cr4056 and Alzheimer-Disease

Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer's disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aβ levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoproteins E; Blood-Brain Barrier; Disease Models, Animal; Imidazoles; Imidazolines; Ligands; Mice; Mice, Transgenic; Quinazolines

Imidazoline I

Topics: Alzheimer Disease; Animals; Chlorocebus aethiops; Cycloaddition Reaction; Dogs; Female; HeLa Cells; Hippocampus; Humans; Imidazoles; Imidazoline Receptors; Ligands; Madin Darby Canine Kidney Cells; Mice; Molecular Structure; Nootropic Agents; Organophosphonates; Quantitative Structure-Activity Relationship; Vero Cells

Aberrant activation of signaling pathways plays a pivotal role in central nervous system disorders, such as Alzheimer's disease (AD). Using a combination of virtual screening and experimental testing, novel small molecule inhibitors of tPA-mediated extracellular signal-regulated kinase (Erk)1/2 activation were identified that provide higher levels of neuroprotection from Aβ-induced apoptosis than Memantine, the most recently FDA-approved drug for AD treatment. Subsequent target deconvolution efforts revealed that they all share low micromolar affinity for the imidazoline I(2) receptor, while being devoid of any significant affinity to a list of AD-relevant targets, including the N-methyl-d-aspartate receptor (NMDAR), acetylcholinesterase (AChE), and monoamine oxidase B (MAO-B). Targeting the imidazoline I(2) receptor emerges as a new mechanism of action to inhibit tPA-induced signaling in neurons for the treatment of AD and other neurodegenerative diseases.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Cells, Cultured; Embryo, Mammalian; Enzyme-Linked Immunosorbent Assay; Extracellular Signal-Regulated MAP Kinases; Hippocampus; Imidazoline Receptors; In Situ Nick-End Labeling; Mice; Molecular Structure; Monoamine Oxidase; Neurons; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Structure-Activity Relationship