title: 3,4-dihydroxyphenylethanol attenuates spatio-cognitive deficits in an Alzheimer's disease mouse model: modulation of the molecular signals in neuronal survival-apoptotic programs.
abstract: Alzheimer's disease (AD), the most common type of dementia, is a devastating neurodegenerative disease characterized by progressive neuro-cognitive dysfunction. In our study, we investigated the potential of 3,4-dihydroxyphenylethanol (DOPET), a dopamine metabolite, and also a polyphenol from olive oil, in ameliorating soluble oligomeric amyloid β1-42 plus ibotenic acid (oA42i)-induced neuro-behavioral dysfunction in C57BL/6 mice. The results depicted that intracerebroventricular injection of oA42i negatively altered the spatial reference and working memories in mice, whereas DOPET treatment significantly augmented the spatio-cognitive abilities against oA42i. Upon investigation of the underlying mechanisms, oA42i-intoxicated mice displayed significantly activated death kinases including JNK- and p38-MAPKs with concomitantly inhibited ERK-MAPK/RSK2, PI3K/Akt1, and JAK2/STAT3 survival signaling pathways in the hippocampal neurons. Conversely, DOPET treatment reversed these dysregulated signaling mechanisms comparable to the sham-operated mice. Notably, oA42i administration altered the Bcl-2/Bad levels and activated the caspase-dependent mitochondria-mediated apoptotic pathway involving cytochrome c, apoptotic protease activating factor-1, and caspase-9/3. In contrary, DOPET administration stabilized the dysregulated activities of these apoptotic/anti-apoptotic markers and preserved the mitochondrial ultra-architecture. Besides, we observed that oA42i intoxication substantially down-regulated the expression of genes involved in the regulation of survival and memory functions including sirtuin-1, cyclic AMP response element-binding protein (CREB), CREB-target genes (BDNF, c-Fos, Nurr1, and Egr1) and a disintegrin and metalloprotease 10. Fascinatingly, DOPET treatment significantly diminished these aberrations when compared to the oA42i group. Taken together, these results accentuate that DOPET may be a multipotent agent to combat AD.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Vels University, Pallavaram, Chennai, 600117, India.
authors.forename: Mohanasundaram
authors.initials: M
authors.lastname: Arunsundar
authors.forename: Thukani Sathanantham
authors.initials: TS
authors.lastname: Shanmugarajan
authors.forename: Velayutham
authors.initials: V
authors.lastname: Ravichandran
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D007051:Ibotenic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000633:toxicity; D010626:Phenylethyl Alcohol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C005975:3,4-dihydroxyphenylethanol; D007051:Ibotenic Acid; D010626:Phenylethyl Alcohol