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McCullough Thomas posted an update 6 months, 2 weeks ago
efficient therapeutic choices and novel strategies based on multifunctional and biocompatible nanocarriers, which can deliver the drug sufficiently into the brain.
To conclude, understanding the mechanism of neurodegeneration and reviewing the current drug delivery systems for Alzheimer’s disease and other dementia types are significant for medical and pharmaceutical society to produce efficient therapeutic choices and novel strategies based on multifunctional and biocompatible nanocarriers, which can deliver the drug sufficiently into the brain.Alzheimer’s disease (AD) is a persistent neuropathological stipulation manifested in the form of neuronal/synapse demise, the formation of senile plaques, hyperphosphorylated tau tangles, neuroinflammation, and apoptotic cell death. The absence of a therapeutic breakthrough for AD has continued the quest to find a suitable intervention. Apart from various candidates, the cyclic AMPprotein kinase A-cAMP response element-binding protein (cAMP/PKA/CREB) pathway is the most sought-after drug target AD as the bulk of quality literature documents that there is downregulation of cAMP signaling and CREB mediated transcriptional cascade in AD. cAMP signaling is evolutionarily conserved and can be found in all species. cAMP response element-binding protein (CREB) is a ubiquitous and integrally articulated transcription aspect that regulates neuronal growth, neuronal differentiation/ proliferation, synaptic plasticity, neurogenesis, maturation of neurons, spatial memory, longterm memory formation as well as ensures neuronal survival. CREB is a central part of the molecular machinery that has a role in transforming short-term memory to long-term. Besides AD, impairment of CREB signaling has been well documented in addiction, Parkinsonism, schizophrenia, Huntington’s disease, hypoxia, preconditioning effects, ischemia, alcoholism, anxiety, and depression. The current work highlights the role and influence of CREB mediated transcriptional signaling on major pathological markers of AD (amyloid β, neuronal loss, inflammation, apoptosis, etc.). The present work justifies the continuous efforts being made to explore the multidimensional role of CREB and related downstream signaling pathways in cognitive deficits and neurodegenerative complications in general and AD particularly. Moreover, it is reaffirmed that cyclic nucleotide signaling may have vast potential to treat neurodegenerative complications like AD.
Benzimidazole is an interesting pharmacophore which has been extensively studied in medicinal chemistry due to its high affinity towards various enzymes and receptors. Its derivatives have been previously shown to possess a wide range of biological activities including anthelmintic, antihypertensive, antiulcer, as well as anticholinesterase activity.
The objective of this study is to search for more potent benzimidazole-based cholinesterase inhibitors, through the modification of the 1- and 2-positions of the benzimidazole core.
Synthesis of compounds were carried out via a 4-step reaction scheme following a previously reported protocol. Structure-activity relationship of the compounds are established through in vitro cholinesterase assays and in silico docking studies. Furthermore, cytotoxicity and blood brain barrier (BBB) permeability of the compounds were also investigated.
Among the synthesised compounds, three of them (5IIa, 5IIb, and 5IIc) exhibited potent selective butyrylcholinesterase inhibition at low micromolar level. The compounds did not show any significant cytotoxicity when tested against a panel of human cell lines. Moreover, the most active compound, 5IIc, was highly permeable across the blood brain barrier.
In total 10 benzimidazole derivatives were synthesized and screened for their AChE and BuChE inhibitory activities. Lead compound 5Iic, represents a valuable compound for further development as potential AD therapeutics.
In total 10 benzimidazole derivatives were synthesized and screened for their AChE and BuChE inhibitory activities. Lead compound 5Iic, represents a valuable compound for further development as potential AD therapeutics.
Early detection of Alzheimer’s disease (AD) and its early stage, the mild cognitive impairment (MCI), has important scientific, clinical and social significance. Magnetic resonance imaging (MRI) based statistical shape analysis provides an opportunity to detect regional structural abnormalities of brain structures caused by AD and MCI.
In this work, we aimed to employ a well-established statistical shape analysis pipeline, in the framework of large deformation diffeomorphic metric mapping, to identify and quantify the regional shape abnormalities of the bilateral hippocampus and amygdala at different prodromal stages of AD, using three Chinese MRI datasets collected from different domestic hospitals.
We analyzed the region-specific shape abnormalities at different stages of the neuropathology of AD by comparing the localized shape characteristics of the bilateral hippocampi and amygdalas between healthy controls and two disease groups (MCI and AD). In addition to group comparison analyses, we also investus of an AD patient.
Our results suggested that the amygdalar and hippocampal morphometrics, especially those of shape morphometrics, can be used as auxiliary indicators for monitoring the disease status of an AD patient.
Mild cognitive impairment (MCI) represents an intermediate and modifiable stage between normal aging and dementia. There is an urgent need for simple, non-invasive testing of MCI by blood biomarkers.
This study aimed to retrospectively evaluate the association of red blood cell (RBC) indices with MCI, and select the best hematologic characteristic for detection of MCI in elderly Chinese.
Matched case-control study was carried out with 85 pairs of MCI subjects and healthy controls. Simvastatin chemical structure The matching criteria was age, gender and education attainment. All samples were analyzed for RBC indices, including hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC) and red cell distribution width-standard deviation (RDW-SD). A conditional logistic regression model was used to evaluate the association between RBC indices and MCI. The diagnostic efficacy of the biomarkers was evaluated by receiver operating characteristics (ROC).
Among all RBC indices, there were significant differences in HGB (124.