mobic and Alzheimer-Disease

Among the most widely prescribed drugs worldwide, non-steroidal anti-inflammatory drugs (NSAIDs) are effective for relieving pain, but they are also associated with a high incidence of gastrointestinal (GI) adverse events. Both the beneficial and harmful effects of NSAIDs result from inhibition of the cyclo-oxygenase (COX) enzyme. Recognition of the two distinct COX isoforms prompted development of drugs that selectively block the activity of COX-2, thus providing pain relief and reducing inflammation while sparing COX-1, the enzyme apparently responsible for most protective prostaglandin synthesis in the mucosa of the stomach and duodenum. The results of preclinical and clinical studies indicate that COX-2 inhibitors exhibit high selectivity in inhibiting COX-2, provide excellent pain relief, and cause significantly less GI toxicity than do conventional nonselective NSAIDs. Although they represent a significant advance over nonselective NSAIDs, selective COX-2 inhibitors are not without limitations. They do not completely eliminate GI toxicity or the renal side effects associated with use of conventional NSAIDs. Moreover, in cases of inflammation or ulceration in the GI tract, COX-2 inhibition may delay ulcer healing. Finally, case reports and the results of animal experiments suggest that COX-2 inhibitors may adversely affect ovulation and cause a tendency towards prothrombotic events.

Topics: Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cyclooxygenase Inhibitors; Humans; Lactones; Meloxicam; Neoplasms; Pyrazoles; Sulfonamides; Sulfones; Thiazines; Thiazoles

Neuronal apoptosis is considered to be a critical cause of Alzheimer's disease (AD). Recently, meloxicam has shown neuroprotective effects; however, the inherent mechanisms are highly overlooked. Using APP/PS1 transgenic (Tg) mice as in vivo animal models, we found that meloxicam inhibits apoptosis in neurons by deactivating tumor necrosis factor receptor superfamily member 25 (TNFRSF25), leading to the suppression of the expression of fas-associated protein with death domain (FADD) and the cleavage of DNA fragmentation factor subunit α (DFFA) and cysteine aspartic acid protease-3 (caspase 3) via β-amyloid protein (Aβ)-depressing mechanisms. Moreover, the meloxicam treatment blocked the effects of β-amyloid protein oligomers (Aβo) on stimulating the synthesis of tumor necrosis factor α (TNF-α) and TNF-like ligand 1A (TL1A) in neuroblastoma (N) 2a cells. TNF-α and TL1A induce apoptosis in neurons via TNFR- and TNFRSF25-dependent caspase 3-activating mechanisms, respectively. Knocking down the expression of TNFRSF25 blocked the effects of TL1A on inducing apoptosis in neurons by deactivating the signaling cascades of FADD, caspase 3, and DFFA. Consistently, TNFRSF25 shRNA blocked the effects of Aβo on inducing neuronal apoptosis, which was corroborated by the efficacy of meloxicam in inhibiting Aβo-induced neuronal apoptosis. By ameliorating neuronal apoptosis, meloxicam improved memory loss in APP/PS1 Tg mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Caspase 3; DNA Fragmentation; Meloxicam; Mice; Mice, Transgenic; Neurons; Receptors, Tumor Necrosis Factor, Member 25; Tumor Necrosis Factor-alpha

Alzheimer's disease (AD) is a neurodegenerative disease majorly affecting old age populations. Various factors that affect the progression of the disease include, amyloid plaque formation, neurofibrillary tangles, inflammation, oxidative stress, etc. Herein we report of a new series of substituted (2-aminothiazol-5-yl)(imidazo[1,2-a]pyridin-3-yl)methanones. The designed compounds were synthesized and characterized by spectral data. In vivo anti-inflammatory activity was carried out for screening of anti-inflammatory potential of synthesized compounds. All the compounds were tested for acute inflammatory activity by using carrageenan induced acute inflammation model. Compounds 10b, 10c, and 10o had shown promising acute anti-inflammatory activity and they were further tested for formalin induced chronic inflammation model. Compound 10c showed both acute and chronic anti-inflammatory activity. Compound 10c also showed promising results in AlCl

Topics: Aluminum Chloride; Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Edema; Female; Formaldehyde; Imidazoles; Inflammation; Male; Molecular Structure; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

The objective of this study was to investigate the effect of meloxicam-loaded nanocapsules (M-NC) on the treatment of the memory impairment induced by amyloid β-peptide (aβ) in mice. The involvement of Na(+), K(+)-ATPase and cyclooxygenase-2 (COX-2) activities in the hippocampus and cerebral cortex was also evaluated. Mice received aβ (3 nmol/ 3 μl/ per site, intracerebroventricular) or vehicle (3 μl/ per site, i.c.v.). The next day, the animals were treated with blank nanocapsules (17 mL/kg) or M-NC (5 mg/kg) or free meloxicam (M-F) (5 mg/kg). Treatments were performed every other day, until the twelfth day. Animals were submitted to the behavioral tasks (open-field, object recognition, Y-maze and step-down inhibitory avoidance tasks) from the twelfth day. Na(+), K(+)-ATPase and COX-2 activities were performed in hippocampus and cerebral cortex. aβ caused a memory deficit, an inhibition of the hippocampal Na(+), K(+)-ATPase activity and an increase in the hippocampal COX-2 activity. M-NC were effective against all behavioral and biochemical alterations, while M-F restored only the COX-2 activity. In conclusion, M-NC were able to reverse the memory impairment induced by aβ, and Na(+), K(+)-ATPase is involved in the effect of M-NC.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Cerebral Cortex; Cyclooxygenase 2; Disease Models, Animal; Hippocampus; Meloxicam; Memory; Memory Disorders; Mice; Nanocapsules; Sodium-Potassium-Exchanging ATPase; Thiazines; Thiazoles

To investigate the effect and mechanism of meloxicam on the inflammatory reaction induced by beta amyloid protein (AB) in Alzheimer's disease (AD) rats.. The rat model was established by microinjection of Abeta(1-40) into hippocampus. The expression of NF-kappaB p65 and glial fibrillary acidic protein (GFAP) in hippocampus were detected by immunohistochemistry. The content of GFAP in cortex was tested by Western-blot. The content of TNF-alpha in cortex was tested by ELISA. The expression of IL-1beta mRNA was tested by RT-PCR.. The expression of NF-kappaB p65, GFAP and TNF-alpha as well as IL-1beta mRNA were decreased by meloxicam.. Meloxicam can reduce the proliferation of astrocyte by decreasing the expression of GFAP in AD model rat's hippocampus and cortex. And the depression of NF-kappaB p65 may significantly decrease the expression of TNF-alpha1 and IL-1beta to lessen the inflammatory reaction in cerebral tissue.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebral Cortex; Glial Fibrillary Acidic Protein; Inflammation; Interleukin-1beta; Male; Meloxicam; Peptide Fragments; Rats; Rats, Sprague-Dawley; Thiazines; Thiazoles; Transcription Factor RelA; Tumor Necrosis Factor-alpha