oxadiazoles and Cognitive-Dysfunction

Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms.. To assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia.. A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity.. Oral avagacestat or placebo daily.. Safety and tolerability of avagacestat.. Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures.. Avagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD.. clinicaltrials.gov Identifier: NCT00890890.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Cognitive Dysfunction; Disease Progression; Female; Humans; Male; Oxadiazoles; Prodromal Symptoms; Radionuclide Imaging; Skin Neoplasms; Sulfonamides; Treatment Failure

Physical exercise is well-established paradigm for improving adult neurogenesis and brain functions. As considered as an alternative therapeutic strategy, treadmill running could reduce cognitive impairment and psychiatric abnormalities associating post-traumatic stress disorder (PTSD), which might associate with the promote effects to adult neurogenesis. In current study, we aimed to address how treadmill exercise benefit adult hippocampal neurogenesis in PTSD model and the underlying molecular mechanism related with Akt signaling. PTSD was induced by exposure to aggressor and treatments were conducted with different intensity of compulsory treadmill running. We observed treadmill running improved hippocampal neurogenesis including proliferation and neural differentiation of neural stem cells (NSCs). Moreover, behavioral tests showed treadmill could attenuate the cognitive deficit and depressive/anxiety like behaviors in correlating with PTSD model. Moreover, treadmill running recovered the Akt activity in hippocampus. Interrupting treadmill running administrated mice with Akt inhibitor GSK690693 resulted in the blocked the effects of treadmill running to hippocampal neurogenesis and behavioral improvement in PTSD mice model. In conclusion, treadmill running could mediate behavioral functions and improve hippocampal neurogenesis in PTSD model by regulating Akt signaling.

Topics: Animals; Anxiety; Behavior, Animal; Cognitive Dysfunction; Depression; Disease Models, Animal; Exercise Therapy; Hippocampus; Male; Memory, Short-Term; Mice; Mice, Inbred C57BL; Neurogenesis; Oxadiazoles; Proto-Oncogene Proteins c-akt; Running; Signal Transduction; Stress Disorders, Post-Traumatic

Acetylcholinesterase has been a promising target for the development of putative therapeutics against cognitive decline. The deleterious effect of oxidative stress on the learning and memory paradigms of an individual has also been well documented. In view of this, the present study demonstrates the design, synthesis and pharmacological evaluation of triazole-oxadiazole conjugates. Eighteen novel hybrids (6-23) have been synthesised by employing suitable synthetic procedures and characterized by various spectral and elemental techniques. Further these synthesised compounds were evaluated against behavioural alterations using step down passive avoidance and escape learning protocol at a dose of 0.5 mg/kg with reference to the standard, donepezil. All the synthesised compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibition at five different concentrations using mice brain homogenate as the source of the enzyme. Biochemical estimation of markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione and catalase) has also been carried out to assess the role of synthesised molecules on the oxidative damage induced by scopolamine. The compounds 13, 17 and 23 displayed appreciable activity towards acetylcholinesterase inhibition. These compounds also decreased scopolamine induced oxidative stress, thus serving as promising leads for the amelioration of oxidative stress induced cognitive decline. The molecular docking study performed to predict the binding mode of the compounds also suggested that these compounds bind appreciably to the amino acids present in the active site of the recombinant human acetylcholinesterase (rhAChE). The results indicated that these compounds could be further traversed as inhibitors of AChE and oxidative stress for the treatment of cognitive dysfunction.

Topics: Animals; Cognitive Dysfunction; Humans; Male; Molecular Docking Simulation; Oxadiazoles; Triazoles

The diverse nature of Alzheimer's disease (AD) has prompted researchers to develop multi-functional agents. Herein, we have designed and synthesized molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles. Biological activities of synthesized compounds suggested significant and balanced inhibitory potential against target enzymes. In particular, compound 49 containing 2,4-difluoro substitution at terminal phenyl ring considered as most potential lead with inhibition of acetylcholinesterase (hAChE, IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Antioxidants; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Cognitive Dysfunction; Female; Humans; Kinetics; Molecular Docking Simulation; Neuroprotective Agents; Oxadiazoles; Piperazines; Protein Aggregates; Pyridines; Rats, Wistar; Structure-Activity Relationship

Novel hybrids bearing a 2-aminopyrimidine (2-AP) moiety linked to substituted 1,3,4-oxadiazoles were designed, synthesized and biologically evaluated. Among the developed compounds, 28 noncompetitively inhibited human acetylcholinesterase (hAChE; pIC

Topics: Acetylcholinesterase; Animals; Butyrylcholinesterase; Cell Line; Cholinesterase Inhibitors; Cognitive Dysfunction; Dose-Response Relationship, Drug; Drug Design; Humans; Mice; Models, Molecular; Molecular Structure; Oxadiazoles; Pyrimidines; Structure-Activity Relationship

The novel hybrids bearing 4-aminopyridine (4-AP) tethered with substituted 1,3,4-oxadiazole nucleus were designed, synthesized, and evaluated for their potential AChE inhibitory property along with significant antioxidant potential. The inhibitory potential (IC

Topics: Acetylcholinesterase; Amyloid beta-Peptides; Animals; Avoidance Learning; Butyrylcholinesterase; Cholinesterase Inhibitors; Cognitive Dysfunction; Dose-Response Relationship, Drug; Drug Development; Electrophorus; Horses; Humans; Male; Memory; Mice; Molecular Structure; Oxadiazoles; Peptide Fragments; Protein Aggregates; Scopolamine; Structure-Activity Relationship