS generation, leading to an influx of Ca(2+) via TRPV channels and, subsequently, activation of calcineurin.

Topics: Acetophenones; Acetylcysteine; Animals; beta-Cyclodextrins; Calcium; Calcium Signaling; Capsaicin; Cholesterol; Cyclosporine; Exocytosis; Neuromuscular Junction; Okadaic Acid; Ranidae; Reactive Oxygen Species; Ruthenium Red; Synaptic Membranes; TRPV Cation Channels

The effects of capsaicin cytosolic Ca2+ concentration ([Ca2+]i) were measured in individual dorsal root ganglion neurons of the rat in culture. Capsaicin produced a rapid concentration-dependent (EC50 value of 72 nM) increase in [Ca2+]i which was entirely dependent on Ca2+ entry. Exposure of the neurons to a high concentration of capsaicin resulted in desensitization, but only in the presence of external Ca2+. Raising [Ca2+]i with a depolarizing concentration of potassium or the Ca2+ ionophore ionomycin did not reduce the response to a subsequent application of capsaicin. Capsaicin did not induce desensitization in Ca(2+)-free medium even if [Ca2+]i was simultaneously raised with a combination of ionomycin plus carbonyl cyanide m-chlorophenyl-hydrazone. Okadaic acid, a known inhibitor of protein phosphatases 1 and 2A, caused a transient dose-dependent (EC50 value, 100nM) rise in [Ca2+]i, but had no effect on either the responsiveness to capsaicin or capsaicin induced desensitization. The capsaicin antagonist capsazepine blocked the increase in [Ca2+]i evoked by capsaicin and prevented desensitization. These results suggest that desensitization requires the presence of extracellular Ca2+, cannot be mimicked by raising the concentration of [Ca2+]i and may involve Ca2+ entry through activated capsaicin-operated ion channels.

Topics: Animals; Bradykinin; Calcium; Capsaicin; Cells, Cultured; Drug Tolerance; Ethers, Cyclic; Extracellular Space; Ganglia, Spinal; Inositol Phosphates; Ion Channels; Ionomycin; Mitochondria; Neurons, Afferent; Okadaic Acid; Potassium Chloride; Rats; Rats, Sprague-Dawley; Signal Transduction